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Sample records for inhibits carcinoid cell

  1. FAIM2, as a novel diagnostic maker and a potential therapeutic target for small-cell lung cancer and atypical carcinoid

    PubMed Central

    Kang, Hio Chung; Kim, Jong In; Chang, Hee Kyung; Woodard, Gavitt; Choi, Young Sik; Ku, Ja-Lok; Jablons, David M.; Kim, Il-Jin

    2016-01-01

    Lung neuroendocrine (NE) tumors are a heterogeneous group of tumors arising from neuroendocrine cells that includes typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC), and large cell NE cancer. The subtyping of NE tumors is based on the number of mitoses per high powered field and the presences of necrosis. However, the best diagnostic criteria to differentiate various subtypes of lung NE tumors remains controversial and few diagnostic markers distinguish typical and atypical carcinoid. In this study, we show that FAIM2, an inhibitory molecule in the Fas-apoptosis pathway, is significantly overexpressed in SCLC compared to non-small cell lung cancer. In addition, FAIM2 expression is significantly higher in atypical carcinoid than typical carcinoid. As atypical carcinoid has been shown to have worse clinical outcomes than typical carcinoid, our data suggests that FAIM2 may be a useful diagnostic marker for atypical carcinoid. Knockdown of FAIM2 expression increases Fas-induced apoptotic cell death in SCLC cells. Etoposide treatment combined with FAIM2 inhibition also shows modest but significant reduction of viable SCLC cells. Taken together, our results suggest that FAIM2 is a potential NE tumor marker with higher expression in atypical carcinoid and SCLC, and could be a new therapeutic target for SCLC. PMID:27677402

  2. Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas.

    PubMed

    Reubi, J C; Kvols, L K; Waser, B; Nagorney, D M; Heitz, P U; Charboneau, J W; Reading, C C; Moertel, C

    1990-09-15

    Somatostatin (SS) receptor status was investigated in the tumor tissues from 62 patients with carcinoid tumors and 15 patients with islet cell carcinomas using receptor autoradiography techniques with two different iodinated somatostatin analogues as radioligands, a [Leu8, DTrp22, Tyr25]somatostatin-28 and a somatostatin octapeptide, Tyr3-octreotide. The carcinoid tumors were either primaries (n = 32) or metastases (n = 43), sampled as surgical specimens or as small needle liver biopsies. Fifty-four of 62 carcinoid patients had SS receptor-positive tumors (87%). All 15 islet cell carcinoma patients had positive tumors (4 primaries, 11 metastases), i.e., 3 vipomas, 3 insulinomas, 2 glucagonomas, 1 gastrinoma, 2 polyfunctional tumors, and 4 nonfunctioning tumors. Saturation and competition experiments on tissue sections revealed saturable, high affinity binding sites pharmacologically specific for bioactive SS analogues. In a majority of the tumors, the receptors were densely distributed and were always homogeneously found in the whole tumor. All except two tumors were labeled with both radioligands. Multiple liver metastases (n = 16) from three different patients were all shown to contain a comparable amount of receptors. SS receptors could be demonstrated even in very small tissue samples of liver metastases obtained by percutaneous liver biopsies (mean weight, 6.8 mg). The majority of the eight SS receptor-negative carcinoids were mainly bronchial carcinoids (n = 5), usually poorly differentiated. On the contrary, SS receptor-positive cases were never found to be anaplastic. All tumors except one from patients pretreated with octreotide (3 days to 3.8 years) were SS receptor positive. In the majority of carcinoids or islet cell carcinomas, the SS receptor status correlated with the in vivo biochemical response (hormone inhibition) to octreotide. These data demonstrate (a) the high prevalence of SS receptors in the primary tumors of both carcinoids and islet cell

  3. Combination of carbonic anhydrase inhibitor, acetazolamide, and sulforaphane, reduces the viability and growth of bronchial carcinoid cell lines

    PubMed Central

    2013-01-01

    Background Bronchial carcinoids are pulmonary neuroendocrine cell-derived tumors comprising typical (TC) and atypical (AC) malignant phenotypes. The 5-year survival rate in metastatic carcinoid, despite multiple current therapies, is 14-25%. Hence, we are testing novel therapies that can affect the proliferation and survival of bronchial carcinoids. Methods In vitro studies were used for the dose–response (AlamarBlue) effects of acetazolamide (AZ) and sulforaphane (SFN) on clonogenicity, serotonin-induced growth effect and serotonin content (LC-MS) on H-727 (TC) and H-720 (AC) bronchial carcinoid cell lines and their derived NOD/SCID mice subcutaneous xenografts. Tumor ultra structure was studied by electron microscopy. Invasive fraction of the tumors was determined by matrigel invasion assay. Immunohistochemistry was conducted to study the effect of treatment(s) on proliferation (Ki67, phospho histone-H3) and neuroendocrine phenotype (chromogranin-A, tryptophan hydroxylase). Results Both compounds significantly reduced cell viability and colony formation in a dose-dependent manner (0–80 μM, 48 hours and 7 days) in H-727 and H-720 cell lines. Treatment of H-727 and H-720 subcutaneous xenografts in NOD/SCID mice with the combination of AZ + SFN for two weeks demonstrated highly significant growth inhibition and reduction of 5-HT content and reduced the invasive capacity of H-727 tumor cells. In terms of the tumor ultra structure, a marked reduction in secretory vesicles correlated with the decrease in 5-HT content. Conclusions The combination of AZ and SFN was more effective than either single agent. Since the effective doses are well within clinical range and bioavailability, our results suggest a potential new therapeutic strategy for the treatment of bronchial carcinoids. PMID:23927827

  4. Goblet cells carcinoid with mucinous adenocarcinoma of the vermiform appendix: a step towards the unitary intestinal stem cell theory?

    PubMed

    Gravante, G; Yahia, S; Gopalakrishnan, K; Mathew, G

    2014-06-01

    Associations of various histotypes in appendiceal neoplasms may help elucidate the histogenesis of such uncommon tumors. We present the fourth published case of Goblet Cell Carcinoid (GCC) associated with mucinous adenocarcinoma of the appendix. This association has been described only for GCC and not for classic appendix carcinoids which are thought to originate from neuroendocrine-committed cells. The GCC-mucinous association adds more towards the theory of a pluripotent intestinal stem cell with amphicrine possibilities of differentiation.

  5. The effect of a somatostatin analogue on the release of hormones from human midgut carcinoid tumour cells.

    PubMed

    Wängberg, B; Nilsson, O; Theodorsson, E; Dahlström, A; Ahlman, H

    1991-07-01

    The use of a somatostatin analogue (SMS 201-995) has greatly facilitated the treatment of patients with the midgut carcinoid syndrome. Clinical studies have shown that SMS reduces the peripheral levels of tumour-produced serotonin (5-HT) and tachykinins, e.g. neuropeptide K (NPK), basally and after pentagastrin provocation. Some studies have indicated an inhibitory effect of SMS on tumour cell growth as well. In the present study we have investigated the effects of SMS on four different human midgut carcinoid tumours maintained in long term culture. Media levels of 5-HT and NPK-LI in tumour cell cultures decreased rapidly during incubation with SMS (10(-8)-10(-10) M) in all four tumours studied without evidence for tachyphylaxis (up to 6 weeks observation period). SMS treatment (10(-8) M) during 4 days reduced the media concentrations of 5-HT by 56%, while the intracellular contents of 5-HT were decreased by 27% indicating dual inhibitory effects on synthesis and secretion of 5-HT from tumour cells. The DNA contents of cultures were not affected by SMS (10(-8) M or 10(-10) M) treatment for 4 or 14 days. When tumour cell cultures were challenged with isoprenaline (IP) (10(-6) M) no reduction of the IP induced release of 5-HT could be detected after pretreatment of tumour cell cultures with SMS (10(-8) M) for 1 h, 4 h or 4 days. These studies provide evidence for a direct action of the somatostatin analogue on midgut carcinoid tumour cells, reducing both synthesis and secretion of hormones from tumour cells. This effect appears not to be related to inhibition of tumour cell growth. The inhibition of 5-HT secretion from tumour cells by SMS seems to operate via a second messenger system different from the one mediating the beta-adrenoceptor stimulated release of 5-HT. PMID:1713051

  6. Incidentally discovered goblet cell carcinoid clinically presenting as acute intestinal obstruction: a case report with review of literature.

    PubMed

    Afroz, Nishat; Shamim, Nida; Sofi, Lateef Ahmed; Rizvi, Syed Amjad Ali

    2014-01-01

    Goblet cell carcinoid (GCC) is a rare variant of carcinoid tumor that exclusively involves the appendix. It usually occurs in 5th-6th decade with the most common clinical presentation being acute appendicitis. The natural history of this tumor is intermediate between carcinoids and adenocarcinomas. We here report a case of GCC diagnosed incidentally in a patient presenting with acute intestinal obstruction. Ultrasonographic examination supported the clinical diagnosis of acute intestinal obstruction, following which the patient underwent laparotomy and resection of ileum along with appendix was done. On gross pathological examination, a nodular growth was present on the tip and body of appendix that was yellow in color with a semi-solid to mucoid consistency on cut section. On microscopy, lakes of mucin with few acinar structures floating in them were seen. The submucosa as well as serosa were infiltrated by clusters of goblet cells and well-formed acini, with little atypia. Glands and nests were positive for periodic acid Schiff and immunohistochemistry showed focal chromogranin positivity in glandular structures, thereby confirming the diagnosis of GCC. Although the prognosis of GCC is better than adenocarcinomas, it is one of the carcinoids having a poorer outcome when compared with other variants of carcinoid tumor. Therefore, it is important to rule out other differential diagnoses of goblet cell carcinoid, the most important being mucinous adenocarcinomas. PMID:24739849

  7. Carcinoid Cancer Foundation

    MedlinePlus

    ... Pay? Resources for Carcinoid and NET Cancer Insurance Appeals Mobile App A Review of Carcinoid Cancer UN ... Pay? Resources for Carcinoid and NET Cancer Insurance Appeals Mobile App A Review of Carcinoid Cancer UN ...

  8. A Rare Combination of Ovarian and Uterine Leiomyomas with Goblet Cell Carcinoid of the Appendix

    PubMed Central

    Al-Shaikh, Abdulrahman F.; Darwish, Abdulla; Nagaraj, Veena; Alsada, Abeer

    2015-01-01

    We present a case of the rare combination of unilateral ovarian leiomyoma, uterine leiomyoma, and goblet cell carcinoid tumor of the appendix in a premenopausal woman who presented with right iliac pain. Immunohistochemistry study for desmin (muscle marker) and chromogranin and synaptophysin (neuroendocrine markers) confirmed immunophenotyping origin. Interestingly, both tumors showed positive reaction for estrogen receptor. To our knowledge, such a combination has not been reported previously in the literature. In this paper, the pathogenesis and differential diagnosis of both types of tumors are discussed. PMID:25685587

  9. Primary renal carcinoid tumour with lung metastasis misdiagnosed as renal cell carcinoma.

    PubMed

    Daboul, Nour; Monga, Dulabh; Bunker, Mark

    2016-01-01

    A 58-year-old man with a history of metastatic renal cell carcinoma (RCC) diagnosed 10 years prior, status post right nephrectomy, presented for evaluation of pulmonary nodules. A year after the nephrectomy, he had undergone cutaneous metastasectomy in the right flank area, and a further 2 years later he had had his second cutaneous metastasectomy in the right chest wall. Both cutaneous pathologies had, at the time, shown metastatic neoplasm with histological features compatible with those of the previous renal tumour. He was treated with sorafenib. 3 years later he developed asymptomatic pulmonary nodules, which gradually doubled in size over the next 2.5 years. He underwent bronchoscopy and left lower lobe biopsy. Pathology revealed a metastatic renal carcinoid/neuroendocrine tumour. Second review of the previous renal neoplasm and the cutaneous metastatic pathology showed trabecular architecture, consistent with carcinoid, but mimicking the long parallel arrays that have been described in some cases of papillary RCC. PMID:26951438

  10. What's New in Lung Carcinoid Tumor Research and Treatment?

    MedlinePlus

    ... Topic Additional resources for lung carcinoid tumors What’s new in lung carcinoid tumor research and treatment? Many ... controlling when our cells grow and divide into new cells. Certain genes that cause cells to grow, ...

  11. Temsirolimus and Bevacizumab in Treating Patients With Advanced Endometrial, Ovarian, Liver, Carcinoid, or Islet Cell Cancer

    ClinicalTrials.gov

    2016-07-05

    Adult Hepatocellular Carcinoma; Advanced Adult Hepatocellular Carcinoma; Endometrial Serous Adenocarcinoma; Localized Non-Resectable Adult Liver Carcinoma; Lung Carcinoid Tumor; Malignant Pancreatic Gastrinoma; Malignant Pancreatic Glucagonoma; Malignant Pancreatic Insulinoma; Malignant Pancreatic Somatostatinoma; Metastatic Digestive System Neuroendocrine Tumor G1; Ovarian Carcinosarcoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Surface Papillary Adenocarcinoma; Pancreatic Alpha Cell Adenoma; Pancreatic Beta Cell Adenoma; Pancreatic Delta Cell Adenoma; Pancreatic G-Cell Adenoma; Pancreatic Polypeptide Tumor; Recurrent Adult Liver Carcinoma; Recurrent Digestive System Neuroendocrine Tumor G1; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Pancreatic Neuroendocrine Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Regional Digestive System Neuroendocrine Tumor G1; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIA Uterine Corpus Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IIIC Uterine Corpus Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer; Uterine Carcinosarcoma

  12. Atypical carcinoid and large cell neuroendocrine carcinoma of the lung: a proteomic dataset from formalin-fixed archival samples.

    PubMed

    Tanca, Alessandro; Addis, Maria Filippa; Pisanu, Salvatore; Abbondio, Marcello; Pagnozzi, Daniela; Eccher, Albino; Rindi, Guido; Cossu-Rocca, Paolo; Uzzau, Sergio; Fanciulli, Giuseppe

    2016-06-01

    Here we present a dataset generated using formalin-fixed paraffin-embedded archival samples from two rare lung neuroendocrine tumor subtypes (namely, two atypical carcinoids, ACs, and two large-cell neuroendocrine carcinomas, LCNECs). Samples were subjected to a shotgun proteomics pipeline, comprising full-length protein extraction, SDS removal through spin columns, in solution trypsin digestion, long gradient liquid chromatography peptide separation and LTQ-Orbitrap mass spectrometry analysis. A total of 1260 and 2436 proteins were identified in the AC and LCNEC samples, respectively, with FDR <1%. MS data are available in the PeptideAtlas repository at http://www.peptideatlas.org/PASS/PASS00375.

  13. Atypical carcinoid and large cell neuroendocrine carcinoma of the lung: a proteomic dataset from formalin-fixed archival samples

    PubMed Central

    Tanca, Alessandro; Addis, Maria Filippa; Pisanu, Salvatore; Abbondio, Marcello; Pagnozzi, Daniela; Eccher, Albino; Rindi, Guido; Cossu-Rocca, Paolo; Uzzau, Sergio; Fanciulli, Giuseppe

    2016-01-01

    Here we present a dataset generated using formalin-fixed paraffin-embedded archival samples from two rare lung neuroendocrine tumor subtypes (namely, two atypical carcinoids, ACs, and two large-cell neuroendocrine carcinomas, LCNECs). Samples were subjected to a shotgun proteomics pipeline, comprising full-length protein extraction, SDS removal through spin columns, in solution trypsin digestion, long gradient liquid chromatography peptide separation and LTQ-Orbitrap mass spectrometry analysis. A total of 1260 and 2436 proteins were identified in the AC and LCNEC samples, respectively, with FDR <1%. MS data are available in the PeptideAtlas repository at http://www.peptideatlas.org/PASS/PASS00375. PMID:27054153

  14. Atypical carcinoid and large cell neuroendocrine carcinoma of the lung: a proteomic dataset from formalin-fixed archival samples.

    PubMed

    Tanca, Alessandro; Addis, Maria Filippa; Pisanu, Salvatore; Abbondio, Marcello; Pagnozzi, Daniela; Eccher, Albino; Rindi, Guido; Cossu-Rocca, Paolo; Uzzau, Sergio; Fanciulli, Giuseppe

    2016-06-01

    Here we present a dataset generated using formalin-fixed paraffin-embedded archival samples from two rare lung neuroendocrine tumor subtypes (namely, two atypical carcinoids, ACs, and two large-cell neuroendocrine carcinomas, LCNECs). Samples were subjected to a shotgun proteomics pipeline, comprising full-length protein extraction, SDS removal through spin columns, in solution trypsin digestion, long gradient liquid chromatography peptide separation and LTQ-Orbitrap mass spectrometry analysis. A total of 1260 and 2436 proteins were identified in the AC and LCNEC samples, respectively, with FDR <1%. MS data are available in the PeptideAtlas repository at http://www.peptideatlas.org/PASS/PASS00375. PMID:27054153

  15. Lung Carcinoid Tumor: Surgery

    MedlinePlus

    ... for lung carcinoid tumor symptoms Surgery to treat lung carcinoid tumors Surgery is the main treatment for ... often be cured by surgery alone. Types of lung surgery Different operations can be used to treat ( ...

  16. Gastric carcinoids: Between underestimation and overtreatment

    PubMed Central

    Massironi, Sara; Sciola, Valentina; Spampatti, Matilde Pia; Peracchi, Maddalena; Conte, Dario

    2009-01-01

    Gastric carcinoids (GCs), which originate from gastric enterochromaffin-like (ECL) mucosal cells and account for 2.4% of all carcinoids, are found increasingly in the course of upper gastrointestinal tract endoscopy. Current nosography includes those occurring in chronic conditions with hypergastrinemia, as the type 1 associated with chronic atrophic gastritis, and the type 2 associated with Zollinger-Ellison syndrome in multiple endocrine neoplasia type 1, and type 3, which is unrelated to hypergastrinemia and is frequently malignant, with distant metastases. The optimal clinical approach to GCs remains to be elucidated, depending upon type, size and number of carcinoids. While there is agreement concerning the treatment of type 3 carcinoids, for types 1 and 2, current possibilities include simple surveillance, endoscopic polypectomy, surgical excision, associated or not with surgical antrectomy, or total gastrectomy. Moreover, the recent introduction of somatostatin analogues represents a therapeutic option of possibly outstanding relevance. PMID:19437556

  17. [A case of recurrent cough in bronchial carcinoid].

    PubMed

    Strano, M; Funis, M; Frediani, S; Duvina, P L

    1999-01-01

    The carcinoid tumors of the bronchial are extremely uncommon, with an incidence of 5% of all pulmonary neoplasms. The carcinoid is the more frequent tumor of the lung in paediatric age. The symptoms most often reported were cough, recurring infection, chest pain, hemoptysis, fever, dyspnea, mild dyspnea attacks after physical effort or nervousness. The carcinoid syndrome is uncommon. Neuroendocrine tumors of the lung embrace a spectrum from low-grade typical carcinoid, intermediate-grade atypical carcinoid, and high-grade categories of large cell neuroendocrine carcinoma and small cell carcinoma. Low grade neoplasms may metastasize to adjacent nodes. Atypical carcinoids are considered low grade malignancies. Most malignant end of neuroendocrine neoplasm group is small cell carcinoma. Typical carcinoids carry an excellent prognosis and should be offered conservative lung resection, whilst atypical carcinoids which behave aggressively should be treated by radical lung resection. The authors report a case of the young patients with bronchial typical carcinoid tumor who had suffered from cough and mild dyspnea attacks after physical effort or nervousness in the last year. PMID:10570790

  18. Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors

    ClinicalTrials.gov

    2016-11-04

    Atypical Carcinoid Tumor; Foregut Carcinoid Tumor; Hindgut Carcinoid Tumor; Lung Carcinoid Tumor; Metastatic Carcinoid Tumor; Metastatic Digestive System Neuroendocrine Tumor G1; Midgut Carcinoid Tumor; Recurrent Digestive System Neuroendocrine Tumor G1; Regional Digestive System Neuroendocrine Tumor G1

  19. Giant thymic carcinoid.

    PubMed

    John, L C; Hornick, P; Lang, S; Wallis, J; Edmondson, S J

    1991-05-01

    Thymic carcinoid is a rare tumour. It may present with ectopic endocrine secretion or with symptoms of compression as a result of its size. A case is reported which presented with symptoms of compression where the size of the tumour was uniquely large such as to warrant the term giant thymic carcinoid. The typical histological features are described, together with its possible origin and its likely prognosis.

  20. [Ultrasonographic study of rectal carcinoid tumors].

    PubMed

    Nomura, M; Fujita, N; Matsunaga, A; Ando, M; Tominaga, G; Noda, Y; Kobayashi, G; Kimura, K; Yuki, T; Ishida, K; Yago, A; Mochizuki, F; Chonan, A

    1996-11-01

    To compare intraluminal ultrasonographic (ILUS) findings with histological findings of rectal carcinoid tumors, 35 patients with rectal carcinoid tumors were reviewed. The results were as follows: 1) The rectal wall was visualized as a seven- or nine-layer structure by means of ILUS in 81% of the patients. 2) The possibility that the thin hyperechoic third layer above the tumor on ILUS corresponds to the muscularis mucosae and fibrointerstitium above the tumor histologically. 3) In cases with relatively high internal echoes, the amount of fibrointerstitium exceeded that of tumor cells histologically. 4) In cases with nonuniform internal echo patterns, tumor cells were separated by thick fibrointerstitium forming nodular nests.

  1. Stages of Gastrointestinal Carcinoid Tumors

    MedlinePlus

    ... symptoms of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (last part ... Treatment of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (last part ...

  2. Carcinoid tumor of the middle ear.

    PubMed

    Nikanne, Elina; Kantola, Olli; Parviainen, Tapani

    2004-08-01

    Although carcinoid tumors are labeled as neuroendocrine tumors they can also originate in tissue lacking neuroendocrine cells, such as that in the middle ear. Symptoms of a carcinoid tumor in the middle ear are common ear symptoms such as fullness, pain and hearing loss. Carcinoid tumors have also been considered to be slow-growing. Both these aspects can easily lead to a relatively late diagnosis of carcinoid tumor of the middle ear. The diagnosis is made histologically, and the tumor is primarily treated surgically. In the follow-up of patients, octreotide scanning has proved to be a sensitive method in cases of both recurrence and metastasis. Our patient was a 34-year-old, otherwise healthy female with left-sided acute otitis media and facial palsy in her left ear. She had also suffered from the same symptoms 4 years earlier. She was treated with an operation, and the histologic diagnosis was a carcinoid tumor. In the follow-up of the patient we used octreotide scanning.

  3. PHACES syndrome associated with carcinoid endobronchial tumor.

    PubMed

    Mama, Nadia; H'mida, Dorra; Lahmar, Imen; Yacoubi, Mohamed Tahar; Tlili-Graiess, Kalthoum

    2014-05-01

    PHACES syndrome consists of the constellation of manifestations including posterior fossa anomalies of the brain (most commonly Dandy-Walker malformations), hemangiomas of the face and scalp, arterial abnormalities, cardiac defects, eye anomalies and sternal defects. We present a case with a possible PHACES syndrome including sternal cleft and supraumbilical raphé, precordial skin tag, persistent left superior vena cava and subtle narrowing of the aorta with an endobronchial carcinoid tumor. All these anomalies were discovered on chest multi-detector CT. This is a unique case of PHACES syndrome associated with carcinoid tumor. Review of the literature revealed 3 cases of PHACES syndrome with glial tumor. The authors tried to find the relationship between PHACES syndrome and carcinoid tumors or gliomas, which all derive from the neural crest cells.

  4. Adenocarcinoma ex-goblet cell carcinoid (appendiceal-type crypt cell adenocarcinoma) is a morphologically distinct entity with highly aggressive behavior and frequent association with peritoneal/intra-abdominal dissemination: an analysis of 77 cases.

    PubMed

    Reid, Michelle D; Basturk, Olca; Shaib, Walid L; Xue, Yue; Balci, Serdar; Choi, Hye-Jeong; Akkas, Gizem; Memis, Bahar; Robinson, Brian S; El-Rayes, Bassel F; Staley, Charles A; Staley, Christopher A; Winer, Joshua H; Russell, Maria C; Knight, Jessica H; Goodman, Michael; Krasinskas, Alyssa M; Adsay, Volkan

    2016-10-01

    High-grade versions of appendiceal goblet cell carcinoids ('adenocarcinoma ex-goblet cell carcinoids') are poorly characterized. We herein document 77 examples. Tumors occurred predominantly in females (74%), mean age 55 years (29-84), most with disseminated abdominal (77% peritoneal, 58% gynecologic tract involvement) and stage IV (65%) disease. Many presented to gynecologic oncologists, and nine had a working diagnosis of ovarian carcinoma. Metastases to liver (n=3) and lung (n=1) were uncommon and none arose in adenomatous lesions. Tumors had various histologic patterns, in variable combinations, most of which were fairly specific, making them recognizable as appendiceal in origin, even at metastatic sites: I: Ordinary goblet cell carcinoid/crypt pattern (rounded, non-luminal acini with well-oriented goblet cells), in variable amounts in all cases. II: Poorly cohesive goblet cell pattern (diffusely infiltrative cords/single files of signet ring-like/goblet cells). III: Poorly cohesive non-mucinous cell (diffuse-infiltrative growth of non-mucinous cells). IV: Microglandular (rosette-like glandular) pattern without goblet cells. V: Mixed 'other' carcinoma foci (including ordinary intestinal/mucinous). VI: goblet cell carcinoid pattern with high-grade morphology (marked nuclear atypia). VII: Solid sheet-like pattern punctuated by goblet cells/microglandular units. Ordinary nested/trabecular ('carcinoid pattern') was very uncommon. In total, 33(52%) died of disease, with median overall survival 38 months and 5-year survival 32%. On multivariate analysis perineural invasion and younger age (<55) were independently associated with worse outcome while lymph-vascular invasion, stage, and nodal status trended toward, but failed to reach, statistical significance. Worse behavior in younger patients combined with female predilection and ovarian-affinity raise the possibility of hormone-assisted tumor progression. In conclusion, 'adenocarcinoma ex-goblet cell carcinoid' is

  5. ECL-cell carcinoids and carcinoma in patients homozygous for an inactivating mutation in the gastric H(+) K(+) ATPase alpha subunit.

    PubMed

    Fossmark, Reidar; Calvete, Oriol; Mjønes, Patricia; Benitez, Javier; Waldum, Helge L

    2016-07-01

    A family with a missense variant of the ATP4A gene encoding the alpha subunit of the gastric proton pump (H(+) K(+) ATPase) has recently been described. Homozygous siblings were hypergastrinemic (median gastrin 486 pM) and had gastric tumours diagnosed at a median age of 33 years. In the current histopathological study, we further characterized the tumours found in the gastric corpus. The tumours had the histological appearance of carcinoids (NET G1 or G2) and were immunoreactive for the general neuroendocrine markers chromogranin A (CgA) and synaptophysin as well as the ECL-cell markers vesicular monoamine transporter 2 (VMAT2) and histidine decarbozylase (HDC). One of the tumours consisted of a NET G2 component, but also had a component with glandular growth, which morphologically was classified as an intestinal type adenocarcinoma. Many glands of the adenocarcinoma contained a large proportion of cells positive for neuroendocrine markers, especially the small vesicle marker synaptophysin and the cytoplasmic enzyme HDC. In conclusion, patients homozygous for an inactivating ATP4A mutation develop gastric ECL-cell carcinoids in their 3rd or 4th decade. The adenocarcinoma may be classified as neuroendocrine with ECL-cell differentiation. PMID:27150581

  6. Carcinoid of the Appendix During Laparoscopic Cholecystectomy: Unexpected Benefits

    PubMed Central

    Haluck, Randy; Cooney, Robert N.; Minnick, Kathleen E.; Ruggiero, Francesco; Smith, J. Stanley

    1999-01-01

    Carcinoid tumors of the midgut arise from the distal duodenum, jejunum, ileum, appendix, ascending and right transverse colon. The appendix and terminal ileum are the most common location. The majority of carcinoid tumors originate from neuroendocrine cells along the gastrointestinal tract, but they are also found in the lung, ovary, and biliary tracts. We report the first case of elective laparoscopic cholecystectomy in which we found a suspicious lesion at the tip of the appendix and proceeded to perform a laparoscopic appendectomy. The lesion revealed a carcinoid tumor of the appendix. PMID:10323177

  7. Can Gastrointestinal Carcinoid Tumors Be Found Early?

    MedlinePlus

    ... problems. Carcinoid tumors often are found incidentally (by accident). These tumors aren’t causing any symptoms but ... Carcinoid Tumors? Causes, Risk Factors, and Prevention Early Detection, Diagnosis, and Staging Treating Gastrointestinal Carcinoid Tumors Talking ...

  8. Carcinoid syndrome from gastrointestinal carcinoids without liver metastasis.

    PubMed

    Feldman, J M; Jones, R S

    1982-07-01

    Although patients with bronchial and ovarian carcinoid tumors can develop the carcinoid syndrome (diarrhea and/or flushing) in the absence of hepatic metastasis, it is believed that development of the carcinoid syndrome in patients with carcinoid tumors of gastrointestinal origin occurs only after the patient has hepatic metastasis. This is explained by hepatic inactivation of most of the serotonin in the portal circulation or by the fact that hepatic metastases are larger than the primary tumor in the gastrointestinal tract. Three patients with ileal and jejunal carcinoid tumors who developed the carcinoid syndrome without obvious hepatic metastasis are described. Two of the patients had intra-abdominal, but extrahepatic, metastasis that probably drained directly into the systemic circulation. The third patient had an ileal carcinoid with clinical involvement limited to adjacent mesenteric lymph nodes. Following resection of her tumor, her urinary 5-HIAA excretion and platelet serotonin level returned to normal, and her attacks of carcinoid flushing virtually ceased. She has occasional spells of "blushing" that are thought to be benign; however, further close follow-up study will be needed to be certain that she is free of disease. It is suggested that each patient with the carcinoid syndrome be evaluated with CT and technetium-99 pertechnetate liver scans. If there is no liver involvement detected with these studies, one should consider hepatic arteriogram or laparotomy to determine if the patient's tumor might be totally resectable. PMID:7092350

  9. Frequent mutations in chromatin-remodeling genes in pulmonary carcinoids

    PubMed Central

    Lu, Xin; Sun, Ruping; Ozretić, Luka; Seidal, Danila; Zander, Thomas; Leenders, Frauke; George, Julie; Müller, Christian; Dahmen, Ilona; Pinther, Berit; Bosco, Graziella; Konrad, Kathryn; Altmüller, Janine; Nürnberg, Peter; Achter, Viktor; Lang, Ulrich; Schneider, Peter M; Bogus, Magdalena; Soltermann, Alex; Brustugun, Odd Terje; Helland, Åslaug; Solberg, Steinar; Lund-Iversen, Marius; Ansén, Sascha; Stoelben, Erich; Wright, Gavin M.; Russell, Prudence; Wainer, Zoe; Solomon, Benjamin; Field, John K; Hyde, Russell; Davies, Michael PA.; Heukamp, Lukas C; Petersen, Iver; Perner, Sven; Lovly, Christine; Cappuzzo, Federico; Travis, William D; Wolf, Jürgen; Vingron, Martin; Brambilla, Elisabeth; Haas, Stefan A.; Buettner, Reinhard; Thomas, Roman K

    2014-01-01

    Pulmonary carcinoids are rare neuroendocrine tumors of the lung. The molecular alterations underlying the pathogenesis of these tumors have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodeling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40% and 22.2% of the cases respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine tumors, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumors but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin remodeling genes is sufficient to drive transformation in pulmonary carcinoids. PMID:24670920

  10. Treatment of Lung Carcinoid by Type and Extent of Disease

    MedlinePlus

    ... your doctor about lung carcinoid tumors? Treatment of lung carcinoid, by type and extent of disease The ... those that can’t be removed completely Resectable lung carcinoid tumors Resectable carcinoid tumors haven’t spread ...

  11. Primary Hepatic Carcinoid Tumor with Poor Outcome.

    PubMed

    Parkash, Om; Ayub, Adil; Naeem, Buria; Najam, Sehrish; Ahmed, Zubair; Jafri, Wasim; Hamid, Saeed

    2016-03-01

    Primary Hepatic Carcinoid Tumor (PHCT) represents an extremely rare clinical entity with only a few cases reported to date. These tumors are rarely associated with metastasis and surgical resection is usually curative. Herein, we report two cases of PHCT associated with poor outcomes due to late diagnosis. Both cases presented late with non-specific symptoms. One patient presented after a 2-week history of symptoms and the second case had a longstanding two years symptomatic interval during which he remained undiagnosed and not properly worked up. Both these cases were diagnosed with hepatic carcinoid tumor, which originates from neuroendocrine cells. Case 1 opted for palliative care and expired in one month’s time. Surgical resection was advised to the second case, but he left against medical advice. PMID:26975959

  12. Primary Hepatic Carcinoid Tumor with Poor Outcome.

    PubMed

    Parkash, Om; Ayub, Adil; Naeem, Buria; Najam, Sehrish; Ahmed, Zubair; Jafri, Wasim; Hamid, Saeed

    2016-03-01

    Primary Hepatic Carcinoid Tumor (PHCT) represents an extremely rare clinical entity with only a few cases reported to date. These tumors are rarely associated with metastasis and surgical resection is usually curative. Herein, we report two cases of PHCT associated with poor outcomes due to late diagnosis. Both cases presented late with non-specific symptoms. One patient presented after a 2-week history of symptoms and the second case had a longstanding two years symptomatic interval during which he remained undiagnosed and not properly worked up. Both these cases were diagnosed with hepatic carcinoid tumor, which originates from neuroendocrine cells. Case 1 opted for palliative care and expired in one month’s time. Surgical resection was advised to the second case, but he left against medical advice.

  13. [Renal neuroendocrine tumor (carcinoid) : a case report].

    PubMed

    Inagaki, Yusuke; Fujita, Kazutoshi; Nakai, Yasutomo; Takayama, Hitoshi; Tsujimura, Akira; Nonomura, Norio

    2013-11-01

    A 32-year-old man was referred to our hospital for treatment of left renal cystic tumor, which was detected by computed tomographic (CT) scan 3 years ago. CT scan showed a multilocular cyst (5 cm in diameter) with a solid tumor in the left kidney which was enhanced with contrast. There was no evidence of extrarenal invasion or distant metastasis. We performed retroperitoneal laparoscopic radical nephrectomy. Pathological examinations revealed a cellular arrangement specific to carcinoid tumor and positive for CD56 (NCAM) and neuron-specific enolase. The cell proliferation rate was estimated to be under 2% with Ki67 staining. The pathological diagnosis was renal neuroendocrine tumor (carcinoid). At the 9-month follow up, he had no evidence of local recurrence or metastasis.

  14. How Are Lung Carcinoid Tumors Diagnosed?

    MedlinePlus

    ... Research Get Involved Find Local ACS Learn About Cancer » Lung Carcinoid Tumor » Detailed Guide » How are lung carcinoid tumors diagnosed? Share this Page Close Push escape to close share window. Print ...

  15. Treatment Options for Gastrointestinal Carcinoid Tumors

    MedlinePlus

    ... symptoms of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (last part ... Treatment of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (last part ...

  16. General Information about Gastrointestinal Carcinoid Tumors

    MedlinePlus

    ... symptoms of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (last part ... Treatment of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (last part ...

  17. Treatment Option Overview (Gastrointestinal Carcinoid Tumors)

    MedlinePlus

    ... symptoms of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (last part ... Treatment of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (last part ...

  18. Case of peptide-YY-producing strumal carcinoid of the ovary: a case report and review.

    PubMed

    Takatori, Eriko; Shoji, Tadahiro; Miura, Jiyu; Takeuchi, Satoshi; Yoshizaki, Akira; Sugiyama, Toru

    2012-10-01

    Ovarian carcinoid is a rare tumor accounting for approximately 0.1% of all ovarian malignancies. We describe a case of peptide-YY-producing strumal carcinoid of the ovary associated with severe constipation. A 48-year-old woman was found to have a pelvic mass on ultrasonography when she visited her primary doctor for a health check-up. She was thus referred to our department. Magnetic resonance imaging revealed a solid right ovarian tumor 60 × 50 mm in size. The patient underwent a right adnexectomy and was histopathologically diagnosed as having strumal carcinoid of the ovary. On immunohistochemical examination, the tumor cells were positive for peptide YY. The patient's constipation resolved rapidly after surgery. Based on her clinical course, her constipation was considered to have been caused by the strumal carcinoid of the ovary. The clinical course of this case supports the previously recognized correlation between peptide-YY-producing ovarian carcinoid and constipation.

  19. What's New in Gastrointestinal Carcinoid Tumors Research and Treatment?

    MedlinePlus

    ... Topic Additional resources for gastrointestinal carcinoid tumors What’s new in gastrointestinal carcinoid tumor research and treatment? There ... for the causes of , ways to prevent , and new approaches to diagnose and treat GI carcinoid tumors. ...

  20. Thiocoraline activates the Notch pathway in carcinoids and reduces tumor progression in vivo

    PubMed Central

    Wyche, Thomas P.; Dammalapati, Ajitha; Cho, Hyunah; Harrison, April D.; Kwon, Glen S.; Chen, Herbert; Bugni, Tim S.; Jaskula-Sztul, Renata

    2014-01-01

    Carcinoids are slow-growing neuroendocrine tumors (NETs) that are characterized by hormone overproduction; surgery is currently the only option for treatment. Activation of the Notch pathway has previously been shown to have a role in tumor suppression in NETs. The marine-derived thiodepsipeptide thiocoraline was investigated in vitro in two carcinoid cell lines (BON and H727). Carcinoid cells treated with nanomolar concentrations of thiocoraline resulted in a decrease in cell proliferation and an alteration of malignant phenotype evidenced by decrease of NET markers, ASCL-1, CgA, and NSE. Western blot analysis demonstrated the activation of Notch1 on the protein level in BON cells. Additionally, thiocoraline activated downstream Notch targets HES1, HES5, and HEY2. Thiocoraline effectively suppressed carcinoid cell growth by promoting cell cycle arrest in BON and H727 cells. An in vivo study demonstrated that thiocoraline, formulated with polymeric micelles, slowed carcinoid tumor progression. Thus, the therapeutic potential of thiocoraline, which induced activation of the Notch pathway, in carcinoid tumors was demonstrated. PMID:25412645

  1. [Atypical case of bronchial carcinoid].

    PubMed

    Andrzejak, R; Mydłowski, R; Krajewski, E; Orłowski, T; Bochnia, M

    1997-01-01

    This article illustrates problems in diagnosis and treatment of an atypical form of bronchial carcinoid. We described the case of a 49-year old man, exposed to granite dust and noise for 25 years who had suffered from frequent bronchitis inflammations and pneumonias for 5 years prior to the diagnosis. He was admitted to our clinic because of supposed occupational nature of hearing deficiency. Although a pneumoconiosis was excluded before the admission, we found clinical and X-ray features of the right lung emphysema with medium restrictive ventilation disturbances. Bronchoscopy was performed because of "bright" right lung and ventilation disturbances and it showed presence of the carcinoid. Unusual in this case were tiny anamnestical findings (mild dyspnea attacks after physical effort or nervousness) plus increasing frequency of reported from the childhood bronchitis and pneumonias and uncharacteristic "bright" right lung in X-ray. Therapeutical difficulties resulted from atypical histological form of the tumor, its diameter, polypous-infiltrative character, and inconvenient localization. In spite of late diagnosis of carcinoid and significant acceleration of respiratory decompensation symptoms after the diagnosis the attempt of surgical therapy was appropriate but unsuccessful. After the operation the patient was suffering long lasting lowering of arterial pressure (what was corrected with catecholamine infusions) probably as a result of serotonin secretion. However it was not established because of technical reasons.

  2. Primary carcinoid tumors of the testis: a clinicopathologic study of 29 cases.

    PubMed

    Wang, Wenle P; Guo, Charles; Berney, Daniel M; Ulbright, Thomas M; Ubright, Thomas M; Hansel, Donna E; Shen, Rulong; Ali, Tehmina; Epstein, Jonathan I

    2010-04-01

    Testicular carcinoid tumors are rare with only limited studies. We identified 29 primary testicular carcinoid cases from 7 academic institutions. Patients ranged in age from 12 to 65 years old (mean 36). The most common presenting symptom was the sole finding of either a testicular mass or swelling seen in 15/24 cases with available information. The next most common mode of presentation was as an incidental finding seen in 6 cases. Two patients had carcinoid syndrome including diarrhea, hot flashes, and palpitations. Nineteen were pure carcinoid tumors, 3 were associated with cystic teratoma, 2 with cysts lacking epithelial lining, 4 with epidermoid cyst, and 1 with dermoid cyst. The mean size was 2.5 cm. All 29 primary carcinoids lacked associated intratubular germ cell neoplasia, unclassified type. Mitotic figures were rare in primary carcinoid tumors with only 3 cases showing more than 2 per 10 HPF; necrosis was found in only 1 case. Random scattered mild to moderate nuclear atypia was seen in 12/29 cases. Of the 28 cases found premortem, treatment included focal excision in 3 patients and radical orchiectomy in 25 patients. Follow-up, available in 24 cases, ranged from 1 to 228 months (mean 52.7 mo); of the 20 patients with testicular typical carcinoid tumors found premortem, all were alive at last follow-up without recurrences or metastases. Of the 4 patients with a primary atypical carcinoid tumor, 1 at the time of diagnosis had retroperitoneal and lung metastases who after chemotherapy underwent resection of the retroperitoneal tumor showing metastatic yolk sac tumor and embryonal carcinoma. After resection, serum AFP levels remained elevated and the patient is scheduled for salvage chemotherapy and bone marrow transplant. The other 2 patients with atypical carcinoid and follow-up had no evidence of disease at 68 and 114 months. Most primary carcinoid tumors of the testis have a benign clinical course even if associated with epidermoid/dermoid cysts, or

  3. Primary hepatic carcinoid tumor: case report and literature review

    PubMed Central

    Camargo, Éden Sartor; Viveiros, Marcelo de Melo; Corrêa, Isaac José Felippe; Robles, Laercio; Rezende, Marcelo Bruno

    2014-01-01

    Primary hepatic carcinoid tumors are extremely rare neoplasms derived from hormone-producing neuroendocrine cells. It is difficult to make their diagnosis before biopsy, surgical resection or necropsy. A recent publication described only 94 cases of these tumors. There is no sex predilection and apparently it has no association with cirrhosis or preexisting hepatic disease. The most effective treatment is hepatectomy, and resection is determined by size and location of the lesions. PMID:25628206

  4. Diagnosis and Management of Hereditary Carcinoids.

    PubMed

    Benafif, Sarah; Eeles, Rosalind

    2016-01-01

    Carcinoid tumours arise in cells of the diffuse neuroendocrine system and can develop in a number of anatomical sites including the lungs and the gastrointestinal tract. There has been a move away from the use of the term carcinoid tumour to the more appropriate use of neuroendocrine tumour (NET) to highlight the potential for invasion and metastasis associated with some NETs. Although most cases are sporadic, 15-20% of cases are related to a hereditary syndrome, the most common of these being multiple endocrine neoplasia 1 (MEN1). Other hereditary syndromes include the following: von Hippel-Lindau (VHL), neurofibromatosis 1 and tuberous sclerosis complex (TSC), which are all associated with a germline mutation of the associated tumour suppressor gene and an autosomal dominant inheritance pattern. Familial small intestinal NET (SI NET) is a recently described condition which is also inherited in an autosomal dominant manner. There appears to be more than one causative gene; thus far, only the IPMK gene has been identified as a causative germline mutation. This was identified by carrying out whole-exome sequencing of germline and tumour DNA in a family with multiple members diagnosed with SI NET. Identification of NET predisposition genes in other families via these methods will allow the development of dedicated NET gene panels which can be used to screen NET patients and at-risk relatives for hereditary mutations. Close surveillance of at-risk individuals is important to detect NETs early when curative surgery can be offered and the morbidity and mortality of metastatic NETs can be avoided. PMID:27075353

  5. Carcinoid heart disease: Diagnosis and management.

    PubMed

    Luis, Sushil A; Pellikka, Patricia A

    2016-01-01

    Hedinger syndrome refers to carcinoid valvular heart disease. The disease is believed to be triggered by vasoactive substances that result in valvular fibrosis. It classically occurs in patients with metastatic carcinoid and preferentially involves the right sided cardiac valves. Affected valves become thickened and retracted, exhibiting regurgitation and sometimes, stenosis. Echocardiography is recommended in patients with carcinoid syndrome and a follow up study is advisable in those who develop a murmur or other symptoms or signs of valvular heart disease. For appropriately selected patients, valve replacement surgery appears to improve outcomes.

  6. Progesterone inhibits mast cell secretion.

    PubMed

    Vasiadi, M; Kempuraj, D; Boucher, W; Kalogeromitros, D; Theoharides, T C

    2006-01-01

    Mast cells are involved in allergic reactions, where they secrete numerous vasoactive, inflammatory and nociceptive mediators in response to immunoglobulin E (IgE) and antigen. However, they have also been implicated in inflammatory conditions, such as painful bladder syndrome/interstitial cystitis (PBS/IC), irritable bowel syndrome (IBS) and migraines, all of which occur more often in women and are exacerbated during ovulation, but are suppressed during pregnancy. Mast cells express high affinity estrogen receptors and estradiol augments their secretion, while tamoxifen inhibits it. Here we report that progesterone (100 nM), but not the structurally related cholesterol, inhibits histamine secretion from purified rat peritoneal mast cells stimulated immunologically or by substance P (SP), an effect also documented by electron microscopy. These results suggest that mast cell secretion may be regulated by progesterone and may explain the reduced symptoms of certain inflammatory conditions during pregnancy.

  7. What Are the Key Statistics for Lung Carcinoid Tumors?

    MedlinePlus

    ... Research Get Involved Find Local ACS Learn About Cancer » Lung Carcinoid Tumor » Detailed Guide » What are the key statistics about lung carcinoid tumors? Share this Page Close Push escape to close share window. Print ...

  8. What Are the Risk Factors for Lung Carcinoid Tumors?

    MedlinePlus

    ... Research Get Involved Find Local ACS Learn About Cancer » Lung Carcinoid Tumor » Detailed Guide » What are the risk factors for lung carcinoid tumors? Share this Page Close Push escape to close share window. Print ...

  9. What Should You Ask Your Doctor about Lung Carcinoid Tumors?

    MedlinePlus

    ... Research Get Involved Find Local ACS Learn About Cancer » Lung Carcinoid Tumor » Detailed Guide » What should you ask your doctor about lung carcinoid tumors? Share this Page Close Push escape to close share window. Print ...

  10. What Happens after Treatment for Lung Carcinoid Tumors?

    MedlinePlus

    ... Research Get Involved Find Local ACS Learn About Cancer » Lung Carcinoid Tumor » Detailed Guide » What happens after treatment for lung carcinoid tumors? Share this Page Close Push escape to close share window. Print ...

  11. [Ileal carcinoid tumors. Value of small intestine transit].

    PubMed

    Mugel-Riwer, B; Bersani, D; Mugel, J L

    1983-05-01

    The authors describe two personnel observations of ileal carcinoid tumors, demonstrated by double contrast small bowel examination. Confirmation came from operation and histology. Small bowel examination can demonstrate limited carcinoid tumors giving no angiographic traduction.

  12. Two cases of endobronchial carcinoid masked by superimposed aspergillosis: a review of the literature of primary lung cancers associated with Aspergillus.

    PubMed

    Nilsson, John Robert; Restrepo, Carlos S; Jagirdar, Jaishree

    2013-02-01

    We describe 2 cases of endobronchial pulmonary carcinoid tumor with superimposed Aspergillus colonization. The Aspergillus hyphae were associated with fibrin, ulcer debris, and granulomatous inflammation in part masking the carcinoid tumor. Presence of necrotic debris made diagnosis on biopsy difficult, and atypical carcinoid could not be ruled out. The association of carcinoid tumor with aspergillosis is rare and has been reported in 4 other cases thus far. A review of the literature reveals at least 35 cases of lung carcinoma with coexisting Aspergillus upon presentation. Most of these carcinomas are either cavitary squamous cell or adenocarcinomas harboring an aspergilloma. The other carcinomas are associated with bronchial obstruction as in carcinoids or are a minor component of a preexisting cavity raising the possibility of "scar carcinoma." As in aspergillomas not associated with carcinoma, upper lobe involvement predominates. Diagnosis can be challenging with delayed discovery of underlying neoplasm leading to suboptimal treatment. PMID:22079170

  13. Cryo-recanalization in a case of carcinoid tumor - An interesting case report

    PubMed Central

    Chawla, Rakesh K; Madan, Arun; Chawla, Aditya; Arora, Harsh Nandini

    2015-01-01

    The term “cryotherapy” comes from the Greek cryo (κρύο) meaning cold, and therapy (θεραπεία) meaning cure. Cryosurgery is the application of extreme cold to destroy abnormal or diseased tissue. Carcinoid tumors of the lung are a fascinating but uncommon group of pulmonary neoplasms. In the past, these tumors were grouped with benign or less aggressive malignant pulmonary tumors, namely bronchial adenomas. Recent studies have revealed that carcinoid lung tumors are the most indolent form of a spectrum of bronchopulmonary neuroendocrine tumors that, at its extreme, include small cell carcinoma of the lung as its most malignant member. They commonly present as endobronchial obstructions, and if complete, can be life-threatening and require immediate intervention.[1] Recently, we have treated a patient of carcinoid tumor of lung who was managed with cryo-recanalization with excellent response. PMID:26628773

  14. Gastric carcinoids and therapeutic options. Case report and review of the literature.

    PubMed

    Dobru, Daniela; Boeriu, Alina; Mocan, Simona; Pascarenco, Ofelia; Boeriu, Cristian; Molnar, Calin

    2013-03-01

    Neuroendocrine tumors (carcinoids) are tumors originating from neuroendocrine cells. The distinction between different types of gastric carcinoids is important for their management. We present the case of a 38-year old woman with type 1 gastric neuroendocrine tumors (NETs) associated with autoimmune atrophic gastritis. The management of these tumors has not been yet codified and different therapeutic strategies have been suggested. A proper evaluation before therapy is indicated in order to rule out both the malignant transformation as well as the presence of synchronous lesions, such as dysplasia or gastric adenocarcinoma. We describe our diagnostic and therapeutic strategies with references to previously published reports. PMID:23539397

  15. Primary renal carcinoid tumor: A radiologic review

    PubMed Central

    Lamb, Leslie; Shaban, Wael

    2015-01-01

    Carcinoid tumor is the classic famous anonym of neuroendocrine neoplasms. Primary renal carcinoid tumors are extremely rare, first described by Resnick and colleagues in 1966, with fewer than a total of 100 cases reported in the literature. Thus, given the paucity of cases, the clinical and histological behavior is not well understood, impairing the ability to predict prognosis. Computed tomography and (occasionally) octreotide studies are used in the diagnosis and followup of these rare entites. A review of 85 cases in the literature shows that no distinctive imaging features differentiate them from other primary renal masses. The lesions tend to demonstrate a hypodense appearance and do not usually enhance in the arterial phases, but can occasionally calcify. Octreotide scans do not seem to help in the diagnosis; however, they are more commonly used in the postoperative followup. In addition, we report a new case of primary renal carcinoid in a horseshoe kidney. PMID:27186242

  16. Pneumothorax as atypical presentation of bronchial carcinoid.

    PubMed

    Madrid-Carbajal, Claudia J; García-Clemente, Marta M; Gutiérrez-Rodríguez, Margarita; Pando-Sandoval, Ana; Alvarez-Santín, Laura; Casan-Clarà, Pere

    2013-12-01

    We present a case of pneumothorax associated with an endobronchial carcinoid tumor in a 18-year-old man with dyspnea and chest pain. Additional tests were done, identifying in the chest roentgenogram a complete left pneumothorax with persistent leak, which was confirmed by computed tomography of the chest, and also finding an endobronchial lesion that limited the complete reexpansion of the left lung. Surgical excision was performed, and the lesion was identified as a typical bronchial carcinoid, with satisfactory outcome after the intervention. PMID:24296189

  17. Pneumothorax as atypical presentation of bronchial carcinoid.

    PubMed

    Madrid-Carbajal, Claudia J; García-Clemente, Marta M; Gutiérrez-Rodríguez, Margarita; Pando-Sandoval, Ana; Alvarez-Santín, Laura; Casan-Clarà, Pere

    2013-12-01

    We present a case of pneumothorax associated with an endobronchial carcinoid tumor in a 18-year-old man with dyspnea and chest pain. Additional tests were done, identifying in the chest roentgenogram a complete left pneumothorax with persistent leak, which was confirmed by computed tomography of the chest, and also finding an endobronchial lesion that limited the complete reexpansion of the left lung. Surgical excision was performed, and the lesion was identified as a typical bronchial carcinoid, with satisfactory outcome after the intervention.

  18. Atypical Bronchial Carcinoid Masquerading as Bronchial Asthma.

    PubMed

    Rajendran, V; Iqbal; Kumar, Vinod

    2015-11-01

    A case study of 35-year-old woman with persistent breathlessness and wheezing that had been unsuccessfully treated with inhaled beta 2-agonists and steroids for about two years. Patient developed dry cough and haemoptysis, so investigated further. Spirometry demonstrated a restrictive pattern. Chest CT demonstrated well defined hyperdense lesion in right middle lobe. Biopsy taken from the mass during bronchoscopy demonstrated the picture of atypical bronchial carcinoid. In this case, due to the lack of awareness, diagnosis of carcinoid was delayed by two years. PMID:27608788

  19. JNK Inhibition Inhibits Lateral Line Neuromast Hair Cell Development

    PubMed Central

    Cai, Chengfu; Lin, Jinchao; Sun, Shaoyang; He, Yingzi

    2016-01-01

    JNK signaling is known to play a role in regulating cell behaviors such as cell cycle progression, cell proliferation, and apoptosis, and recent studies have suggested important roles for JNK signaling in embryonic development. However, the precise function of JNK signaling in hair cell development remains poorly studied. In this study, we used the small molecule JNK inhibitor SP600125 to examine the effect of JNK signaling abrogation on the development of hair cells in the zebrafish lateral line neuromast. Our results showed that SP600125 reduced the numbers of both hair cells and supporting cells in neuromasts during larval development in a dose-dependent manner. Additionally, JNK inhibition strongly inhibited the proliferation of neuromast cells, which likely explains the decrease in the number of differentiated hair cells in inhibitor-treated larvae. Furthermore, western blot and in situ analysis showed that JNK inhibition induced cell cycle arrest through induction of p21 expression. We also showed that SP600125 induced cell death in developing neuromasts as measured by cleaved caspase-3 immunohistochemistry, and this was accompanied with an induction of p53 gene expression. Together these results indicate that JNK might be an important regulator in the development of hair cells in the lateral line in zebrafish by controlling both cell cycle progression and apoptosis. PMID:26903805

  20. [Atypical carcinoid of larynx: a case report].

    PubMed

    Gu, Wenjing; Wang, Xin; Shi, Jinfeng

    2015-09-01

    An 70-year-old male come for swallowing pain 5 years, turning worse 10 months. Laryngoscopy showed a tumor with rough surface at the laryngeal surface of epiglottic. Outpatient pathology: poorly differentiated carcinoma of the larynx. CT: the root of epiglottic is slightly thickened. He accepted the partial laryngectomy, tracheotomy, bilateral functional neck dissection. Pathology: atypical carcinoid of larynx.

  1. Genetics of neuroendocrine and carcinoid tumours.

    PubMed

    Leotlela, P D; Jauch, A; Holtgreve-Grez, H; Thakker, R V

    2003-12-01

    Neuroendocrine tumours (NETs) originate in tissues that contain cells derived from the embryonic neural crest, neuroectoderm and endoderm. Thus, NETs occur at many sites in the body, although the majority occur within the gastro-entero-pancreatic axis and can be subdivided into those of foregut, midgut and hindgut origin. Amongst these, only those of midgut origin are generally argentaffin positive and secrete serotonin, and hence only these should be referred to as carcinoid tumours. NETs may occur as part of complex familial endocrine cancer syndromes, such as multiple endocrine neoplasia type 1 (MEN1), although the majority occur as non-familial (i.e. sporadic) isolated tumours. Molecular genetic studies have revealed that the development of NETs may involve different genes, each of which may be associated with several different abnormalities that include point mutations, gene deletions, DNA methylation, chromosomal losses and chromosomal gains. Indeed, the foregut, midgut and hindgut NETs develop via different molecular pathways. For example, foregut NETs have frequent deletions and mutations of the MEN1 gene, whereas midgut NETs have losses of chromosome 18, 11q and 16q and hindgut NETs express transforming growth factor-alpha and the epidermal growth factor receptor. Furthermore, in lung NETs, a loss of chromosome 3p is the most frequent change and p53 mutations and chromosomal loss of 5q21 are associated with more aggressive tumours and poor survival. In addition, methylation frequencies of retinoic acid receptor-beta, E-cadherin and RAS-associated domain family genes increase with the severity of lung NETs. Thus the development and progression of NETs is associated with specific genetic abnormalities that indicate the likely involvement of different molecular pathways.

  2. Carcinoid tumor arising in a mature cystic teratoma: A case report

    PubMed Central

    TOSUNER, ZEYNEP; SÖNMEZ, FATMA CAVİDE; ARICI, DİLEK SEMA; DANSUK, RAMAZAN

    2015-01-01

    Mature cystic teratomas are common benign tumors of the ovary. The most common form of malignant transformation is squamous cell carcinoma, however, malignant transformation is rarely observed and cases are usually asymptomatic. Carcinoid tumors are rare tumors of the neuroendocrine system. A number of the carcinoids result in clinical syndromes due to the secretion of vasoactive substances produced by the tumor. A 75-year-old woman suffering from groin pain was admitted to the Faculty of Medicine at Bezmialem Vakıf University (Istanbul, Turkey). An adnexal mass was detected during the physical examination. Magnetic resonance imaging scans exhibited an 8×7-cm mass in the right ovary. Surgical excision of the mass was performed and histopathological examination revealed a mature cystic teratoma with three germ layers. An area consisting of nests and trabeculae was evident in the cyst wall. The pathological diagnosis was of an insular and trabecular variant of carcinoid tumor arising in a mature cystic teratoma. The patient did not present with carcinoid syndrome, and no recurrence was observed after 11 months of follow-up examinations. PMID:26137048

  3. Acromegaly due to a Macroinvasive Plurihormonal Pituitary Adenoma and a Rectal Carcinoid Tumor

    PubMed Central

    Chin, Sang Ouk; Hwang, Jin-Kyung; Rhee, Sang Youl; Chon, Suk; Oh, Seungjoon; Lee, Misu; Pellegata, Natalia S.

    2015-01-01

    A macroinvasive pituitary adenoma with plurihormonality usually causes acromegaly and hyperprolactinemia, and also accompanies with neurologic symptoms such as visual disturbances. However, its concurrent presentation with a rectal carcinoid tumor is rarely observed. This study reports the history, biochemical, colonoscopic and immunohistochemical results of a 48-year-old female with acromegaly and hyperprolactinemia. Despite the large size and invasive nature of the pituitary adenoma to adjacent anatomical structures, she did not complain of any neurologic symptoms such as visual disturbance or headache. Immunohistochemical staining of the surgical specimen from the pituitary adenoma revealed that the tumor cells were positive for growth hormone (GH), prolactin (PRL), and thyroid stimulating hormone (TSH). Staining for pituitary-specific transcription factor-1 (Pit-1) was shown to be strongly positive, which could have been possibly contributing to the plurihormonality of this adenoma. Colonoscopy found a rectal polyp that was identified to be a carcinoid tumor using immunohistochemical staining. A macroinvasive pituitary adenoma with concomitant rectal carcinoid tumor was secreting GH, PRL, and TSH, which were believed to be in association with over-expression of Pit-1. This is the first case report of double primary tumors comprising a plurihormonal pituitary macroadenoma and rectal carcinoid tumor. PMID:25559714

  4. Carcinoid Tumor in Accidental, Asymptomatic Meckel's Diverticulum.

    PubMed

    Baranyai, Zsolt; Jósa, Valeria; Merkel, Keresztely; Zolnai, Zsofia

    2013-01-01

    Although Meckel's diverticulum is the most common congenital gastrointestinal disorder, it is controversial whether asymptomatic diverticula in adults should be respected. The authors report the case of a patient who was operated due to ileus caused by adhesions and a Meckel's diverticulum without any sign of inflammation was accidentally noted and removed. As a surprise, the pathological examination of the diverticulum proved carcinoid tumor, a neuroendocrine malignant tumor. The case raises the importance of the removal of asymptomatic Meckel's diverticulum.

  5. Expression of neurotensin messenger RNA in a human carcinoid tumor.

    PubMed Central

    Evers, B M; Ishizuka, J; Townsend, C M; Rajaraman, S; Thompson, J C

    1991-01-01

    Neurotensin (NT), a distal gut peptide, has important regulatory and trophic effects throughout the gut; however the intracellular mechanisms that regulate the gene expression and release of human NT are not known. The purpose of this endeavor was to study a functioning human pancreatic carcinoid cell line (called BON) in vitro that expresses the NT gene, and to study the effect of the cyclic adenosine monophosphate (cAMP) signal-transduction pathway on the expression and release of human NT. RNA was prepared from BON cell line (which has been established in this laboratory); the RNA was analyzed for NT mRNA expression by Northern hybridization with a complementary DNA probe. RNA blot analysis demonstrated that the NT gene is expressed in BON and is transcribed to two mRNAs of 1.0- and 1.5-kb sizes. In the second part of this study, BON cells were treated with either forskolin (FSK), which increases intracellular levels of cAMP, or with serotonin (5-HT), which reduces cAMP in BON cells. Forskolin produced a dose-dependent increase in NT peptide release and, furthermore, FSK (10(-6) mol/L) rapidly increased NT mRNA abundance 1 hour after addition; conversely, 5-HT (10(-5) mol/L) decreased NT mRNA at 1 hour. Neurotensin mRNA levels returned to control values by 3 hours after either FSK or 5-HT, which suggests that the transcript half-life for NT is relatively short. These findings show that the expression and peptide release of human NT is mediated, in part, by the cAMP signal-transduction pathway. Our human carcinoid cell line will provide a useful model to study the in vitro regulation of NT gene expression and peptide release. Images Fig. 1. Fig. 2. Fig. 3. Fig. 5. Fig. 6. PMID:1659338

  6. In vitro chemoresistance testing in well differentiated carcinoid tumors.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Well-differentiated, “typical” carcinoid tumors traditionally have a very poor response to chemotherapy. We hypothesized that tumor specimens from well differentiated carcinoid tumors would be highly resistant to the effects of chemotherapy when tested against a variety of antineoplastic agents in v...

  7. Primary pulmonary carcinoid tumor with metastasis to endometrial polyp

    PubMed Central

    Momeni, Mazdak; Kolev, Valentin; Costin, Dan; Mizrachi, Howard H.; Chuang, Linus; Warner, Richard R.P.; Gretz, Herbert F.

    2012-01-01

    INTRODUCTION A carcinoid tumor occurring in the endometrium has been documented in the literature, but there is no report in regard to carcinoid tumor metastasis to endometrium. PRESENTATION OF CASE We report a case of a malignant carcinoid metastasis to an endometrial polyp. Patient underwent hysteroscopy, and polypectomy. The pathology demonstrated an endometrial polyp containing a 4 mm x 5 mm nodule of metastatic carcinoid tumor, consistent with metastasis from patient's known pulmonary carcinoid. The tumor was morphologically similar to the tumors of the right lung, with similar immune-profile. DISCUSSION This patient presented with a suspicious pelvic ultrasound. Due to her age, the first priority was to exclude uterine cancer. The endometrial polyp, which was found, had a small focus of metastatic carcinoid tumor. To the best of our knowledge, this finding has not been previously recorded in the literature. Our patient also had a history of metastatic carcinoid tumor to breast. This finding is also very uncommon. CONCLUSION This is the first case in the literature described a malignant carcinoid metastasis to an endometrial polyp. PMID:23127865

  8. [Carcinoid tumours of the lung and definition of the medico-legal term "lung cancer" used in the list of occupational disease in Germany--results of the German Mesothelioma Register].

    PubMed

    Neumann, V; Fischer, M; Tannapfel, A

    2008-09-01

    Carcinoid tumours are considered to be malignant epithelial tumours according to the recent WHO classification. This study is based on the examinations of tissue from 108 patients with carcinoid tumours. Our data agree with those of other studies: carcinoid tumours developed mainly in the right lung (40 %) and the lower lobe (30 %), mean age was 56 years, typical carcinoid tumours (74 %) predominated, comparatively high proportion of females (32 %), the mean latency period after asbestos exposure - assuming asbestos as one causal factor - was 35 years. A higher incidence of carcinoid tumours (1.3 %) in the collective of the mesothelioma register compared to the incidence in the collective of all lung carcinomas (1 - 2 %) was not observed. The increased pulmonary asbestos burden analysed in 26 % of patients is explained by the exposure-dependent selection of patients in the register. So far, no association between smoking habits or exposure to other, i. e., occupational pollutions and the development of carcinoid tumours could be established. In the list of occupational diseases (No. 4104) the term "lung cancer" is used without further specification. Thus the following question remains open for discussion: does the term "lung cancer" include carcinoid tumours such as malignant epithelial lung tumours, or is it restricted to the common subtypes such as small cell carcinoma, squamous cell carcinoma, adenocarcinoma, large cell carcinoma with regard to occupational disease and compensation?

  9. CCR7 signaling inhibits T cell proliferation.

    PubMed

    Ziegler, Ekkehard; Oberbarnscheidt, Martin; Bulfone-Paus, Silvia; Förster, Reinhold; Kunzendorf, Ulrich; Krautwald, Stefan

    2007-11-15

    CCR7 and its ligands, CCL19 and CCL21, are responsible for directing the migration of T cells and dendritic cells into lymph nodes, where these cells play an important role in the initiation of the immune response. Recently, we have shown that systemic application of CCL19-IgG is able to inhibit the colocalization of T cells and dendritic cells within secondary lymphoid organs, resulting in pronounced immunosuppression with reduced allograft rejection after organ transplantation. In this study, we demonstrate that the application of sustained high concentrations of either soluble or immobilized CCL19 and CCL21 elicits an inhibitory program in T cells. We show that these ligands specifically interfere with cell proliferation and IL-2 secretion of CCR7(+) cells. This could be demonstrated for human and murine T cells and was valid for both CD4(+) and CD8(+) T cells. In contrast, CCL19 had no inhibitory effect on T cells from CCR7 knockout mice, but CCR7(-/-) T cells showed a proliferative response upon TCR-stimulation similar to that of CCL19-treated wild-type cells. Furthermore, the inhibition of proliferation is associated with delayed degradation of the cyclin-dependent kinase (CDK) inhibitor p27(Kip1) and the down-regulation of CDK1. This shows that CCR7 signaling is linked to cell cycle control and that sustained engagement of CCR7, either by high concentrations of soluble ligands or by high density of immobilized ligands, is capable of inducing cell cycle arrest in TCR-stimulated cells. Thus, CCR7, a chemokine receptor that has been demonstrated to play an essential role during activation of the immune response, is also competent to directly inhibit T cell proliferation. PMID:17982037

  10. Massive hepatic resection for the carcinoid syndrome

    PubMed Central

    Zeegen, R.; Rothwell-Jackson, R.; Sandler, M.

    1969-01-01

    Removal of the right lobe of the liver which was occupied largely by metastases, together with resection of ileal primary tumours, brought about complete remission of symptoms and signs in a 43-year-old man with a six-year history of the carcinoid syndrome. Investigations should be orientated toward surgery. When practicable, radical surgery of the type described here appears to offer the best hope of alleviating the distressing clinical features of the condition. ImagesFIG. 1aFIG. 1bFIG. 2aFIG. 2bFIG. 3 PMID:5810970

  11. Malignant metastatic carcinoid presenting as brain tumor

    PubMed Central

    Sundar, I. Vijay; Jain, S. K.; Kurmi, Dhrubajyoti; Sharma, Rakesh; Chopra, Sanjeev; Singhvi, Shashi

    2016-01-01

    Carcinoid tumors are rarely known to metastasise to the brain. It is even more rare for such patients to present with symptoms related to metastases as the initial and only symptom. We present a case of a 60-year-old man who presented with hemiparesis and imaging features suggestive of brain tumor. He underwent surgery and the histopathology revealed metastatic malignant lesion of neuroendocrine origin. A subsequent work up for the primary was negative. Patient was treated with adjuvant radiotherapy. We present this case to highlight the pathophysiological features, workup and treatment options of this rare disease and discuss the methods of differentiating it from more common brain tumors. PMID:27366273

  12. Carcinoid tumor of the middle ear: a case report and review of literature

    PubMed Central

    Liu, Guo; Chen, Fei; Li, Jin-Nan; Liu, Shi-Xi

    2014-01-01

    Carcinoid tumors of the middle ear are very rare. Here we describe a 37-year-old man with multiple recurrent carcinoid tumor of the right middle ear. The CT demonstrated the recurrent mass that filled the tympanum and mastoid with osteolytic invasion, and the tumor was removed by surgery. The pathological findings showed the tumor cells, without necrosis and mitotic activity, had round, oval, or slightly irregular nuclei and finely-dispersed chromatin, arranged in cords, nests, and glandular structures. They were strongly positive for synaptophysin and CD56, but were negative for S-100 and chromogranin A. Ki-67 proliferation activity was low (<2%). With a review of the literature, the clinical, pathological characteristics and treatment modalities of this rare tumor are discussed. PMID:25400805

  13. Chondroitin sulphate inhibits connective tissue mast cells

    PubMed Central

    Theoharides, T C; Patra, P; Boucher, W; Letourneau, R; Kempuraj, D; Chiang, G; Jeudy, S; Hesse, Leah; Athanasiou, A

    2000-01-01

    Mast cells derive from the bone marrow and are responsible for the development of allergic and possibly inflammatory reactions. Mast cells are stimulated by immunoglobulin E (IgE) and specific antigen, but also by a number of neuropeptides such as neurotensin (NT), somatostatin or substance P (SP), to secrete numerous pro-inflammatory molecules that include histamine, cytokines and proteolytic enzymes.Chondroitin sulphate, a major constituent of connective tissues and of mast cell secretory granules, had a dose-dependent inhibitory effect on rat peritoneal mast cell release of histamine induced by the mast cell secretagogue compound 48/80 (48/80). This inhibition was stronger than that of the clinically available mast cell ‘stabilizer' disodium cromoglycate (cromolyn). Inhibition by chondroitin sulphate increased with the length of preincubation and persisted after the drug was washed off, while the effect of cromolyn was limited by rapid tachyphylaxis.Immunologic stimulation of histamine secretion from rat connective tissue mast cells (CTMC) was also inhibited, but this effect was weaker in umbilical cord-derived human mast cells and was absent in rat basophilic leukemia (RBL) cells which are considered homologous to mucosal mast cells (MMC). Oligo- and monosaccharides were not as effective as the polysaccharides.Inhibition, documented by light and electron microscopy, involved a decrease of intracellular calcium ion levels shown by confocal microscopy and image analysis. Autoradiography at the ultrastructural level showed that chondroitin sulphate was mostly associated with plasma and perigranular membranes.Chondroitin sulphate appears to be a potent mast cell inhibitor of allergic and nonimmune stimulation with potential clinical implications. PMID:11082109

  14. Clinicopathologic and DNA cytometric analysis of carcinoid tumors of the thymus.

    PubMed

    Goto, K; Kodama, T; Matsuno, Y; Yokose, T; Asamura, H; Kamiya, N; Shimosato, Y

    2001-10-01

    Twelve cases of carcinoid tumors of the thymus were reviewed in terms of clinicopathologic, histochemical, and immunohistochemical features and DNA ploidy patterns. The collective consisted of nine male and three female patients, aged 34 to 74 years, of whom five (42%) had symptoms. Eleven patients underwent surgical resection, and one with systemic metastases was autopsied. In the 11 resected patients, tumors had invaded surrounding structures in four cases, and mediastinal lymph node metastases were detected in six. Recurrence occurred in two of the resected patients (18%), and the 5-year survival rate was 82%. Histologically, all tumors showed an organoid growth pattern with delicate fibrovascular stroma. In addition, three tumors had unusual morphologic features such as combined features of carcinoid tumor and thymoma and solid growth pattern with occasional large tumor cells. Mitotic counts ranged from 1 to 14 per 10 high-power fields with a mean count of 4.9. Central necrosis within solid nests was observed in nine tumors. Classification of this series using the WHO histologic classification system resulted in categorization of all 12 tumors as atypical carcinoids. All tumors were positive for Grimelius staining and for cytokeratin. Immunohistochemical staining documented the presence of moderately to strongly positive neuroendocrine markers such as neuron-specific enolase, chromogranin A, synaptophysin, and neural cell adhesion molecule. No correlation between proliferative activity based on the Ki67 labeling index and prognosis or lymph node metastasis was found. Concerning DNA ploidy patterns, only one tumor with multiple lymph node metastases was considered to be aneuploid. In conclusion, although all of our cases were histologically classified as atypical carcinoid tumors of the thymus, most were diploid, and the patients enjoyed a relatively good prognosis.

  15. [Retrospective evaluation of carcinoid tumors of the appendix in children].

    PubMed

    San Vicente, B; Bardají, C; Rigol, S; Obiols, P; Melo, M; Bella, R

    2009-04-01

    Carcinoids of the appendix are rare in children. Usually diagnosed incidentally on histologic investigation following appendectomy for acute apendicitis. To investigate the significance of the diagnosis of appendiceal carcinoid tumors in children, we conducted a retrospective study in our institution. Between 1990 and 2007 a total of 1158 appendectomy were done. In four patients the diagnosis was appendiceal carcinoid. We studied treatment, follow-up and prognosis of this patients. Indicacion for appendectomy was acute pain in lower right quadrant. The median tumor diameter was lower than 1 cm and the appropriate treatment was appendectomy. The prognosis was excellent in all the patients.

  16. [Multifocal gastric carcinoid associated with chronic type A atrophic gastritis. Analysis of 2 clinical cases].

    PubMed

    Moneghini, D; Fontana, M G; Villanacci, V; Salerni, B

    2001-01-01

    Gastric carcinoid is a rare disease, representing less than 1% of gastric tumours and 11-41% of all gastrointestinal carcinoids. The recent Solcia's classification distinguishes three subtypes of these neoplasms, which show specific clinical and pathological features. Type one arises in patients with chronic atrophic gastritis (CGA), achlorhydria, hypergastrinemia and consequent enterochromaffin-like cell hyperplasia and dysplasia. Type two is related to Zollinger Ellison syndrome and type three represents the sporadic kind. We report two cases of multifocal gastric carcinoid associated to CGA, one of them with pernicious anemia. Both patients had aspecific abdominal symptoms; the diagnosis was suspected by upper endoscopy and confirmed by histological examination. Patients were submitted to total gastrectomy. They are still alive six years after surgery, without signs or symptoms of recurrences. Treatment of these tumours is controversial, because of their uncertain biological and clinical behaviour. Some Authors propose a conservative strategy (only endoscopic surveillance or removal); others stress importance of surgery (antrectomy or gastric resection). We discuss and underline the role of surgical therapy and the relevance of radical approach.

  17. Pericellular hydrogel/nanonets inhibit cancer cells.

    PubMed

    Kuang, Yi; Shi, Junfeng; Li, Jie; Yuan, Dan; Alberti, Kyle A; Xu, Qiaobing; Xu, Bing

    2014-07-28

    Fibrils formed by proteins are vital components for cells. However, selective formation of xenogenous nanofibrils of small molecules on mammalian cells has yet to be observed. Here we report an unexpected observation of hydrogel/nanonets of a small D-peptide derivative in pericellular space. Surface and secretory phosphatases dephosphorylate a precursor of a hydrogelator to trigger the self-assembly of the hydrogelator and to result in pericellular hydrogel/nanonets selectively around the cancer cells that overexpress phosphatases. Cell-based assays confirm that the pericellular hydrogel/nanonets block cellular mass exchange to induce apoptosis of cancer cells, including multidrug-resistance (MDR) cancer cells, MES-SA/Dx5. Pericellular hydrogel/nanonets of small molecules to exhibit distinct functions illustrates a fundamentally new way to engineer molecular assemblies spatiotemporally in cellular microenvironment for inhibiting cancer cell growth and even metastasis.

  18. Invasive atypical thymic carcinoid: three case reports and literature review

    PubMed Central

    Zhu, Shan; Wang, Zhong-Tang; Liu, Wen-Zhi; Zong, Shi-Xiang; Li, Bao-Sheng

    2016-01-01

    Atypical thymic carcinoid is an extremely rare thymic neuroendocrine tumor derived from the neuroendocrine system. The aims of this paper were to investigate the clinical features of atypical thymic carcinoid and collate information and experience to improve the diagnosis and treatment of this disease. We describe three cases of atypical carcinoid of the thymus; clinical features, pathological data, treatment modalities, and short-term patient outcomes were summarized and analyzed. The initial clinical symptoms and signs of all three patients were nonspecific and an anterior mediastinal mass was found in each patient on chest computed tomography scan. All three patients underwent surgical resection (total thymectomy and complete excision of the tumor), followed by postoperative radiotherapy, with or without chemotherapy. The diagnoses of three patients were confirmed by pathological and immunohistochemical evaluation. We also present a review of the literature to collate as much information as possible and provide a reference for proper diagnosis and treatment of atypical thyroid carcinoid. PMID:27785065

  19. Endobronchial Carcinoid Tumour with Extensive Ossification: An Unusual Case Presentation.

    PubMed

    Osmond, Allison; Filter, Emily; Joseph, Mariamma; Inculet, Richard; Kwan, Keith; McCormack, David

    2016-01-01

    Carcinoid tumour is a well-known primary endobronchial lung neoplasm. Although calcifications may be seen in up to 30% of pulmonary carcinoid tumours, near complete ossification of these tumours is an unusual finding. Such lesions can prove diagnostically challenging at the time of intraoperative frozen section as the latter technique requires thin sectioning of the lesion for microscopic assessment. We present an unusual case of endobronchial carcinoid tumour with extensive ossification in a 45-year-old male. Preliminary intraoperative diagnosis was achieved through the alternative use of cytology scrape smears. The final diagnosis was confirmed after decalcification of the tumour. The prognostic implications of heavily ossified carcinoid tumours remain elusive. Long-term clinical follow-up of these patients is recommended. PMID:27610135

  20. Endobronchial Carcinoid Tumour with Extensive Ossification: An Unusual Case Presentation

    PubMed Central

    Filter, Emily; Joseph, Mariamma; Inculet, Richard; Kwan, Keith; McCormack, David

    2016-01-01

    Carcinoid tumour is a well-known primary endobronchial lung neoplasm. Although calcifications may be seen in up to 30% of pulmonary carcinoid tumours, near complete ossification of these tumours is an unusual finding. Such lesions can prove diagnostically challenging at the time of intraoperative frozen section as the latter technique requires thin sectioning of the lesion for microscopic assessment. We present an unusual case of endobronchial carcinoid tumour with extensive ossification in a 45-year-old male. Preliminary intraoperative diagnosis was achieved through the alternative use of cytology scrape smears. The final diagnosis was confirmed after decalcification of the tumour. The prognostic implications of heavily ossified carcinoid tumours remain elusive. Long-term clinical follow-up of these patients is recommended.

  1. Endobronchial Carcinoid Tumour with Extensive Ossification: An Unusual Case Presentation

    PubMed Central

    Filter, Emily; Joseph, Mariamma; Inculet, Richard; Kwan, Keith; McCormack, David

    2016-01-01

    Carcinoid tumour is a well-known primary endobronchial lung neoplasm. Although calcifications may be seen in up to 30% of pulmonary carcinoid tumours, near complete ossification of these tumours is an unusual finding. Such lesions can prove diagnostically challenging at the time of intraoperative frozen section as the latter technique requires thin sectioning of the lesion for microscopic assessment. We present an unusual case of endobronchial carcinoid tumour with extensive ossification in a 45-year-old male. Preliminary intraoperative diagnosis was achieved through the alternative use of cytology scrape smears. The final diagnosis was confirmed after decalcification of the tumour. The prognostic implications of heavily ossified carcinoid tumours remain elusive. Long-term clinical follow-up of these patients is recommended. PMID:27610135

  2. A rare case of carcinoid tumor in a tailgut cyst

    PubMed Central

    Jehangir, Asad; Le, Brian H.; Carter, Frank M

    2016-01-01

    Tailgut cysts are rare congenital lesions that arise from the failure of regression of the embryological tailgut. We report a case of neoplastic transformation of tailgut cyst to carcinoid tumor which is exceedingly uncommon. PMID:27406449

  3. Inhibition of cell-cell binding by lipid assemblies

    DOEpatents

    Nagy, Jon O.; Bargatze, Robert F.

    2001-05-22

    This invention relates generally to the field of therapeutic compounds designed to interfere between the binding of ligands and their receptors on cell surface. More specifically, it provides products and methods for inhibiting cell migration and activation using lipid assemblies with surface recognition elements that are specific for the receptors involved in cell migration and activation.

  4. Helicobacter pylori inhibits gastric cell cycle progression.

    PubMed

    Ahmed, A; Smoot, D; Littleton, G; Tackey, R; Walters, C S; Kashanchi, F; Allen, C R; Ashktorab, H

    2000-08-01

    Helicobacter pylori infection of the gastric mucosa is associated with changes in gastric epithelial cell proliferation. In vitro studies have shown that exposure to H. pylori inhibits proliferation of gastric cells. This study sought to investigate the cell cycle progression of gastric epithelial cell lines in the presence and absence of H. pylori. Unsynchronized and synchronized gastric epithelial cell lines AGS and KatoIII were exposed to H. pylori over a 24-h period. Cell cycle progression was determined by flow cytometry using propidium iodide (PI), and by analysis of cyclin E, p21, and p53 protein expression using Western blots. In the absence of H. pylori 40, 45, and 15% of unsynchronized AGS cells were in G(0)-G(1), S, and G(2)-M phases, respectively, by flow cytometry analysis. When AGS cells were cultured in the presence of H. pylori, the S phase decreased 10% and the G(0)-G(1) phase increased 17% after 24 h compared with the controls. KatoIII cells, which have a deleted p53 gene, showed little or no response to H. pylori. When G1/S synchronized AGS cells were incubated with media containing H. pylori, the G(1) phase increased significantly (25%, P < 0.05) compared with controls after 24 h. In contrast, the control cells were able to pass through S phase. The inhibitory effects of H. pylori on the cell cycle of AGS cells were associated with a significant increase in p53 and p21 expression after 24 h. The expression of cyclin E was downregulated in AGS cells following exposure of AGS cells to H. pylori for 24 h. This study shows that H. pylori-induced growth inhibition in vitro is predominantly at the G(0)-G(1) checkpoint. Our results suggest that p53 may be important in H. pylori-induced cell cycle arrest. These results support a role for cyclin-dependent kinase inhibitors in the G(1) cell cycle arrest exerted by H. pylori and its involvement in changing the regulatory proteins, p53, p21, and cyclin E in the cell cycle. PMID:11008106

  5. Rectal Mechano-sensory Function in Patients with Carcinoid Diarrhea

    PubMed Central

    Gregersen, Tine; Brock, Christina; Haase, Anne-Mette; Laurberg, Søren; Drewes, Asbjørn M; Grønbæk, Henning; Krogh, Klaus

    2016-01-01

    Background/Aims In patients with neuroendocrine tumors, excessive production of serotonin and other amines may cause the carcinoid syndrome, which is mainly characterized by diarrhea and flushing. Little is known about the pathophysiology of carcinoid diarrhea. In several other groups of patients, diarrhea may be associated with rectal hypersensitivity and increased rectal tone. Therefore, the aim of the present study was to compare rectal sensitivity and compliance in patients with carcinoid diarrhea and in healthy subjects. Methods Twelve patients (6 males, aged 54–78 years, median 65 years), with carcinoid diarrhea and 19 healthy subjects (7 males, aged 50–78 years, median 61 years) were included. Rectal mechanical and heat stimulation was used for assessment of rectal mechano-sensory properties. Results Overall, 5.3% higher temperatures were needed to elicit sensory responses in patients with carcinoid diarrhea than in healthy subjects (P = 0.015). Posthoc analyses revealed that the sensory threshold to heat was 48.1 ± 3.1°C in patients vs 44.7 ± 4.7°C in healthy subjects (P = 0.041). In contrast, patients and healthy subjects showed no overall differences in rectal sensory response to mechanical distension (P = 0.731) or rectal compliance (P = 0.990). Conclusions Patients with carcinoid diarrhea have higher sensory thresholds to heat stimulation in comparison to healthy subjects, but normal rectal sensation to mechanical distension and normal compliance. Therefore, treatment of carcinoid diarrhea should aim at prolonging gastrointestinal transit and decreasing secretion, rather than modifying rectal mechano-sensory function. PMID:26690884

  6. Tetramethypyrazine inhibits renal cell carcinoma cells through inhibition of NKG2D signaling pathways.

    PubMed

    Luan, Yun; Liu, Junli; Liu, Xiaoli; Xue, Xia; Kong, Feng; Sun, Chao; Wang, Jue; Liu, Ling; Jia, Hongying

    2016-10-01

    Tetramethypyrazine (TMP), one of the active compounds extracted from the traditional Chinese medicinal herb (Chuanxiong), has been verified as an anticancer compound against several types of cancer. However, understanding of the molecular mechanisms have not been fully elucidated. In the present study, the anticancer efficacy of TMP was investigated in human clear cell renal cell carcinoma (ccRCC) cells. We showed that TMP significantly inhibited ccRCC cell viability, proliferation, apoptosis, invasion and migration through the methods of MTT, flow cytometry, wound healing and transwell assays. Furthermore, reverse transcription polymerase chain reaction (RT-PCR), western blotting and immunofluorescence results demonstrated TMP upregulation of the expression of NKG2D ligands (NKG2DLs) MHC class I chain-related molecules A and B (MICA/B) and epithelial cell expression marker of E-cadherin, and downregulation of mesenchymal cell expression markers of vimentin and fibronectin. Taken together, the inhibition of TMP on ccRCC cells might be mediated via inhibition of NKG2D related signaling pathway to further suppress epithelial-mesenchymal transition (EMT) progression. The binding of NKG2D to its ligands activates NK cells, giving the rationale for studies on the utilization of TMP as a potential cancer therapeutic compound to increase NK cells-mediated cytotoxicity against high MICA/B expression in cancer cells. PMID:27633040

  7. Transcatheter Pulmonary Valve Replacement in a Carcinoid Heart

    PubMed Central

    Loyalka, Pranav; Schechter, Michael; Nascimbene, Angelo; Raman, Ajay Sundara; Ilieascu, Cezar A.; Gregoric, Igor D.

    2016-01-01

    Carcinoid heart disease presents as right-sided heart failure attributable to the dysfunction of the tricuspid and pulmonary valves. Although surgical valve replacement is the mainstay of treatment when patients become symptomatic, it is associated with substantial perioperative mortality rates. We present a case of severe pulmonary valve stenosis secondary to carcinoid heart disease, treated successfully with percutaneous valve replacement. A 67-year-old man with severe pulmonary valve stenosis was referred to our center for pulmonary valve replacement. The patient had a history of metastatic neuroendocrine tumor of the small bowel with carcinoid syndrome, carcinoid heart disease, and tricuspid valve regurgitation previously treated with surgical valve replacement. Because of the patient's severe chronic obstructive pulmonary disease and hostile chest anatomy seen on a computed tomographic scan dating from previous cardiothoracic surgery, we considered off-label percutaneous valve replacement a viable alternative to open-heart surgery. A 29-mm Edwards Sapien XT valve was successfully deployed over the native pulmonary valve. There were no adverse sequelae after the procedure, and the patient was discharged from the hospital the next day. This case report shows that percutaneous valve replacement can be a valid option in carcinoid heart disease patients who are not amenable to surgical valve replacement. PMID:27547148

  8. Culture at a Higher Temperature Mildly Inhibits Cancer Cell Growth but Enhances Chemotherapeutic Effects by Inhibiting Cell-Cell Collaboration.

    PubMed

    Zhu, Shengming; Wang, Jiangang; Xie, Bingkun; Luo, Zhiguo; Lin, Xiukun; Liao, D Joshua

    2015-01-01

    Acute febrile infections have historically been used to treat cancer. To explore the underlying mechanism, we studied chronic effects of fever on cancer cell growth and chemotherapeutic efficacy in cell culture. We found that culturing cancer cells at 39°C mildly inhibited cell growth by arresting the cells at the G1 phase of the cell cycle. When cells were seeded in culture dishes at a lower density, e.g. about 1000-2000 cells per 35-mm dish, the growth inhibition was much greater, manifested as many fewer cell colonies in the 39°C dishes, compared with the results at a higher density seeding, e.g. 20,000 cells per dish, suggesting that cell-cell collaboration as the Allee effect in cell culture is inhibited at 39°C. Withdrawal of cells from serum enhanced the G1 arrest at 39°C and, for some cell lines such as A549 lung cancer cells, serum replenishment failed to quickly drive the cells from the G1 into the S and G2-M phases. Therapeutic effects of several chemotherapeutic agents, including clove bud extracts, on several cancer cell lines were more potent at 39°C than at 37°C, especially when the cells were seeded at a low density. For some cell lines and some agents, this enhancement is long-lasting, i.e. continuing after the cessation of the treatment. Collectively these results suggest that hyperthermia may inhibit cancer cell growth by G1 arrest and by inhibition of cell-cell collaboration, and may enhance the efficacy of several chemotherapeutic agents, an effect which may persist beyond the termination of chemotherapy. PMID:26495849

  9. Culture at a Higher Temperature Mildly Inhibits Cancer Cell Growth but Enhances Chemotherapeutic Effects by Inhibiting Cell-Cell Collaboration

    PubMed Central

    Zhu, Shengming; Wang, Jiangang; Xie, Bingkun; Luo, Zhiguo; Lin, Xiukun; Liao, D. Joshua

    2015-01-01

    Acute febrile infections have historically been used to treat cancer. To explore the underlying mechanism, we studied chronic effects of fever on cancer cell growth and chemotherapeutic efficacy in cell culture. We found that culturing cancer cells at 39°C mildly inhibited cell growth by arresting the cells at the G1 phase of the cell cycle. When cells were seeded in culture dishes at a lower density, e.g. about 1000–2000 cells per 35-mm dish, the growth inhibition was much greater, manifested as many fewer cell colonies in the 39°C dishes, compared with the results at a higher density seeding, e.g. 20,000 cells per dish, suggesting that cell-cell collaboration as the Allee effect in cell culture is inhibited at 39°C. Withdrawal of cells from serum enhanced the G1 arrest at 39°C and, for some cell lines such as A549 lung cancer cells, serum replenishment failed to quickly drive the cells from the G1 into the S and G2-M phases. Therapeutic effects of several chemotherapeutic agents, including clove bud extracts, on several cancer cell lines were more potent at 39°C than at 37°C, especially when the cells were seeded at a low density. For some cell lines and some agents, this enhancement is long-lasting, i.e. continuing after the cessation of the treatment. Collectively these results suggest that hyperthermia may inhibit cancer cell growth by G1 arrest and by inhibition of cell-cell collaboration, and may enhance the efficacy of several chemotherapeutic agents, an effect which may persist beyond the termination of chemotherapy. PMID:26495849

  10. Ovarian strumal carcinoid producing peptide YY associated with severe constipation: a case report and review of the literature.

    PubMed

    Muller, Kristen E; Tafe, Laura J; Gonzalez, Jorge L; West, Loyd A; Schned, Alan R

    2015-01-01

    Primary carcinoid tumors are rare neoplasms of the ovary. Of the 4 histologic subtypes, ovarian carcinoid tumors with insular patterns produce carcinoid syndrome in approximately one third of cases, versus strumal and trabecular carcinoids which very rarely cause typical carcinoid syndrome. A unique presentation of ovarian carcinoid tumors with concurrent severe constipation has been reported, which is thought to represent a new carcinoid syndrome. The proposed mechanism is the production of peptide YY by the tumor, a gastrointestinal hormone responsible for decreasing gut motility. We report a case of a 34-yr-old white woman who presented with constipation and weight loss for 1 yr, and was found to have a unilateral ovarian strumal carcinoid, which produced peptide YY as demonstrated by immunohistochemistry. The 13 previous case reports of ovarian carcinoids with constipation are reviewed and the clinicopathologic features are discussed. This report and literature review further solidifies this entity as a new type of carcinoid syndrome.

  11. A case of multicentric carcinoid in a patient with psoriatic spondyloarthropathy.

    PubMed

    George, Nabil; Depala, Archana; Al Sweedan, Laith; Chakravarty, Kuntal

    2015-01-01

    We describe the first case of a patient presenting with multicentric carcinoid occurring in the lung and subsequently in the rectum, with chronic psoriatic arthritis. Although reports have been published regarding carcinoid syndrome occurring alongside rheumatoid arthritis, no reports have been made on such a case. Initial presentation of carcinoid syndrome in this patient was insidious and atypical with few symptoms, including shortness of breath and long standing abdominal bloating. Several years later a sudden change in bowel habit prompted a colonoscopy with biopsy that revealed a carcinoid rectal polyp. The case we report describes a rare presentation of carcinoid syndrome in chronic psoriatic arthropathy.

  12. A Case of Multicentric Carcinoid in a Patient with Psoriatic Spondyloarthropathy

    PubMed Central

    George, Nabil; Depala, Archana; Al Sweedan, Laith; Chakravarty, Kuntal

    2015-01-01

    We describe the first case of a patient presenting with multicentric carcinoid occurring in the lung and subsequently in the rectum, with chronic psoriatic arthritis. Although reports have been published regarding carcinoid syndrome occurring alongside rheumatoid arthritis, no reports have been made on such a case. Initial presentation of carcinoid syndrome in this patient was insidious and atypical with few symptoms, including shortness of breath and long standing abdominal bloating. Several years later a sudden change in bowel habit prompted a colonoscopy with biopsy that revealed a carcinoid rectal polyp. The case we report describes a rare presentation of carcinoid syndrome in chronic psoriatic arthropathy. PMID:25802789

  13. SIRT1 controls cell proliferation by regulating contact inhibition.

    PubMed

    Cho, Elizabeth H; Dai, Yan

    2016-09-16

    Contact inhibition keeps cell proliferation in check and serves as a built-in protection against cancer development by arresting cell division upon cell-cell contact. Yet the complete mechanism behind this anti-cancer process remains largely unclear. Here we present SIRT1 as a novel regulator of contact inhibition. SIRT1 performs a wide variety of functions in biological processes, but its involvement in contact inhibition has not been explored to date. We used NIH3T3 cells, which are sensitive to contact inhibition, and H460 and DU145 cancer cells, which lack contact inhibition, to investigate the relationship between SIRT1 and contact inhibition. We show that SIRT1 overexpression in NIH3T3 cells overcomes contact inhibition while SIRT1 knockdown in cancer cells restores their lost contact inhibition. Moreover, we demonstrate that p27 protein expression is controlled by SIRT1 in contact inhibition. Overall, our findings underline the critical role of SIRT1 in contact inhibition and suggest SIRT1 inhibition as a potential strategy to suppress cancer cell growth by restoring contact inhibition.

  14. Carcinoid crisis induced by receptor radionuclide therapy with 90Y-DOTATOC in a case of liver metastases from bronchial neuroendocrine tumor (atypical carcinoid).

    PubMed

    Davì, M V; Bodei, L; Francia, G; Bartolomei, M; Oliani, C; Scilanga, L; Reghellin, D; Falconi, M; Paganelli, G; Lo Cascio, V; Ferdeghini, M

    2006-06-01

    SS receptors are overexpressed in many tumors, mainly of neuroendocrine origin, thus enabling the treatment with SS analogs. The clinical experience of receptor radionuclide therapy with the new analog [90Y-DOTA0-Tyr3 ]-octreotide [90Y-DOTATOC] has been developed over the last decade and is gaining a pivotal role in the therapeutic workout of these tumors. It is well known that some procedures performed in diagnostic and therapeutic management of endocrine tumors, such as agobiopsy and hepatic chemoembolization, can be associated with the occurrence of symptoms related to the release of vasoactive amines and/or hormonal peptides from tumor cell lysis. This is the first report of a severe carcinoid crisis developed after receptor radionuclide therapy with 90Y-DOTATOC administered in a patient affected by liver metastases from bronchial neuroendocrine tumor (atypical carcinoid). Despite protection with H1 receptor antagonists, octreotide and corticosteroids, few days after the therapy the patient complained of persistent flushing of the face and upper trunk, severe labial and periocular oedema, diarrhoea and loss of appetite. These symptoms increased and required new hospitalisation. The patient received iv infusion of octreotide associated with H1 and H2 receptor antagonists and corticosteroid therapy, which induced symptom remission within few days. The case here reported confirms that radionuclide therapy is highly effective in determining early rupture of metastatic tissue and also suggests that pre-medication should be implemented before the radiopeptide administration associated with a close monitoring of the patient in the following days.

  15. Carcinoid Tumour of Caecum: an Unusual Palpable Mass in the Right Iliac Fossa.

    PubMed

    Agrawal, Mohit M; Sude, Nandkishor S

    2016-04-01

    Carcinoid tumour represents 0.8-1.5 % of malignant digestive tumours. Gastrointestinal (GI) carcinoids account for 95 % of all the carcinoids, and caecal carcinoids account for 5 % of all the carcinoids. These tumours are frequent in women (2-4:1) as reported by Spallitta and Termine (Minerva Chir 55:77-87, 2002). In order of frequency, they may occur in the appendix (35 %), ileum (28 %), rectum (13 %) and bronchi. Incidence is less than 1 % in the pancreas, gall bladder, liver, larynx, testes and ovaries. The colon and ileocaecal region are rare sites of origin for gastrointestinal carcinoids as reported by Soga (J Exp Clin Cancer Res 17:139-48, 1998). They remain asymptomatic for years and many a times are diagnosed endoscopically, intraoperatively or during autopsy, based on their histopathological findings. We present a rare case of caecal carcinoid. PMID:27303130

  16. ACTH producing pulmonary carcinoid and pituitary macroadenoma: a fortuitous association?

    PubMed

    Wong, M; Isa, S H Md; Kamaruddin, N A; Khalid, B A K

    2007-06-01

    We report a case of a 45 year-old man who presented initially with a non-functioning pituitary macroadenoma. A routine chest radiography done preoperatively revealed a right lung nodule which was confirmed by computed tomography (CT) of the thorax. Transfrontal hypophysectomy was performed while a conservative approach was taken for the lung nodule. Four years later, he presented acutely with adrenocorticotrophic hormone (ACTH) dependent Cushing's syndrome which resolved following a right lobectomy. Histological examination revealed an atypical carcinoid. To our knowledge, this is the first reported case of an ectopic ACTH secreting pulmonary carcinoid found in association with a non-functioning pituitary macroadenoma.

  17. MET Inhibition in Clear Cell Renal Cell Carcinoma

    PubMed Central

    Xie, Zuoquan; Lee, Young H.; Boeke, Marta; Jilaveanu, Lucia B.; Liu, Zongzhi; Bottaro, Donald P.; Kluger, Harriet M.; Shuch, Brian

    2016-01-01

    Background: Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer. Small molecule VEGFR inhibitors are widely used but are not curative and various resistance mechanisms such as activation of the MET pathway have been described. Dual MET/VEGFR2 inhibitors have recently shown clinical benefit but limited preclinical data evaluates their effects in ccRCC. Methods: An interrogation of the Cancer Genome Atlas (TCGA) dataset was performed to evaluate oncogenic alterations in the MET/VEGFR2 pathway. We evaluated the in vitro effects of Cabozantinib, a dual MET/VEGFR2 inhibitor, using a panel of ccRCC cell lines. Drug effects of cell viability and proliferation, migration, cell scatter, anchorage independent growth, and downstream MET/VEGFR2 signaling pathways were assessed. Results: Twelve percent of TCGA cases had possible MET/HGF oncogenic alterations with co-occurrence noted (p<0.001). MET/HGF altered cases had worse overall survival (p=0.044). Cabozantinib was a potent inhibitor of MET and VEGFR2 in vitro in our cell line panel. PI3K, MAPK and mTOR pathways were also suppressed by cabozantinib, however the effects on cell viability in vitro were modest. At nanomolar concentrations of cabozantinib, HGF-stimulated migration, invasion, cellular scattering and soft agar colony formation were inhibited. Conclusions: We provide further preclinical rationale for dual MET/VEGFR2 inhibition in ccRCC. While the MET pathway is implicated in VEGFR resistance, dual inhibitors may have direct anti-tumor effects in a patient subset with evidence of MET pathway involvement. Cabozantinib is a potent dual MET/VEGFR2 inhibitor, significantly inhibits cell migration and invasion in vitro and likely has anti-angiogenic effects similar to other VEGFR tyrosine kinase inhibitors. Future work involving in vivo models will be useful to better define mechanisms of potential anti-tumor activity. PMID:27390595

  18. A thymic carcinoid in a Bengal tiger (Panthera tigris).

    PubMed

    Powe, Joshua; Castleman, William; Fiorello, Christine

    2005-09-01

    An 18-yr-old Bengal tiger (Panthera tigris) presented with acute onset hind limb paresis. Radiographic and ultrasonographic imaging revealed a caudal abdominal aortic thrombus and a cranial mediastinal mass. Necropsy confirmed aortic thrombosis. Necrotizing enteritis and multifocal renal thrombosis were also noted. The cranial mediastinum contained a bilobed mass that histologically and ultrastructurally was consistent with a carcinoid.

  19. Unusual presentation of carcinoid tumor as acute cholecystitis

    SciTech Connect

    Saxton, C.R.

    1983-07-01

    The patient described had signs, symptoms, and laboratory data consistent with acute cholecystitis. A sonogram also suggested cholecystitis, and the gallbladder was not displayed by nuclear imaging. Cholecystectomy revealed the absence of stones but showed carcinoid tumor metastatic to the gallbladder.

  20. A thymic carcinoid in a Bengal tiger (Panthera tigris).

    PubMed

    Powe, Joshua; Castleman, William; Fiorello, Christine

    2005-09-01

    An 18-yr-old Bengal tiger (Panthera tigris) presented with acute onset hind limb paresis. Radiographic and ultrasonographic imaging revealed a caudal abdominal aortic thrombus and a cranial mediastinal mass. Necropsy confirmed aortic thrombosis. Necrotizing enteritis and multifocal renal thrombosis were also noted. The cranial mediastinum contained a bilobed mass that histologically and ultrastructurally was consistent with a carcinoid. PMID:17312779

  1. Thymic carcinoids in multiple endocrine neoplasia type 1.

    PubMed Central

    Teh, B T; Zedenius, J; Kytölä, S; Skogseid, B; Trotter, J; Choplin, H; Twigg, S; Farnebo, F; Giraud, S; Cameron, D; Robinson, B; Calender, A; Larsson, C; Salmela, P

    1998-01-01

    OBJECTIVE: To study the clinical, pathologic, and genetic features of thymic carcinoids in the setting of multiple endocrine neoplasia type 1 (MEN1) and to study means for detection and prevention of this tumor in patients with MEN1. SUMMARY BACKGROUND DATA: Thymic carcinoid is a rare malignancy, with approximately 150 cases reported to date. It may be associated with MEN1 and carries a poor prognosis, with no effective treatment. Its underlying etiology is unknown. METHODS: Ten patients with MEN1 from eight families with anterior mediastinal tumors were included in a case series study at tertiary referring hospitals. Clinicopathologic studies were done on these patients, with a review of the literature. Mutation analysis was performed on the MEN1 gene in families with clusterings of the tumor to look for genotype-phenotype correlation. Loss of heterozygosity was studied in seven cases to look for genetic abnormalities. RESULTS: Histologic studies of all tumors were consistent with the diagnosis of thymic carcinoid. Clustering of this tumor was found in some of the families-three pairs of brothers and three families with first- or second-degree relatives who had thymic carcinoid. All patients described here were men, with a mean age at detection of 44 years (range 31 to 66). Most of the patients had chest pain or were asymptomatic; none had Cushing's or carcinoid syndrome. All tumors were detected by computed tomography (CT) or magnetic resonance imaging (MRI) of the chest. The results of octreoscans performed in three patients were all positive. Histopathologic studies were consistent with the diagnosis of thymic carcinoid and did not stain for ACTH. Mutation analysis of the families with clustering revealed mutations in different exons/introns of the MEN1 gene. Loss of heterozygosity (LOH) studies of seven tumors did not show LOH in the MEN1 region, but two tumors showed LOH in the 1p region. CONCLUSIONS: MEN1-related thymic carcinoids constitute approximately 25

  2. Cutaneous and Subcutaneous Metastases From Atypical Laryngeal Carcinoids

    PubMed Central

    Wang, Kui-Rong; Jia, Yuan-Jing; Zhou, Shui-Hong; Wang, Qin-Ying; Bao, Yang-Yang; Feng, Zhi-Ying; Yao, Hong-Tian; Fan, Jun

    2016-01-01

    Abstract The incidence of cutaneous and subcutaneous metastases from atypical laryngeal carcinoids is approximately 20%. However, the pathogenesis and natural history of, and prognostic factors for, the condition remain poorly understood. We reported a 54-year-old female presented with cutaneous and subcutaneous metastases from atypical laryngeal carcinoid. Laryngoscopy revealed a 0.5 × 1.5-cm reddish mass on the laryngeal surface of the epiglottis. Under general anesthesia, a biopsy sample was obtained via suspension laryngoscopy. Routine pathology revealed atypical laryngeal carcinoid. Immunohistochemical staining of the sections of primary tumor was positive for cytokeratin, chromogranin A, synaptophysin, hypoxia-inducible factor-1α, P53, and CD56. GLUT-1, p-Akt, and PI3K were negative. The Ki-67 index was 15%. Supraglottic laryngectomy and selective right-neck dissection were performed. After 6 months, the patient complained of pain in the right wall of the chest; multiple cutaneous and subcutaneous nodules were evident at that site and in the abdomen. An abdominal nodule was biopsied and pathology revealed that the atypical metastatic carcinoid had metastasized to both cutaneous and subcutaneous areas of the abdomen. Chemotherapy was then prescribed. Currently, the intrathecal drug delivery system remains in place. No local recurrence has been detected. Furthermore, we systematically reviewed clinical manifestations of the disease, pathogenesis, prognostic factors, and treatment. The metastasis rate (cutaneous and subcutaneous) was approximately 12.2%. Thirty patients (62.5%) with cutaneous and subcutaneous metastases exhibited contemporaneous lymph node invasion. The 3-, 5-, and 10-year survival rates were 44.0%, 22.0%, and 13.0%, respectively. The prognosis of patients with atypical laryngeal carcinoids was poor. Relevant prognostic factors included the level of p53, human papilloma virus status, certain hypoxic markers, and distant metastasis. No

  3. Prognosis of patients with carcinoid heart disease after valvular surgery.

    PubMed

    Manoly, Imthiaz; McAnelly, Sarah-Louise; Sriskandarajah, Sanjeevan; McLaughlin, Kenneth Edward

    2014-08-01

    A best evidence topic in cardiac surgery was written according to a structured protocol. We addressed the following question: in patients who are diagnosed with carcinoid heart disease (CHD), do valvular surgeries improve their prognosis? Fifty percent of the patients with clinically diagnosed carcinoid syndrome had cardiac involvement which was present either as valvular dysfunction or as cardiac metastases. These patients often require surgery due to their heightened risk of cardiac disease. Altogether 217 relevant papers were identified as a result of the below-mentioned search, of which 10 papers represented the best evidence to answer the question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses were tabulated. Of the patients who were identified to have carcinoid heart disease in different studies, 193 patients had valve procedure, mainly replacements at tricuspid, mitral and aortic valve positions and either valvuloplasty or replacement at pulmonary valve. Tricuspid and pulmonary valves represented the majority of the excised valves among patients undergoing valvular surgery for CHD. The pathology of carcinoid valve was attributed to the presence of plaque, causing thickening and retraction. Pure regurgitation was the most common finding in all the valves except pulmonary valve which had both stenosis and insufficiency. Thirty-day mortality was 17% (range 1-63%) and long-term survivors were reported to be alive at an average of 58 months (28-80 months) after the valve surgery. The evidence demonstrates that surgical intervention can lead to improved prognosis and reduce the symptoms of heart failure. Postoperative mortality was mainly due to the carcinoid disease itself and not as a complication of the surgery. Therefore, surgery could be considered for symptomatic palliation in carefully selected individuals.

  4. Carcinoid syndrome, acromegaly, and hypoglycemia due to an insulin-secreting neuroendocrine tumor of the liver.

    PubMed

    Furrer, J; Hättenschwiler, A; Komminoth, P; Pfammatter, T; Wiesli, P

    2001-05-01

    We report a patient with a hepatic neuroendocrine tumor showing an extraordinary change of the tumor's humoral manifestations from a clinically documented extrapituitary acromegaly and a typical carcinoid syndrome toward a hyperinsulinemic hypoglycemia syndrome. At the primary manifestation of the tumor, an increased serum level of insulin-like growth factor I due to overproduction of GHRH and an increased urinary excretion of 5-hydroxyindoleacetic acid were found. The clinical manifestation of the GHRH excess was an arthralgia, which resolved completely after operative tumor debulking and normalization of insulin-like growth factor I and GHRH serum levels. The secretion of serotonin from the tumor resulted in a typical carcinoid syndrome including right-sided valvular heart disease. On the later course of the disease, the humoral manifestations of the tumor were supplemented by the secretion of insulin, leading to recurrent severe hyperinsulinemic hypoglycemia. The hepatic origin of hyperinsulinism was demonstrated by selective arterial calcium stimulation. Moreover, tumor cells revealed insulin and C-peptide immunoreactivity in the immunohistochemical analysis. The patient died 8 yr after the initial diagnosis of the tumor, and a carefully performed autopsy procedure confirmed the absence of any extrahepatic tumor manifestation. PMID:11344231

  5. Carcinoid syndrome, acromegaly, and hypoglycemia due to an insulin-secreting neuroendocrine tumor of the liver.

    PubMed

    Furrer, J; Hättenschwiler, A; Komminoth, P; Pfammatter, T; Wiesli, P

    2001-05-01

    We report a patient with a hepatic neuroendocrine tumor showing an extraordinary change of the tumor's humoral manifestations from a clinically documented extrapituitary acromegaly and a typical carcinoid syndrome toward a hyperinsulinemic hypoglycemia syndrome. At the primary manifestation of the tumor, an increased serum level of insulin-like growth factor I due to overproduction of GHRH and an increased urinary excretion of 5-hydroxyindoleacetic acid were found. The clinical manifestation of the GHRH excess was an arthralgia, which resolved completely after operative tumor debulking and normalization of insulin-like growth factor I and GHRH serum levels. The secretion of serotonin from the tumor resulted in a typical carcinoid syndrome including right-sided valvular heart disease. On the later course of the disease, the humoral manifestations of the tumor were supplemented by the secretion of insulin, leading to recurrent severe hyperinsulinemic hypoglycemia. The hepatic origin of hyperinsulinism was demonstrated by selective arterial calcium stimulation. Moreover, tumor cells revealed insulin and C-peptide immunoreactivity in the immunohistochemical analysis. The patient died 8 yr after the initial diagnosis of the tumor, and a carefully performed autopsy procedure confirmed the absence of any extrahepatic tumor manifestation.

  6. Challenges in the Diagnosis and Management of Well-Differentiated Neuroendocrine Tumors of the Lung (Typical and Atypical Carcinoid): Current Status and Future Considerations

    PubMed Central

    2015-01-01

    Neuroendocrine tumors (NET) of the lung represent approximately 25% of all primary lung tumors and can be classified as low grade (typical carcinoids), intermediate grade (atypical carcinoids), or high grade (large cell neuroendocrine carcinoma or small cell lung carcinoma). Low- and intermediate-grade lung NET are increasingly recognized as biologically distinct from high-grade lung NET based on clinical behavior and underlying molecular abnormalities. This review summarizes current knowledge and challenges in the diagnosis and management of low- and intermediate-grade lung NET. Accurate histopathologic classification of lung NET is critical to determining appropriate treatment options but can be challenging even for experts. For low- and intermediate-grade lung NET, surgery remains the mainstay of treatment for localized disease. Although no standard systemic therapy has been established for the treatment of advanced, unresectable disease, a number of promising treatment options are emerging, including somatostatin analogs, temozolomide-based chemotherapy, targeted therapy with mammalian target of rapamycin or vascular endothelial growth factor inhibitors, and peptide receptor radionuclide therapy. Given the difficulty in accurately diagnosing these tumors, and the paucity of data supporting establishment of standard systemic therapy options, management of patients within the setting of a multidisciplinary team, including specialists with expertise in NET, is recommended. Ongoing and future clinical trials hopefully will provide stronger evidence to support treatment recommendations for low- and intermediate-grade lung NET. Implications for Practice: Treatment of neuroendocrine tumors (NET), particularly those of lung origin, continues to evolve. This review seeks to educate oncologists on the most up-to-date options and supporting data regarding management of two rare lung neoplasms, typical and atypical carcinoid tumors. Although surgical resection has been the

  7. Carcinoid heart disease from ovarian primary presenting with acute pericarditis and biventricular failure

    PubMed Central

    Vergani, D; Massironi, L; Lombardi, F; Fiorentini, C

    1998-01-01

    A case is described of a 54 year old woman who had acute pericarditis with large exudative effusion accompanied by severe right and left ventricular failure. The patient was finally diagnosed with carcinoid heart disease from an ovarian carcinoid teratoma. She was treated with octreotide—a somatostatin analogue—followed by radical surgical resection of the neoplasm. At one year follow up only mild carcinoid tricuspid regurgitation remained. Only 16 cases of carcinoid heart disease from an ovarian primary have been described in literature. Moreover clinically manifest acute, non-metastatic pericarditis and left heart failure are not considered as possible presentations of carcinoid heart disease, whatever the origin. In a recent series a small pericardial effusion was considered an infrequent and unexpected echocardiographic finding in carcinoid heart patients. One case of "carcinoid pericarditis" has previously been described as a consequence of pericardial metastasis. Left sided heart involvement is usually caused by bronchial carcinoids or patency of foramen ovale; both were excluded in the case presented.

 Keywords: carcinoid heart disease;  ovarian tumour;  acute pericarditis;  heart failure PMID:10065036

  8. Inhibition of caspases prevents ototoxic and ongoing hair cell death

    NASA Technical Reports Server (NTRS)

    Matsui, Jonathan I.; Ogilvie, Judith M.; Warchol, Mark E.

    2002-01-01

    Sensory hair cells die after acoustic trauma or ototoxic insults, but the signal transduction pathways that mediate hair cell death are not known. Here we identify several important signaling events that regulate the death of vestibular hair cells. Chick utricles were cultured in media supplemented with the ototoxic antibiotic neomycin and selected pharmacological agents that influence signaling molecules in cell death pathways. Hair cells that were treated with neomycin exhibited classically defined apoptotic morphologies such as condensed nuclei and fragmented DNA. Inhibition of protein synthesis (via treatment with cycloheximide) increased hair cell survival after treatment with neomycin, suggesting that hair cell death requires de novo protein synthesis. Finally, the inhibition of caspases promoted hair cell survival after neomycin treatment. Sensory hair cells in avian vestibular organs also undergo continual cell death and replacement throughout mature life. It is unclear whether the loss of hair cells stimulates the proliferation of supporting cells or whether the production of new cells triggers the death of hair cells. We examined the effects of caspase inhibition on spontaneous hair cell death in the chick utricle. Caspase inhibitors reduced the amount of ongoing hair cell death and ongoing supporting cell proliferation in a dose-dependent manner. In isolated sensory epithelia, however, caspase inhibitors did not affect supporting cell proliferation directly. Our data indicate that ongoing hair cell death stimulates supporting cell proliferation in the mature utricle.

  9. Growth inhibition of Candida by human oral epithelial cells.

    PubMed

    Steele, C; Leigh, J; Swoboda, R; Fidel, P L

    2000-11-01

    Oropharyngeal candidiasis (OPC) caused by Candida albicans is a significant problem in human immunodeficiency virus (HIV)-infected persons. Recognizing the paucity of information on innate and/or adaptive mucosal host defenses against C. albicans, we recently reported that human and nonhuman primate and mouse vaginal epithelial cells inhibit the growth of C. albicans in vitro. In the present study, oral epithelial cells collected from saliva of healthy volunteers and a purified oral epithelial cell line were found to inhibit blastoconidia and/or hyphal growth of several Candida species. Cell contact was a strict requirement for the epithelial cell anti-Candida activity; neither saliva nor culture supernatants alone inhibited Candida growth, and addition of saliva to the coculture did not modulate the epithelial cell activity. Finally, epithelial cell anti-Candida activity was significantly lower in HIV-infected persons with OPC. Together, these results suggest that oral epithelial cells may play a role in innate resistance against OPC.

  10. Hyperoxia Inhibits T Cell Activation in Mice

    NASA Astrophysics Data System (ADS)

    Hughes-Fulford, M.; Meissler, J.; Aguayo, E. T.; Globus, R.; Aguado, J.; Candelario, T.

    2013-02-01

    , spleens were removed and the splenocytes were isolated and kept as individual biological samples. We have also examined transcription factors (JASPAR) and pathways of the immune system to help us understand the mechanism of regulation. Results: Our recent mouse immunology experiment aboard STS-131 suggests that the early T cell immune response was inhibited in animals that have been exposed to spaceflight, even 24 hours after return to earth. Moreover, recent experiments in hyperoxic mice show that many of the same genes involved in early T cell activation were altered. Specifically, expression of IL-2Rα, Cxcl2, TNFα, FGF2, LTA and BCL2 genes are dysregulated in mice exposed to hyperoxia. Conclusions: If these hyperoxia-induced changes of gene expression in early T cell activation are additive to the changes seen in the microgravity of spaceflight, there could be an increased infection risk to EVA astronauts, which should be addressed prior to conducting a Mars or other long-term mission.

  11. Paraneoplastic neuromyelitis optica spectrum disorder associated with stomach carcinoid tumor.

    PubMed

    Al-Harbi, Talal; Al-Sarawi, Adnan; Binfalah, Mohamed; Dermime, Said

    2014-09-01

    Neuromyelitis optica (NMO), or Devic's syndrome, is an autoimmune central nervous system demyelinating disorder primarily affecting the spinal cord and the optic nerves. It is characterized by the presence of NMO antibodies, alongside clinical and radiological findings. NMO and NMO-spectrum disorders (NMO-SD) have been reported in autoimmune disorders, and are infrequently described as a paraneoplastic syndrome with cancers of lung, breast, and carcinoid tumors of the thyroid. We report a patient who presented with severe vomiting, blurring of vision, vertigo, diplopia, left hemiparesis and hemisensory loss and ataxia. She was found to have a longitudinally-extensive demyelinating lesion extending from the medulla to the upper cervical spinal cord on MRI. Her gastric endoscopy revealed carcinoid tumor of the stomach, and classic paraneoplastic antibodies in the serum were negative. She had extremely high serum gastrin level and high titer of NMO IgG autoantibody. The patient made an excellent recovery with tumor resection and immunotherapy, with both clinical and radiological improvement. On rare instances, NMO or NMO-SD may present as a paraneoplastic neurological syndrome associated with carcinoid tumor of the stomach.

  12. Inhibition of brain tumor cell proliferation by alternating electric fields

    SciTech Connect

    Jeong, Hyesun; Oh, Seung-ick; Hong, Sunghoi E-mail: radioyoon@korea.ac.kr; Sung, Jiwon; Jeong, Seonghoon; Yoon, Myonggeun E-mail: radioyoon@korea.ac.kr; Koh, Eui Kwan

    2014-11-17

    This study was designed to investigate the mechanism by which electric fields affect cell function, and to determine the optimal conditions for electric field inhibition of cancer cell proliferation. Low-intensity (<2 V/cm) and intermediate-frequency (100–300 kHz) alternating electric fields were applied to glioblastoma cell lines. These electric fields inhibited cell proliferation by inducing cell cycle arrest and abnormal mitosis due to the malformation of microtubules. These effects were significantly dependent on the intensity and frequency of applied electric fields.

  13. A new role for GABA: inhibition of tumor cell migration.

    PubMed

    Ortega, Arturo

    2003-04-01

    GABA, the main inhibitory neurotransmitter in the vertebrate brain, participates outside the CNS in diverse functions such as platelet aggregation and the acrosomal reaction in spermatozoa. A recent study now demonstrates that GABA inhibits the migration of colon carcinoma cells, paving the way to the development of specific pharmacological agents that delay or inhibit invasion and metastasis of various cancer types.

  14. Marital Status and Survival in Patients with Carcinoid Tumors

    PubMed Central

    Greenleaf, Erin K.; Cooper, Amanda B.; Hollenbeak, Christopher S.

    2016-01-01

    BACKGROUND Marital status is a known prognostic factor in overall and disease-specific survival in several types of cancer. The impact of marital status on survival in patients with carcinoid tumors remains unknown. We hypothesized that married patients have higher rates of survival than similar unmarried patients with carcinoid tumors. METHODS Using the Surveillance, Epidemiology, and End Results database, we identified 23,126 people diagnosed with a carcinoid tumor between 2000 and 2011 and stratified them according to marital status. Univariate and multivariable analyses were performed to compare the characteristics and outcomes between patient cohorts. Overall and cancer-related survival were analyzed using the Kaplan–Meier method. Multivariable survival analyses were performed using Cox proportional hazards models (hazards ratio [HR]), controlling for demographics and tumor-related and treatment-related variables. Propensity score analysis was performed to determine surgical intervention distributions among married and unmarried (ie, single, separated, divorced, widowed) patients. RESULTS Marital status was significantly related to both overall and cancer-related survival in patients with carcinoid tumors. Divorced and widowed patients had worse overall survival (HR, 1.33 [95% confidence interval {CI}, 1.08–1.33] and 1.34 [95% CI, 1.22–1.46], respectively) and cancer-related survival (HR, 1.15 [95% CI, 1.00–1.31] and 1.15 [95% CI, 1.03–1.29], respectively) than married patients over five years. Single and separated patients had worse overall survival (HR, 1.20 [95% CI, 1.08–1.33] and 1.62 [95% CI, 1.25–2.11], respectively) than married patients over five years, but not worse cancer-related survival. Unmarried patients were more likely than matched married patients to undergo definitive surgical intervention (62.67% vs 53.11%, respectively, P < 0.0001). CONCLUSIONS Even after controlling for other prognostic factors, married patients have a

  15. Inhibition Of Call-Cell Binding By Kipid Assemblies

    DOEpatents

    Nagy, Jon O. , Bargatze, Robert F.

    2003-12-16

    This invention relates generally to the field of therapeutic compounds designed to interfere between the binding of ligands and their receptors on cell surface. More specifically, it provides products and methods for inhibiting cell migration and activation using lipid assemblies with surface recognition elements that are specific for the receptors involved in cell migration and activation.

  16. Sickle cell microRNAs inhibit the malaria parasite.

    PubMed

    Duraisingh, Manoj T; Lodish, Harvey F

    2012-08-16

    Sickle cell hemoglobin conveys resistance to malaria. In this issue of Cell Host & Microbe, LaMonte et al. (2012) demonstrate a surprising mechanism for this innate immunity. A microRNA enriched in sickle red blood cells is translocated into the parasite, incorporated covalently into P. falciparum mRNAs and inhibits parasite growth.

  17. Brassinosteroids inhibit in vitro angiogenesis in human endothelial cells.

    PubMed

    Rárová, Lucie; Zahler, Stefan; Liebl, Johanna; Kryštof, Vladimír; Sedlák, David; Bartůněk, Petr; Kohout, Ladislav; Strnad, Miroslav

    2012-11-01

    Antiangiogenic activity of the brassinosteroid plant hormones (BRs) and their derivative cholestanon was investigated in human umbilical vein endothelial cells (HUVEC) and in human microvascular endothelial cells (HMEC-1). 24-Epibrassinolide and 28-homocastasterone from group of 21 tested natural BRs inhibited migration of HUVEC cells. Seven tested BRs decreased the number of tubes significantly. Synthetic analogue cholestanon inhibited angiogenesis in vitro more effectively than natural BRs. Because of the similarity of BRs to human steroids, we have also studied interactions of BRs with human steroid receptors. Synthetic BRs cholestanon showed agonistic effects on estrogen-receptor-α, estrogen-receptor-β and androgen receptor. Of the natural BRs, 24-epibrassinolide was found to be a weak antagonist of estrogen-receptor-α (ERα). Our results provide the first evidence that large group of BRs can inhibit in vitro angiogenesis of primary endothelial cells. BRs constitute a novel group of human steroid receptor activators or inhibitors with capacity to inhibit angiogenesis.

  18. Gastrointestinal carcinoid tumor and chylous ascites, a rare association with a poor prognosis. A case report.

    PubMed

    Portale, Teresa Rosanna; Mosca, Francesco; Minona, Elisa; Trovato, Maria Antonietta; Gangemi, Pietro; Bordonaro, Roberto; Puleo, Stefano

    2008-01-01

    Gastrointestinal carcinoid is a rare tumor. The association of this tumor with chylous ascites is uncommon. A review of the English-language literature carried out in 2002 identified only 15 cases. We report a case of chylous ascites, gastrointestinal carcinoid tumor and elevated blood levels of CA-125 in a patient who did not respond to chemotherapy.

  19. The cost-effectiveness of octreotide acetate in the treatment of carcinoid syndrome and VIPoma.

    PubMed

    Schonfeld, W H; Eikin, E P; Woltering, E A; Modlin, I M; Anthony, L; Villa, K F; Zagari, M

    1998-01-01

    Markov modeling was used to evaluate the cost-effectiveness of octreotide in treating carcinoid syndrome and VIPoma. For each condition, using octreotide was associated with doubled survival time. Octreotide was cost-effective for treating carcinoid tumor ($752 per additional year of life, two additional years on average), and cost saving for VIPoma.

  20. Carcinoid tumour of appendix in a child: a rare case at an uncommon site.

    PubMed

    Vani, B R; Thejaswini, M U; Kumar, B Deepak; Murthy, V Srinivasa; Geethamala, K

    2014-01-01

    Carcinoid tumours of the appendix are uncommon incidentally detected tumours during histopathological examination following appendicectomy for acute appendicitis. Even though considered rare in children, they are the most frequently encountered tumours of the gastrointestinal tract. To our knowledge, carcinoid tumour of appendix in childhood has not yet been reported from Indian Subcontinent. The clinical presentation is similar to acute appendicitis and the signs and symptoms of carcinoid syndrome have not been reported in children. The prognosis of carcinoid tumour of appendix is excellent in children as the tumour is generally small in size and less aggressive with no metastasis. Simple appendicectomy is curative in most of the patients and long term follow up is debatable. We present here a case of carcinoid tumour of the body of appendix, which is an uncommon location in a 6-year-old child.

  1. Thymoquinone Inhibits Escherichia coli ATP Synthase and Cell Growth

    PubMed Central

    Ahmad, Zulfiqar; Laughlin, Thomas F.; Kady, Ismail O.

    2015-01-01

    We examined the thymoquinone induced inhibition of purified F1 or membrane bound F1FO E. coli ATP synthase. Both purified F1 and membrane bound F1FO were completely inhibited by thymoquinone with no residual ATPase activity. The process of inhibition was fully reversible and identical in both membrane bound F1Fo and purified F1 preparations. Moreover, thymoquinone induced inhibition of ATP synthase expressing wild-type E. coli cell growth and non-inhibition of ATPase gene deleted null control cells demonstrates that ATP synthase is a molecular target for thymoquinone. This also links the beneficial dietary based antimicrobial and anticancer effects of thymoquinone to its inhibitory action on ATP synthase. PMID:25996607

  2. Blue light inhibits proliferation of melanoma cells

    NASA Astrophysics Data System (ADS)

    Becker, Anja; Distler, Elisabeth; Klapczynski, Anna; Arpino, Fabiola; Kuch, Natalia; Simon-Keller, Katja; Sticht, Carsten; van Abeelen, Frank A.; Gretz, Norbert; Oversluizen, Gerrit

    2016-03-01

    Photobiomodulation with blue light is used for several treatment paradigms such as neonatal jaundice, psoriasis and back pain. However, little is known about possible side effects concerning melanoma cells in the skin. The aim of this study was to assess the safety of blue LED irradiation with respect to proliferation of melanoma cells. For that purpose we used the human malignant melanoma cell line SK-MEL28. Cell proliferation was decreased in blue light irradiated cells where the effect size depended on light irradiation dosage. Furthermore, with a repeated irradiation of the melanoma cells on two consecutive days the effect could be intensified. Fluorescence-activated cell sorting with Annexin V and Propidium iodide labeling did not show a higher number of dead cells after blue light irradiation compared to non-irradiated cells. Gene expression analysis revealed down-regulated genes in pathways connected to anti-inflammatory response, like B cell signaling and phagosome. Most prominent pathways with up-regulation of genes were cytochrome P450, steroid hormone biosynthesis. Furthermore, even though cells showed a decrease in proliferation, genes connected to the cell cycle were up-regulated after 24h. This result is concordant with XTT test 48h after irradiation, where irradiated cells showed the same proliferation as the no light negative control. In summary, proliferation of melanoma cells can be decreased using blue light irradiation. Nevertheless, the gene expression analysis has to be further evaluated and more studies, such as in-vivo experiments, are warranted to further assess the safety of blue light treatment.

  3. Inhibition of autophagy overcomes glucocorticoid resistance in lymphoid malignant cells.

    PubMed

    Jiang, Lei; Xu, Lingzhi; Xie, Jiajun; Li, Sisi; Guan, Yanchun; Zhang, Yan; Hou, Zhijie; Guo, Tao; Shu, Xin; Wang, Chang; Fan, Wenjun; Si, Yang; Yang, Ya; Kang, Zhijie; Fang, Meiyun; Liu, Quentin

    2015-01-01

    Glucocorticoid (GC) resistance remains a major obstacle to successful treatment of lymphoid malignancies. Till now, the precise mechanism of GC resistance remains unclear. In the present study, dexamethasone (Dex) inhibited cell proliferation, arrested cell cycle in G0/G1-phase, and induced apoptosis in Dex-sensitive acute lymphoblastic leukemia cells. However, Dex failed to cause cell death in Dex-resistant lymphoid malignant cells. Intriguingly, we found that autophagy was induced by Dex in resistant cells, as indicated by autophagosomes formation, LC3-I to LC3-II conversion, p62 degradation, and formation of acidic autophagic vacuoles. Moreover, the results showed that Dex reduced the activity of mTOR pathway, as determined by decreased phosphorylation levels of mTOR, Akt, P70S6K and 4E-BP1 in resistant cells. Inhibition of autophagy by either chloroquine (CQ) or 3-methyladenine (3-MA) overcame Dex-resistance in lymphoid malignant cells by increasing apoptotic cell death in vitro. Consistently, inhibition of autophagy by stably knockdown of Beclin1 sensitized Dex-resistant lymphoid malignant cells to induction of apoptosis in vivo. Thus, inhibition of autophagy has the potential to improve lymphoid malignancy treatment by overcoming GC resistance.

  4. Inhibition of cyclooxygenase (COX)-2 affects endothelial progenitor cell proliferation

    SciTech Connect

    Colleselli, Daniela; Bijuklic, Klaudija; Mosheimer, Birgit A.; Kaehler, Christian M. . E-mail: C.M.Kaehler@uibk.ac.at

    2006-09-10

    Growing evidence indicates that inducible cyclooxygenase-2 (COX-2) is involved in the pathogenesis of inflammatory disorders and various types of cancer. Endothelial progenitor cells recruited from the bone marrow have been shown to be involved in the formation of new vessels in malignancies and discussed for being a key point in tumour progression and metastasis. However, until now, nothing is known about an interaction between COX and endothelial progenitor cells (EPC). Expression of COX-1 and COX-2 was detected by semiquantitative RT-PCR and Western blot. Proliferation kinetics, cell cycle distribution and rate of apoptosis were analysed by MTT test and FACS analysis. Further analyses revealed an implication of Akt phosphorylation and caspase-3 activation. Both COX-1 and COX-2 expression can be found in bone-marrow-derived endothelial progenitor cells in vitro. COX-2 inhibition leads to a significant reduction in proliferation of endothelial progenitor cells by an increase in apoptosis and cell cycle arrest. COX-2 inhibition leads further to an increased cleavage of caspase-3 protein and inversely to inhibition of Akt activation. Highly proliferating endothelial progenitor cells can be targeted by selective COX-2 inhibition in vitro. These results indicate that upcoming therapy strategies in cancer patients targeting COX-2 may be effective in inhibiting tumour vasculogenesis as well as angiogenic processes.

  5. Malaria circumsporozoite protein inhibits the respiratory burst in Kupffer cells.

    PubMed

    Usynin, Ivan; Klotz, Christian; Frevert, Ute

    2007-11-01

    After transmission by infected mosquitoes, malaria sporozoites rapidly travel to the liver. To infect hepatocytes, sporozoites traverse Kupffer cells, but surprisingly, the parasites are not killed by these resident macrophages of the liver. Here we show that Plasmodium sporozoites and recombinant circumsporozoite protein (CSP) suppress the respiratory burst in Kupffer cells. Sporozoites and CSP increased the intracellular concentration of cyclic adenosyl mono-phosphate (cAMP) and inositol 1,4,5-triphosphate in Kupffer cells, but not in hepatocytes or liver endothelia. Preincubation with cAMP analogues or inhibition of phosphodiesterase also inhibited the respiratory burst. By contrast, adenylyl cyclase inhibition abrogated the suppressive effect of sporozoites. Selective protein kinase A (PKA) inhibitors failed to reverse the CSP-mediated blockage and stimulation of the exchange protein directly activated by cAMP (EPAC), but not PKA inhibited the respiratory burst. Both blockage of the low-density lipoprotein receptor-related protein (LRP-1) with receptor-associated protein and elimination of cell surface proteoglycans inhibited the cAMP increase in Kupffer cells. We propose that by binding of CSP to LRP-1 and cell surface proteoglycans, malaria sporozoites induce a cAMP/EPAC-dependent, but PKA-independent signal transduction pathway that suppresses defence mechanisms in Kupffer cells. This allows the sporozoites to safely pass through these professional phagocytes and to develop inside neighbouring hepatocytes.

  6. Cell proliferation inhibition in reduced gravity

    NASA Technical Reports Server (NTRS)

    Moos, P. J.; Fattaey, H. K.; Johnson, T. C.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    Extended durations of spaceflight have been shown to be deleterious on an organismic level; however, mechanisms underlying cellular sensitivity to the gravitational environment remain to be elucidated. The majority of the gravitational studies to date indicates that cell regulatory pathways may be influenced by their gravitational environment. Still, few cell biology experiments have been performed in space flight and even fewer experiments have been repeated on subsequent flights. With flight opportunities on STS-50, 54, and 57, Sf9 cells were flown in the BioServe Fluids Processing Apparatus and cell proliferation was measured with and without exposure to a cell regulatory sialoglycopeptide (CeReS) inhibitor. Results from these flights indicate that the Sf9 cells grew comparable to ground controls, that the CeReS inhibitor bound to its specific receptor, and that its signal transduction cascade was not gravity sensitive.

  7. Chlorpromazine inhibits mitosis of mammalian cells.

    PubMed

    Boder, G B; Paul, D C; Williams, D C

    1983-09-01

    Chlorpromazine (CPZ) at minimally effective concentrations accumulates mammalian cells in mitosis without lethal effects on the cells. Star-metaphase morphology similar to effects seen with classical antimitotic compounds probably results from the preferential action of CPZ on a specific class of microtubules--the pole-to-pole microtubules of the mitotic spindle. At CPZ concentrations of 8 X 10(-6) M, flow cytometry indicates no effect of CPZ on the progress of cells through phases of the cell cycle other than mitosis (M). These results suggest a possible mechanism for toxic side effects of CPZ in man such as granulocytopenia and light sensitization.

  8. Ghrelin Inhibits Oligodendrocyte Cell Death by Attenuating Microglial Activation

    PubMed Central

    Lee, Jee Youn

    2014-01-01

    Background Recently, we reported the antiapoptotic effect of ghrelin in spinal cord injury-induced apoptotic cell death of oligodendrocytes. However, how ghrelin inhibits oligodendrocytes apoptosis, is still unknown. Therefore, in the present study, we examined whether ghrelin inhibits microglia activation and thereby inhibits oligodendrocyte apoptosis. Methods Using total cell extracts prepared from BV-2 cells activated by lipopolysaccharide (LPS) with or without ghrelin, the levels of p-p38 phosphor-p38 mitogen-activated protein kinase (p-p38MAPK), phospho-c-Jun N-terminal kinase (pJNK), p-c-Jun, and pro-nerve growth factor (proNGF) were examined by Western blot analysis. Reactive oxygen species (ROS) production was investigated by using dichlorodihydrofluorescein diacetate. To examine the effect of ghrelin on oligodendrocyte cell death, oligodendrocytes were cocultured in transwell chambers of 24-well plates with LPS-stimulated BV-2 cells. After 48 hours incubation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and terminal deoxynucleotidyl transferase 2'-deoxyuridine, 5'-triphosphate nick end labeling staining were assessed. Results Ghrelin treatment significantly decreased levels of p-p38MAPK, p-JNK, p-c-Jun, and proNGF in LPS-stimulated BV-2 cells. ROS production increased in LPS-stimulated BV-2 cells was also significantly inhibited by ghrelin treatment. In addition, ghrelin significantly inhibited oligodendrocyte cell death when cocultured with LPS-stimulated BV-2 cells. Conclusion Ghrelin inhibits oligodendrocyte cell death by decreasing proNGF and ROS production as well as p38MAPK and JNK activation in activated microglia as an anti-inflammatory hormone. PMID:25309797

  9. MLR-induced inhibition of barosensory cells in the NTS.

    PubMed

    Degtyarenko, Alexandr M; Kaufman, Marc P

    2005-12-01

    A central motor command arising from the mesencephalic locomotor region (MLR) is widely believed to be one of the neural mechanisms that reset the baroreceptor reflex upward during exercise. The nucleus tractus solitarius (NTS), a dorsal medullary site that receives input from baroreceptors, may be the site where central command inhibits baroreceptor input during exercise. We, therefore, examined the effect of electrical stimulation of the MLR on the impulse activity of cells in the NTS in decerebrate paralyzed cats. Of 129 NTS cells tested for baroreceptor input by injection of phenylephrine (7-25 microg/kg iv) or inflation of a balloon in the carotid sinus, 58 were stimulated and 19 were inhibited. MLR stimulation (80-150 microA) inhibited the discharge of 48 of the 58 cells stimulated by baroreceptor input. MLR stimulation had no effect on the discharge of the remaining 10 cells, each of which displayed no spontaneous activity. In contrast to the 77 NTS cells responsive to baroreceptor input, there was no change in activity of 52 cells when arterial pressure was increased by phenylephrine injection or balloon inflation. MLR stimulation activated each of the 52 NTS cells. For 23 of the cells, the onset latency to MLR stimulation was clearly discernable, averaging 6.4 +/- 0.4 ms. Our findings provide electrophysiological evidence for the hypothesis that the MLR inhibits the baroreceptor reflex by activating NTS interneurons unresponsive to baroreceptor input. In turn, these interneurons may release an inhibitory neurotransmitter onto NTS cells receiving baroreceptor input.

  10. Foxp3+ T cells inhibit antitumor immune memory modulated by mTOR inhibition.

    PubMed

    Wang, Yanping; Sparwasser, Tim; Figlin, Robert; Kim, Hyung L

    2014-04-15

    Inhibition of mTOR signaling enhances antitumor memory lymphocytes. However, pharmacologic mTOR inhibition also enhances regulatory T-cell (Treg) activity. To counter this effect, Treg control was added to mTOR inhibition in preclinical models. Tregs were controlled with CD4-depleting antibodies because CD4 depletion has high translational potential and already has a well-established safety profile in patients. The antitumor activity of the combination therapy was CD8 dependent and controlled growth of syngeneic tumors even when an adoptive immunotherapy was not used. Lymphocytes resulting from the combination therapy could be transferred into naïve mice to inhibit aggressive growth of lung metastases. The combination therapy enhanced CD8 memory formation as determined by memory markers and functional studies of immune recall. Removal of FoxP3-expressing T lymphocytes was the mechanism underlying immunologic memory formation following CD4 depletion. This was confirmed using transgenic DEREG (depletion of regulatory T cells) mice to specifically remove Foxp3(+) T cells. It was further confirmed with reciprocal studies where stimulation of immunologic memory because of CD4 depletion was completely neutralized by adoptively transferring tumor-specific Foxp3(+) T cells. Also contributing to tumor control, Tregs that eventually recovered following CD4 depletion were less immunosuppressive. These results provide a rationale for further study of mTOR inhibition and CD4 depletion in patients.

  11. Primary lung carcinoid, a rare cause of paraparesis: report of a case and review of the literature

    PubMed Central

    Visouli, Aikaterini N.; Darwiche, Kaid; Kourtoglou, Georgios I.; Mpakas, Andreas; Machairiotis, Nikolaos; Stylianaki, Aikaterini; Christofis, Chistos; Katsikogiannis, Nikolaos; Tsakiridis, Kosmas; Courcoutsakis, Nicolaos; Zarogoulidis, Konstantinos

    2012-01-01

    Carcinoids are neuroendocrine tumors mainly involving the gastrointestinal tract, lungs and bronchi. They were considered benign with slow growth, but they can be malignant in a substantial percentage of patients (metastasizing to liver, bones, skin, etc). Endocrine activity results in carcinoid syndrome. Proximal myopathy has been reported in 7% of patients with carcinoid syndrome. Bronchopulmonary and thymic carcinoids producing adrenocorticotropic hormone can cause Cushing’s syndrome, a main feature of which is myopathy. There are a few reports of carcinoids associated with paraneoplastic neurological syndromes, including neuropathy. We hereby present an extremely rare case of a primary lung carcinoid presented with paraparesis due to polyneuropathy, and review the relevant literature. To the best of our knowledge there is no similar previous report. Complete resolution of paraparesis after excision of the lung carcinoid suggests paraneoplastic neurological syndrome. PMID:23304441

  12. Nesfatin-1 inhibits ovarian epithelial carcinoma cell proliferation in vitro

    SciTech Connect

    Xu, Yang; Pang, Xiaoyan; Dong, Mei; Wen, Fang Zhang, Yi

    2013-11-01

    Highlights: •Nesfatin-1 inhibits the proliferation and growth of HO-8910 cells by G1 phase arrest. •Nesfatin-1 enhances HO-8910 cell apoptosis. •Nesfatin-1 inhibits HO-8910 cell proliferation via mTOR and RhoA/ROCK signaling pathway. •The first report of nesfatin-1-mediated proliferation in ovarian epithelial carcinoma. -- Abstract: Nesfatin-1, an 82-amino-acid peptide derived from a 396-amino-acid precursor protein nucleobindin 2 (NUCB2), was originally identified in hypothalamic nuclei involved in the regulation of food intake. It was recently reported that nesfatin-1 is a novel depot specific adipokine preferentially produced by subcutaneous tissue, with obesity- and food deprivation-regulated expression. Although a relation between ovarian cancer mortality and obesity has been previously established, a role of nesfatin-1 in ovarian epithelial carcinoma remains unknown. The aim of the present study is to examine the effect of nesfatin-1 on ovary carcinoma cells proliferation. We found that nesfatin-1 inhibits the proliferation and growth of HO-8910 cells by G1 phase arrest, this inhibition could be abolished by nesfatin-1 neutralizing antibody. Nesfatin-1 enhances HO-8910 cell apoptosis, activation of mammalian target of rapamycin (mTOR) and RhoA/ROCK signaling pathway block the effects of nesfatin-1-induced apoptosis, therefore reverses the inhibition of HO-8910 cell proliferation by nesfatin-1. In conclusion, the present study demonstrated that nesfatin-1 can inhibit the proliferation in human ovarian epithelial carcinoma cell line HO-8910 cells through inducing apoptosis via mTOR and RhoA/ROCK signaling pathway. This study provides a novel regulatory signaling pathway of nesfatin-1-regulated ovarian epithelial carcinoma growth and may contribute to ovarian cancer prevention and therapy, especially in obese patients.

  13. Inhibiting ice recrystallization and optimization of cell viability after cryopreservation.

    PubMed

    Chaytor, Jennifer L; Tokarew, Jacqueline M; Wu, Luke K; Leclère, Mathieu; Tam, Roger Y; Capicciotti, Chantelle J; Guolla, Louise; von Moos, Elisabeth; Findlay, C Scott; Allan, David S; Ben, Robert N

    2012-01-01

    The ice recrystallization inhibition activity of various mono- and disaccharides has been correlated with their ability to cryopreserve human cell lines at various concentrations. Cell viabilities after cryopreservation were compared with control experiments where cells were cryopreserved with dimethylsulfoxide (DMSO). The most potent inhibitors of ice recrystallization were 220 mM solutions of disaccharides; however, the best cell viability was obtained when a 200 mM d-galactose solution was utilized. This solution was minimally cytotoxic at physiological temperature and effectively preserved cells during freeze-thaw. In fact, this carbohydrate was just as effective as a 5% DMSO solution. Further studies indicated that the cryoprotective benefit of d-galactose was a result of its internalization and its ability to mitigate osmotic stress, prevent intracellular ice formation and/or inhibit ice recrystallization. This study supports the hypothesis that the ability of a cryoprotectant to inhibit ice recrystallization is an important property to enhance cell viability post-freeze-thaw. This cryoprotective benefit is observed in three different human cell lines. Furthermore, we demonstrated that the ability of a potential cryoprotectant to inhibit ice recrystallation may be used as a predictor of its ability to preserve cells at subzero temperatures.

  14. l-Methionine inhibits growth of human pancreatic cancer cells

    PubMed Central

    Benavides, Maximo A.; Bosland, Maarten C.; da Silva, Cássio P.; Sares, Claudia T. Gomes; de Oliveira, Alana M. Cerqueira; Kemp, Rafael; dos Reis, Rodolfo B.; Martins, Vilma R.; Sampaio, Suely V.; Bland, Kirby I.; Grizzle, William E.; dos Santos, José S.

    2015-01-01

    We have previously shown that l-methionine inhibits proliferation of breast, prostate, and colon cancer cells. This study extends these findings to BXPC-3 (mutated p53) and HPAC (wild-type p53) pancreatic cancer cells and explores the reversibility of these effects. Cells were exposed to l-methionine (5 mg/ml) for 7 days or for 3 days, followed by 4 days of culture without l-methionine (recovery). Cell proliferation, apoptosis, and cell cycle effects were assessed by flow cytometry after staining for Ki-67 or annexin V/propidium iodide. Cell proliferation was reduced by 31–35% after 7 days of methionine exposure; the effect persisted in BXPC-3 and HPAC cells after 4 days of recovery. Methionine increased apoptosis by 40–75% in HPAC cells, but not in BXPC-3 cells. Continuous exposure to methionine caused accumulation of BXPC-3 cells in the S phase and HPAC cells in both the G0/G1 and S phases; however, after 4 days of recovery, these effects disappeared. In conclusion, l-methionine inhibits proliferation and interferes with the cell cycle of BXPC-3 and HPAC pancreatic cancer cells; the effects on apoptosis remarkably persisted after methionine withdrawal. Apoptosis was induced only in BXPC-3 cells. Some of the differences in the effects of methionine between cell lines may be related to disparate p53 status. These findings warrant further studies on the potential therapeutic benefit of l-methionine against pancreatic cancer. PMID:24126240

  15. L-Methionine inhibits growth of human pancreatic cancer cells.

    PubMed

    Benavides, Maximo A; Bosland, Maarten C; da Silva, Cássio P; Gomes Sares, Claudia T; de Oliveira, Alana M Cerqueira; Kemp, Rafael; dos Reis, Rodolfo B; Martins, Vilma R; Sampaio, Suely V; Bland, Kirby I; Grizzle, William E; dos Santos, José S

    2014-02-01

    We have previously shown that L-methionine inhibits proliferation of breast, prostate, and colon cancer cells. This study extends these findings to BXPC-3 (mutated p53) and HPAC (wild-type p53) pancreatic cancer cells and explores the reversibility of these effects. Cells were exposed to L-methionine (5 mg/ml) for 7 days or for 3 days, followed by 4 days of culture without L-methionine (recovery). Cell proliferation, apoptosis, and cell cycle effects were assessed by flow cytometry after staining for Ki-67 or annexin V/propidium iodide. Cell proliferation was reduced by 31-35% after 7 days of methionine exposure; the effect persisted in BXPC-3 and HPAC cells after 4 days of recovery. Methionine increased apoptosis by 40-75% in HPAC cells, but not in BXPC-3 cells. Continuous exposure to methionine caused accumulation of BXPC-3 cells in the S phase and HPAC cells in both the G0/G1 and S phases; however, after 4 days of recovery, these effects disappeared. In conclusion, L-methionine inhibits proliferation and interferes with the cell cycle of BXPC-3 and HPAC pancreatic cancer cells; the effects on apoptosis remarkably persisted after methionine withdrawal. Apoptosis was induced only in BXPC-3 cells. Some of the differences in the effects of methionine between cell lines may be related to disparate p53 status. These findings warrant further studies on the potential therapeutic benefit of L-methionine against pancreatic cancer.

  16. Crocetinic acid inhibits hedgehog signaling to inhibit pancreatic cancer stem cells

    PubMed Central

    Rangarajan, Parthasarathy; Subramaniam, Dharmalingam; Paul, Santanu; Kwatra, Deep; Palaniyandi, Kanagaraj; Islam, Shamima; Harihar, Sitaram; Ramalingam, Satish; Gutheil, William; Putty, Sandeep; Pradhan, Rohan; Padhye, Subhash; Welch, Danny R.; Anant, Shrikant; Dhar, Animesh

    2015-01-01

    Pancreatic cancer is the fourth leading cause of cancer deaths in the US and no significant treatment is currently available. Here, we describe the effect of crocetinic acid, which we purified from commercial saffron compound crocetin using high performance liquid chromatography. Crocetinic acid inhibits proliferation of pancreatic cancer cell lines in a dose- and time-dependent manner. In addition, it induced apoptosis. Moreover, the compound significantly inhibited epidermal growth factor receptor and Akt phosphorylation. Furthermore, crocetinic acid decreased the number and size of the pancospheres in a dose-dependent manner, and suppressed the expression of the marker protein DCLK-1 (Doublecortin Calcium/Calmodulin-Dependent Kinase-1) suggesting that crocetinic acid targets cancer stem cells (CSC). To understand the mechanism of CSC inhibition, the signaling pathways affected by purified crocetinic acid were dissected. Sonic hedgehog (Shh) upon binding to its cognate receptor patched, allows smoothened to accumulate and activate Gli transcription factor. Crocetinic acid inhibited the expression of both Shh and smoothened. Finally, these data were confirmed in vivo where the compound at a dose of 0.5 mg/Kg bw suppressed growth of tumor xenografts. Collectively, these data suggest that purified crocetinic acid inhibits pancreatic CSC, thereby inhibiting pancreatic tumorigenesis. PMID:26317547

  17. Hydroxyflavanone inhibits gastric carcinoma MGC-803 cell proliferation

    PubMed Central

    Zhang, Haiyan; Zhan, Zhuo; Cui, Mingfu; Gao, Yongjian; Wang, Dayu; Feng, Ye

    2015-01-01

    Gastric carcinoma (GC) is the most common primary malignancy of the digestive tract, with increasing incidence in many countries. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to assess inhibition of HepG2 cell proliferation by 2’-hydroxyflavanone. The STAT3 pathway was performed. 2’-hydroxyflavanone reduced inhibitory effects on MGC-803 cell proliferation. 2’-hydroxyflavanone exhibited the highest inhibition rate. Treatment of MGC-803 cells with 400, 200, and 100 μg/ml 2’-hydroxyflavanone resulted in 88.9±0.7%, 81.2±0.5%, 68.4±0.5% decrease in cell viability, respectively, indicating an IC50 of 9.3 μg/ml. The 100 μg/ml 2’-hydroxyflavanone can significantly inhibit the STAT3 pathway activation. 2’-hydroxyflavanone inhibits MGC-803 cell proliferation by inhibiting STAT3 pathway activation. This extract is therefore a potential drug candidate for treatment of liver cancer. PMID:26629250

  18. Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity

    PubMed Central

    Kim, Tae-Hee; Li, Fugen; Ferreiro-Neira, Isabel; Ho, Li-Lun; Luyten, Annouck; Nalapareddy, Kodandaramireddy; Long, Henry; Verzi, Michael; Shivdasani, Ramesh A.

    2014-01-01

    Cells differentiate when transcription factors (TFs) bind accessible cis-regulatory elements to establish specific gene expression programs. In differentiating embryonic stem (ES) cells, chromatin at lineage-restricted genes becomes sequentially accessible1-4, probably by virtue of “pioneer” TF activity5, but tissues may utilize other strategies in vivo. Lateral inhibition is a pervasive process in which one cell forces a different identity on its neighbors6, and it is unclear how chromatin in equipotent progenitors undergoing lateral inhibition quickly enables distinct, transiently reversible cell fates. Here we report the chromatin and transcriptional underpinnings of differentiation in mouse small intestine crypts, where Notch signaling mediates lateral inhibition to assign progenitor cells into absorptive or secretory lineages7-9. Transcript profiles in isolated LGR5+ intestinal stem cells (ISC)10 and secretory and absorptive progenitors indicated that each cell population was distinct and the progenitors specified. Nevertheless, secretory and absorptive progenitors showed comparable levels of H3K4me2 and H3K27ac histone marks and DNaseI hypersensitivity - signifying accessible, permissive chromatin - at most of the same cis-elements. Enhancers acting uniquely in progenitors were well-demarcated in LGR5+ ISC, revealing early priming of chromatin for divergent transcriptional programs, and retained active marks well after lineages were specified. On this chromatin background, ATOH1, a secretory-specific TF, controls lateral inhibition through Delta-like Notch ligand genes and also drives numerous secretory lineage genes. Depletion of ATOH1 from specified secretory cells converted them into functional enterocytes, indicating prolonged responsiveness of marked enhancers to presence or absence of a key TF. Thus, lateral inhibition and intestinal crypt lineage plasticity involve interaction of a lineage-restricted TF with broadly permissive chromatin established

  19. Carcinoid tumor associated with adjacent dysplastic columnar epithelium in the renal pelvis: A case report and literature review.

    PubMed

    Kim, Sung Sun; Choi, Chan; Kang, Taek Won; Choi, Yoo Duk

    2016-01-01

    Carcinoid tumors are well documented in the pulmonary and gastrointestinal systems, but very rare in the urinary tract, especially in the renal pelvis. We report on a 60-year-old female patient who presented with left flank pain and fever. Abdominal computed tomography demonstrated a heterogeneously enhancing mass in the left renal pelvis and a stone at the left proximal ureter. Multiple parenchymal lesions were also observed, which were identified as uneven caliectasis displaying air-fluid levels and renal parenchymal atrophy. The patient underwent simple nephro-ureterectomy. Macroscopically, a polypoid mass was observed in the renal pelvis. Microscopically, the tumor revealed acinar, tubular, and solid pattern and was composed of small, monotonous and hyperchromatic cells. Lining epithelia in renal pelvis and ureter revealed columnar epithelia with dysplastic change. The tumor cells were positive for chromogranin A, synaptophysin, CD56, and focally positive for cytokeratin. Immunohistochemical staining of synaptophysin and chromogranin A highlighted the neuroendocrine cells in the columnar epithelium. Ki-67 (1:50; MIB-1) labeling index was less than 1% in the area with highest uptake. We report here a case of carcinoid tumor of the renal pelvis that was associated with adjacent dysplastic columnar epithelium. PMID:26644387

  20. Targeting Btk with ibrutinib inhibit gastric carcinoma cells growth

    PubMed Central

    Wang, Jin Dao; Chen, Xiao Ying; Ji, Ke Wei; Tao, Feng

    2016-01-01

    Bruton’s tyrosine kinase (Btk) is a member of the Tec-family non-receptor tyrosine kinases family. It has previously been reported to be expressed in B cells and has an important role in B-cell malignancies. While the roles of Btk in the pathogenesis of certain B-cell malignancies are well established, the functions of Btk in gastric carcinoma have never been investigated. Herein, we found that Btk is over-expressed in gastric carcinoma tissues and gastric cancer cells. Knockdown of Btk expression selectively inhibits the growth of gastric cancer cells, but not that of the normal gastric mucosa epithelial cell, which express very little Btk. Inhibition of Btk by its inhibitor ibrutinib has an additive inhibitory effect on gastric cancer cell growth. Treatment of gastric cancer cells, but not immortalized breast epithelial cells with ibrutinib results in effective cell killing, accompanied by the attenuation of Btk signals. Ibrutinib also induces apoptosis in gastric carcinoma cells as well as is a chemo-sensitizer for docetaxel (DTX), a standard of care for gastric carcinoma patients. Finally, ibrutinib markedly reduces tumor growth and increases tumor cell apoptosis in the tumors formed in mice inoculated with the gastric carcinoma cells. Given these promising preclinical results for ibrutinib in gastric carcinoma, a strategy combining Btk inhibitor warrants attention in gastric cancer. PMID:27508020

  1. Anandamide inhibits adhesion and migration of breast cancer cells

    SciTech Connect

    Grimaldi, Claudia; Pisanti, Simona; Laezza, Chiara; Malfitano, Anna Maria; Santoro, Antonietta; Vitale, Mario; Caruso, Maria Gabriella; Notarnicola, Maria; Iacuzzo, Irma; Portella, Giuseppe; Di Marzo, Vincenzo . E-mail: vdimarzo@icmib.na.cnr.it; Bifulco, Maurizio . E-mail: maubiful@unina.it

    2006-02-15

    The endocannabinoid system regulates cell proliferation in human breast cancer cells. We reasoned that stimulation of cannabinoid CB{sub 1} receptors could induce a non-invasive phenotype in breast mtastatic cells. In a model of metastatic spreading in vivo, the metabolically stable anandamide analogue, 2-methyl-2'-F-anandamide (Met-F-AEA), significantly reduced the number and dimension of metastatic nodes, this effect being antagonized by the selective CB{sub 1} antagonist SR141716A. In MDA-MB-231 cells, a highly invasive human breast cancer cell line, and in TSA-E1 cells, a murine breast cancer cell line, Met-F-AEA inhibited adhesion and migration on type IV collagen in vitro without modifying integrin expression: both these effects were antagonized by SR141716A. In order to understand the molecular mechanism involved in these processes, we analyzed the phosphorylation of FAK and Src, two tyrosine kinases involved in migration and adhesion. In Met-F-AEA-treated cells, we observed a decreased tyrosine phosphorylation of both FAK and Src, this effect being attenuated by SR141716A. We propose that CB{sub 1} receptor agonists inhibit tumor cell invasion and metastasis by modulating FAK phosphorylation, and that CB{sub 1} receptor activation might represent a novel therapeutic strategy to slow down the growth of breast carcinoma and to inhibit its metastatic diffusion in vivo.

  2. Actein Inhibits Cell Proliferation and Migration in Human Osteosarcoma

    PubMed Central

    Chen, Zhi; Wu, Jingdong; Guo, Qinghao

    2016-01-01

    Background Osteosarcoma is one of the most common malignant bone cancers worldwide. Although the traditional chemotherapies have made some progression in the past decades, the mortality of osteosarcoma in children and adolescent is very high. Herein, the role of actein in osteosarcoma was explored. Material/Methods Cell viability assay was performed in osteosarcoma cell lines 143B and U2OS. Colony formation analysis was included when cells were treated with different doses of actin. Cell cycle assay was conducted to further examine the role of actein. Cell apoptotic rate and the relative activities of caspase-3, caspase-8, and caspase-9 were detected in 143B and U2OS osteosarcoma cells. Moreover, transwell assays were used to explore the effects of actein on cell metastasis. Results Actein significantly inhibited osteosarcoma cell viability in a time- and dose-dependent manner. Actein also dramatically suppressed the colony formation ability in osteosarcoma143B and U2OS cells. It was revealed that osteosarcoma cells were arrested in G0/G1 phase in the cell cycle progression and induced to apoptosis by administration of actein. The activities of pro-apoptotic factors such as caspase-3 and caspase-9 were significantly increased by actein. Furthermore, administration of actein decreased cell migrated and invasive abilities in both 143B and U2OS cell lines. Conclusions Actein inhibits tumor growth by inducing cell apoptosis in osteosarcoma. The inhibitive roles of actein in cell proliferation, migration and invasion suggest that actein may serve as a potential therapeutic agent in the treatment of osteosarcoma. PMID:27173526

  3. Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration.

    PubMed

    Detaille, D; Vial, G; Borel, A-L; Cottet-Rouselle, C; Hallakou-Bozec, S; Bolze, S; Fouqueray, P; Fontaine, E

    2016-01-01

    Imeglimin is the first in a new class of oral glucose-lowering agents, having recently completed its phase 2b trial. As Imeglimin did show a full prevention of β-cell apoptosis, and since angiopathy represents a major complication of diabetes, we studied Imeglimin protective effects on hyperglycemia-induced death of human endothelial cells (HMEC-1). These cells were incubated in several oxidative stress environments (exposure to high glucose and oxidizing agent tert-butylhydroperoxide) which led to mitochondrial permeability transition pore (PTP) opening, cytochrome c release and cell death. These events were fully prevented by Imeglimin treatment. This protective effect on cell death occurred without any effect on oxygen consumption rate, on lactate production and on cytosolic redox or phosphate potentials. Imeglimin also dramatically decreased reactive oxygen species production, inhibiting specifically reverse electron transfer through complex I. We conclude that Imeglimin prevents hyperglycemia-induced cell death in HMEC-1 through inhibition of PTP opening without inhibiting mitochondrial respiration nor affecting cellular energy status. Considering the high prevalence of macrovascular and microvascular complications in type 2 diabetic subjects, these results together suggest a potential benefit of Imeglimin in diabetic angiopathy. PMID:27551496

  4. Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration

    PubMed Central

    Detaille, D; Vial, G; Borel, A-L; Cottet-Rouselle, C; Hallakou-Bozec, S; Bolze, S; Fouqueray, P; Fontaine, E

    2016-01-01

    Imeglimin is the first in a new class of oral glucose-lowering agents, having recently completed its phase 2b trial. As Imeglimin did show a full prevention of β-cell apoptosis, and since angiopathy represents a major complication of diabetes, we studied Imeglimin protective effects on hyperglycemia-induced death of human endothelial cells (HMEC-1). These cells were incubated in several oxidative stress environments (exposure to high glucose and oxidizing agent tert-butylhydroperoxide) which led to mitochondrial permeability transition pore (PTP) opening, cytochrome c release and cell death. These events were fully prevented by Imeglimin treatment. This protective effect on cell death occurred without any effect on oxygen consumption rate, on lactate production and on cytosolic redox or phosphate potentials. Imeglimin also dramatically decreased reactive oxygen species production, inhibiting specifically reverse electron transfer through complex I. We conclude that Imeglimin prevents hyperglycemia-induced cell death in HMEC-1 through inhibition of PTP opening without inhibiting mitochondrial respiration nor affecting cellular energy status. Considering the high prevalence of macrovascular and microvascular complications in type 2 diabetic subjects, these results together suggest a potential benefit of Imeglimin in diabetic angiopathy. PMID:27551496

  5. Ribavirin Inhibits Parrot Bornavirus 4 Replication in Cell Culture

    PubMed Central

    Musser, Jeffrey M. B.; Heatley, J. Jill; Koinis, Anastasia V.; Suchodolski, Paulette F.; Guo, Jianhua; Escandon, Paulina; Tizard, Ian R.

    2015-01-01

    Parrot bornavirus 4 is an etiological agent of proventricular dilatation disease, a fatal neurologic and gastrointestinal disease of psittacines and other birds. We tested the ability of ribavirin, an antiviral nucleoside analog with antiviral activity against a range of RNA and DNA viruses, to inhibit parrot bornavirus 4 replication in duck embryonic fibroblast cells. Two analytical methods that evaluate different products of viral replication, indirect immunocytochemistry for viral specific nucleoprotein and qRT-PCR for viral specific phosphoprotein gene mRNA, were used. Ribavirin at concentrations between 2.5 and 25 μg/mL inhibited parrot bornavirus 4 replication, decreasing viral mRNA and viral protein load, in infected duck embryonic fibroblast cells. The addition of guanosine diminished the antiviral activity of ribavirin suggesting that one possible mechanism of action against parrot bornavirus 4 may likely be through inosine monophosphate dehydrogenase inhibition. This study demonstrates parrot bornavirus 4 susceptibility to ribavirin in cell culture. PMID:26222794

  6. Ribavirin Inhibits Parrot Bornavirus 4 Replication in Cell Culture.

    PubMed

    Musser, Jeffrey M B; Heatley, J Jill; Koinis, Anastasia V; Suchodolski, Paulette F; Guo, Jianhua; Escandon, Paulina; Tizard, Ian R

    2015-01-01

    Parrot bornavirus 4 is an etiological agent of proventricular dilatation disease, a fatal neurologic and gastrointestinal disease of psittacines and other birds. We tested the ability of ribavirin, an antiviral nucleoside analog with antiviral activity against a range of RNA and DNA viruses, to inhibit parrot bornavirus 4 replication in duck embryonic fibroblast cells. Two analytical methods that evaluate different products of viral replication, indirect immunocytochemistry for viral specific nucleoprotein and qRT-PCR for viral specific phosphoprotein gene mRNA, were used. Ribavirin at concentrations between 2.5 and 25 μg/mL inhibited parrot bornavirus 4 replication, decreasing viral mRNA and viral protein load, in infected duck embryonic fibroblast cells. The addition of guanosine diminished the antiviral activity of ribavirin suggesting that one possible mechanism of action against parrot bornavirus 4 may likely be through inosine monophosphate dehydrogenase inhibition. This study demonstrates parrot bornavirus 4 susceptibility to ribavirin in cell culture.

  7. Measles Virus Matrix Protein Inhibits Host Cell Transcription.

    PubMed

    Yu, Xuelian; Shahriari, Shadi; Li, Hong-Mei; Ghildyal, Reena

    2016-01-01

    Measles virus (MeV) is a highly contagious virus that still causes annual epidemics in developing countries despite the availability of a safe and effective vaccine. Additionally, importation from endemic countries causes frequent outbreaks in countries where it has been eliminated. The M protein of MeV plays a key role in virus assembly and cytopathogenesis; interestingly, M is localised in nucleus, cytoplasm and membranes of infected cells. We have used transient expression of M in transfected cells and in-cell transcription assays to show that only some MeV M localizes to the nucleus, in addition to cell membranes and the cytoplasm as previously described, and can inhibit cellular transcription via binding to nuclear factors. Additionally, MeV M was able to inhibit in vitro transcription in a dose-dependent manner. Importantly, a proportion of M is also localized to nucleus of MeV infected cells at early times in infection, correlating with inhibition of cellular transcription. Our data show, for the first time, that MeV M may play a role early in infection by inhibiting host cell transcription. PMID:27551716

  8. Measles Virus Matrix Protein Inhibits Host Cell Transcription

    PubMed Central

    Yu, Xuelian; Shahriari, Shadi; Li, Hong-Mei; Ghildyal, Reena

    2016-01-01

    Measles virus (MeV) is a highly contagious virus that still causes annual epidemics in developing countries despite the availability of a safe and effective vaccine. Additionally, importation from endemic countries causes frequent outbreaks in countries where it has been eliminated. The M protein of MeV plays a key role in virus assembly and cytopathogenesis; interestingly, M is localised in nucleus, cytoplasm and membranes of infected cells. We have used transient expression of M in transfected cells and in-cell transcription assays to show that only some MeV M localizes to the nucleus, in addition to cell membranes and the cytoplasm as previously described, and can inhibit cellular transcription via binding to nuclear factors. Additionally, MeV M was able to inhibit in vitro transcription in a dose-dependent manner. Importantly, a proportion of M is also localized to nucleus of MeV infected cells at early times in infection, correlating with inhibition of cellular transcription. Our data show, for the first time, that MeV M may play a role early in infection by inhibiting host cell transcription. PMID:27551716

  9. Quinotrierixin inhibits proliferation of human retinal pigment epithelial cells

    PubMed Central

    Chen, Chen; Wang, Joshua J.; Li, Jingming; Yu, Qiang

    2013-01-01

    Purpose To investigate the effect of quinotrierixin, a previously reported inhibitor of X-box binding protein 1 (XBP1), on cell proliferation and viability in human retinal pigment epithelium (RPE) cells. Methods Subconfluent human RPE cells (ARPE-19) were exposed to quinotrierixin for 16–24 h. Cell proliferation was determined with 3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay, hemocytometer counts, and CyQUANT NF Cell Proliferation Assay. Apoptosis was detected with terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end labeling assay. XBP1 mRNA splicing and expression of endoplasmic reticulum stress response genes were determined in cells exposed to thapsigargin in the presence or absence of quinotrierixin. Overexpression of spliced XBP1 was achieved with adenovirus. Results Quinotrierixin reduced RPE cell proliferation in a dose-dependent manner without inducing apoptosis. In cells exposed to thapsigargin, quinotrierixin inhibited XBP1 mRNA splicing and PKR-like endoplasmic reticulum kinase activation, and reduced cellular and nuclear levels of spliced XBP1 and C/EBP homologous protein. Paradoxically, quinotrierixin exacerbated endoplasmic reticulum stress-induced phosphorylation of eIF2α, which in turn led to decreased protein translation. Overexpressing spliced XBP1 partially reversed the inhibition of cell proliferation by quinotrierixin. These results suggest that inhibiting XBP1 splicing contributes to quinotrierixin’s negative effect on RPE cell proliferation, but other mechanisms such as reduction of protein translation are also involved. Conclusions Quinotrierixin inhibits RPE cell proliferation and may be used as a novel antiproliferative drug for treating proliferative vitreoretinopathy. Future studies are needed to investigate the in vivo effect of quinotrierixin on RPE proliferation in animal models of proliferative vitreoretinopathy. PMID:23335849

  10. Inhibition of cytokine production by a tumor cell product.

    PubMed Central

    Farram, E; Nelson, M; Nelson, D S; Moon, D K

    1982-01-01

    Supernatants from cultured mouse and human tumour cells, but not mouse or guinea-pig fibroblasts, inhibited the production of a lymphokine, macrophage chemotactic factor, by PHA-stimulated mouse spleen cells. The supernatants affected spleen cells from old, but not young, mice. They were most active if added at the start of the spleen cell culture and did not act by binding phytohaemagglutinin (PHA). The active material had an approximate molecular weight, on membrane filtration, of 1000-10,000 and could be bound to and eluted from Con A-Sepharose. Tumour supernatant factor(s) of similar molecular weight inhibited the production of interleukin 1 (lymphocyte activating factor) in response to lipopolysaccharide by stimulated thioglycollate-induced peritoneal exudate macrophages, but not by Corynebacterium parvum-activated macrophages. Similar tumour-produced material has been found to inhibit the early phase of delayed-type hypersensitivity reactions in older mice. It is suggested that this effect is due, at least in part, to inhibition of interleukin 1 production leading to inhibition of lymphokine production. PMID:7047385

  11. Lutein inhibits the migration of retinal pigment epithelial cells via cytosolic and mitochondrial Akt pathways (lutein inhibits RPE cells migration).

    PubMed

    Su, Ching-Chieh; Chan, Chi-Ming; Chen, Han-Min; Wu, Chia-Chun; Hsiao, Chien-Yu; Lee, Pei-Lan; Lin, Victor Chia-Hsiang; Hung, Chi-Feng

    2014-08-08

    During the course of proliferative vitreoretinopathy (PVR), the retinal pigment epithelium (RPE) cells will de-differentiate, proliferate, and migrate onto the surfaces of the sensory retina. Several studies have shown that platelet-derived growth factor (PDGF) can induce migration of RPE cells via an Akt-related pathway. In this study, the effect of lutein on PDGF-BB-induced RPE cells migration was examined using transwell migration assays and Western blot analyses. We found that both phosphorylation of Akt and mitochondrial translocation of Akt in RPE cells induced by PDGF-BB stimulation were suppressed by lutein. Furthermore, the increased migration observed in RPE cells with overexpressed mitochondrial Akt could also be suppressed by lutein. Our results demonstrate that lutein can inhibit PDGF-BB induced RPE cells migration through the inhibition of both cytoplasmic and mitochondrial Akt activation.

  12. Complications from carcinoid syndrome: review of the current evidence

    PubMed Central

    Mota, José Mauricio; Sousa, Luana Guimarães; Riechelmann, Rachel P

    2016-01-01

    Patients with well-differentiated neuroendocrine tumours may develop carcinoid syndrome (CS), which is characterised by flushing, abdominal cramps, diarrhoea, and bronchospasms. In this scenario, long-term secretion of vasoactive substances—serotonin, tachynins, and others, may induce fibrogenic responses in local or distant tissues, leading to complications such as carcinoid heart disease (CHD), mesenteric and/or retroperitoneal fibrosis. Rare cases of lung/pleural fibrosis and scleroderma have also been described. Despite it not being well described yet, current evidence suggests the pathogenesis of such fibrogenic complications relies on signalling through 5-HT2B and TGF-β1. Medical management is still very limited and lacks prospective and randomised studies for definitive recommendations. Surgical procedures remain the best definitive treatment option for CHD and abdominal fibrosis. Recently, cognitive impairment has also been described as a potential consequence of CS. This review critically discusses the literature concerning the epidemiology, pathogenesis, clinical features, diagnosis, and treatment options for CS-related long-term complications. PMID:27594907

  13. Complications from carcinoid syndrome: review of the current evidence

    PubMed Central

    Mota, José Mauricio; Sousa, Luana Guimarães; Riechelmann, Rachel P

    2016-01-01

    Patients with well-differentiated neuroendocrine tumours may develop carcinoid syndrome (CS), which is characterised by flushing, abdominal cramps, diarrhoea, and bronchospasms. In this scenario, long-term secretion of vasoactive substances—serotonin, tachynins, and others, may induce fibrogenic responses in local or distant tissues, leading to complications such as carcinoid heart disease (CHD), mesenteric and/or retroperitoneal fibrosis. Rare cases of lung/pleural fibrosis and scleroderma have also been described. Despite it not being well described yet, current evidence suggests the pathogenesis of such fibrogenic complications relies on signalling through 5-HT2B and TGF-β1. Medical management is still very limited and lacks prospective and randomised studies for definitive recommendations. Surgical procedures remain the best definitive treatment option for CHD and abdominal fibrosis. Recently, cognitive impairment has also been described as a potential consequence of CS. This review critically discusses the literature concerning the epidemiology, pathogenesis, clinical features, diagnosis, and treatment options for CS-related long-term complications.

  14. Complications from carcinoid syndrome: review of the current evidence.

    PubMed

    Mota, José Mauricio; Sousa, Luana Guimarães; Riechelmann, Rachel P

    2016-01-01

    Patients with well-differentiated neuroendocrine tumours may develop carcinoid syndrome (CS), which is characterised by flushing, abdominal cramps, diarrhoea, and bronchospasms. In this scenario, long-term secretion of vasoactive substances-serotonin, tachynins, and others, may induce fibrogenic responses in local or distant tissues, leading to complications such as carcinoid heart disease (CHD), mesenteric and/or retroperitoneal fibrosis. Rare cases of lung/pleural fibrosis and scleroderma have also been described. Despite it not being well described yet, current evidence suggests the pathogenesis of such fibrogenic complications relies on signalling through 5-HT2B and TGF-β1. Medical management is still very limited and lacks prospective and randomised studies for definitive recommendations. Surgical procedures remain the best definitive treatment option for CHD and abdominal fibrosis. Recently, cognitive impairment has also been described as a potential consequence of CS. This review critically discusses the literature concerning the epidemiology, pathogenesis, clinical features, diagnosis, and treatment options for CS-related long-term complications. PMID:27594907

  15. Regulatory T cells inhibit CD34+ cell differentiation into NK cells by blocking their proliferation

    PubMed Central

    Pedroza-Pacheco, Isabela; Shah, Divya; Domogala, Anna; Luevano, Martha; Blundell, Michael; Jackson, Nicola; Thrasher, Adrian; Madrigal, Alejandro; Saudemont, Aurore

    2016-01-01

    Graft versus Host Disease (GvHD) remains one of the main complications after hematopoietic stem cell transplantation (HSCT). Due to their ability to suppress effector cells, regulatory T cells (Tregs) have been proposed as a cellular therapy to prevent GvHD, however they also inhibit the functions of natural killer (NK) cells, key effectors of the Graft versus Leukemia effect. In this study, we have explored whether a Tregs therapy will also impact on NK cell differentiation. Using an in vitro model of hematopoietic stem cell (HSC) differentiation into NK cells, we found that activated Tregs led to a 90% reduction in NK cell numbers when added at the time of commitment to the NK cell lineage. This effect was contact dependent and was reversible upon Tregs depletion. The few NK cells that developed in these cultures were mature and exhibited normal functions. Furthermore, adoptive transfer of activated Tregs in rag-/- γc-/- mice abrogated HSC differentiation into NK cells thus confirming our in vitro findings. Collectively, these results demonstrate for the first time that activated Tregs can inhibit NK cell differentiation from HSC under specific conditions. PMID:26915707

  16. Pirin inhibits cellular senescence in melanocytic cells.

    PubMed

    Licciulli, Silvia; Luise, Chiara; Scafetta, Gaia; Capra, Maria; Giardina, Giuseppina; Nuciforo, Paolo; Bosari, Silvano; Viale, Giuseppe; Mazzarol, Giovanni; Tonelli, Chiara; Lanfrancone, Luisa; Alcalay, Myriam

    2011-05-01

    Cellular senescence has been widely recognized as a tumor suppressing mechanism that acts as a barrier to cancer development after oncogenic stimuli. A prominent in vivo model of the senescence barrier is represented by nevi, which are composed of melanocytes that, after an initial phase of proliferation induced by activated oncogenes (most commonly BRAF), are blocked in a state of cellular senescence. Transformation to melanoma occurs when genes involved in controlling senescence are mutated or silenced and cells reacquire the capacity to proliferate. Pirin (PIR) is a highly conserved nuclear protein that likely functions as a transcriptional regulator whose expression levels are altered in different types of tumors. We analyzed the expression pattern of PIR in adult human tissues and found that it is expressed in melanocytes and has a complex pattern of regulation in nevi and melanoma: it is rarely detected in mature nevi, but is expressed at high levels in a subset of melanomas. Loss of function and overexpression experiments in normal and transformed melanocytic cells revealed that PIR is involved in the negative control of cellular senescence and that its expression is necessary to overcome the senescence barrier. Our results suggest that PIR may have a relevant role in melanoma progression. PMID:21514450

  17. Pirin Inhibits Cellular Senescence in Melanocytic Cells

    PubMed Central

    Licciulli, Silvia; Luise, Chiara; Scafetta, Gaia; Capra, Maria; Giardina, Giuseppina; Nuciforo, Paolo; Bosari, Silvano; Viale, Giuseppe; Mazzarol, Giovanni; Tonelli, Chiara; Lanfrancone, Luisa; Alcalay, Myriam

    2011-01-01

    Cellular senescence has been widely recognized as a tumor suppressing mechanism that acts as a barrier to cancer development after oncogenic stimuli. A prominent in vivo model of the senescence barrier is represented by nevi, which are composed of melanocytes that, after an initial phase of proliferation induced by activated oncogenes (most commonly BRAF), are blocked in a state of cellular senescence. Transformation to melanoma occurs when genes involved in controlling senescence are mutated or silenced and cells reacquire the capacity to proliferate. Pirin (PIR) is a highly conserved nuclear protein that likely functions as a transcriptional regulator whose expression levels are altered in different types of tumors. We analyzed the expression pattern of PIR in adult human tissues and found that it is expressed in melanocytes and has a complex pattern of regulation in nevi and melanoma: it is rarely detected in mature nevi, but is expressed at high levels in a subset of melanomas. Loss of function and overexpression experiments in normal and transformed melanocytic cells revealed that PIR is involved in the negative control of cellular senescence and that its expression is necessary to overcome the senescence barrier. Our results suggest that PIR may have a relevant role in melanoma progression. PMID:21514450

  18. TACE (ADAM17) inhibits Schwann cell myelination.

    PubMed

    La Marca, Rosa; Cerri, Federica; Horiuchi, Keisuke; Bachi, Angela; Feltri, M Laura; Wrabetz, Lawrence; Blobel, Carl P; Quattrini, Angelo; Salzer, James L; Taveggia, Carla

    2011-06-12

    Tumor necrosis factor-α-converting enzyme (TACE; also known as ADAM17) is a proteolytic sheddase that is responsible for the cleavage of several membrane-bound molecules. We report that TACE cleaves neuregulin-1 (NRG1) type III in the epidermal growth factor domain, probably inactivating it (as assessed by deficient activation of the phosphatidylinositol-3-OH kinase pathway), and thereby negatively regulating peripheral nervous system (PNS) myelination. Lentivirus-mediated knockdown of TACE in vitro in dorsal root ganglia neurons accelerates the onset of myelination and results in hypermyelination. In agreement, motor neurons of conditional knockout mice lacking TACE specifically in these cells are significantly hypermyelinated, and small-caliber fibers are aberrantly myelinated. Further, reduced TACE activity rescues hypomyelination in NRG1 type III haploinsufficient mice in vivo. We also show that the inhibitory effect of TACE is neuron-autonomous, as Schwann cells lacking TACE elaborate myelin of normal thickness. Thus, TACE is a modulator of NRG1 type III activity and is a negative regulator of myelination in the PNS.

  19. Prolonged cyclic strain inhibits human endothelial cell growth.

    PubMed

    Peyton, Kelly J; Liu, Xiao-ming; Durante, William

    2016-01-01

    The vascular endothelium is continuously exposed to cyclic mechanical strain due to the periodic change in vessel diameter as a result of pulsatile blood flow. Since emerging evidence indicates the cyclic strain plays an integral role in regulating endothelial cell function, the present study determined whether application of a physiologic regimen of cyclic strain (6% at 1 hertz) influences the proliferation of human arterial endothelial cells. Prolonged exposure of human dermal microvascular or human aortic endothelial cells to cyclic strain for up to 7 days resulted in a marked decrease in cell growth. The strain-mediated anti-proliferative effect was associated with the arrest of endothelial cells in the G2/M phase of the cell cycle, did not involve cell detachment or cytotoxicity, and was due to the induction of p21. Interestingly, the inhibition in endothelial cell growth was independent of the strain regimen since prolonged application of constant or intermittent 6% strain was also able to block endothelial cell proliferation. The ability of chronic physiologic cyclic strain to inhibit endothelial cell growth represents a previously unrecognized mechanism by which hemodynamic forces maintain these cells in a quiescent, non-proliferative state. PMID:26709656

  20. Sphingosylphosphorylcholine inhibits macrophage adhesion to vascular smooth muscle cells.

    PubMed

    Wirrig, Christiane; McKean, Jenny S; Wilson, Heather M; Nixon, Graeme F

    2016-09-01

    Inflammation in de-endothelialised arteries contributes to the development of cardiovascular diseases. The process that initiates this inflammatory response is the adhesion of monocytes/macrophages to exposed vascular smooth muscle cells, typically stimulated by cytokines such as tumour necrosis factor-α (TNF). The aim of this study was to determine the effect of the sphingolipid sphingosylphosphorylcholine (SPC) on the interaction of monocytes/macrophages with vascular smooth muscle cells. Rat aortic smooth muscle cells and rat bone marrow-derived macrophages were co-cultured using an in vitro assay following incubation with sphingolipids to assess inter-cellular adhesion. We reveal that SPC inhibits the TNF-induced adhesion of macrophages to smooth muscle cells. This anti-adhesive effect was the result of SPC-induced changes to the smooth muscle cells (but not the macrophages) and was mediated, at least partly, via the sphingosine 1-phosphate receptor subtype 2. Lipid raft domains were also required. Although SPC did not alter expression or membrane distribution of the adhesion proteins intercellular adhesion molecule-1 and vascular cellular adhesion protein-1 in smooth muscle cells, SPC preincubation inhibited the TNF-induced increase in inducible nitric oxide synthase (NOS2) resulting in a subsequent decrease in nitric oxide production. Inhibiting NOS2 activation in smooth muscle cells led to a decrease in the adhesion of macrophages to smooth muscle cells. This study has therefore delineated a novel pathway which can inhibit the interaction between macrophages and vascular smooth muscle cells via SPC-induced repression of NOS2 expression. This mechanism could represent a potential drug target in vascular disease.

  1. Inhibition of rhotekin exhibits antitumor effects in lung cancer cells

    PubMed Central

    ZHANG, WEIZHEN; LIANG, ZHENYU; LI, JING

    2016-01-01

    Lung cancer is the leading cause for cancer-related death, however, the pathogenesis mechanism is poorly understood. Although the rhotekin (RTKN) gene has been reported to encode an effector for the Rho protein that has critical roles in regulating cell growth, the role of RTKN in lung cancer has not been investigated. In clinical lung cancer patient tumor samples, we identified that the RTKN gene expression level was significantly higher in tumor tissues compared to that of the adjacent normal tissues. To investigate the molecular mechanisms of RTKN in lung cancer, we established RTKN stable knock-down A549 and SPC-A-1 lung adenocarcinoma cell lines using lentiviral transfection of RTKN shRNA and evaluated the antitumor effects. The results showed that RTKN knock-down inhibited lung adenocarcinoma cell viability, induced S phase arrest and increased cell apoptosis. In addition, RTKN knock-down inhibited lung cancer cell invasion and adhesion. Further analysis showed that the S phase promoting factors cyclindependent kinase (CDK)1 and CDK2 levels were decreased in RTKN knock-down cells, and that the DNA replication initiation complex proteins Minichromosome maintenance protein complex (MCM)2 and MCM6 were decreased as well in RTKN knock-down cells. These results indicated that the RTKN protein was associated with lung cancer in clinic samples and exerted anticancer activity in lung adenocarcinoma cells through inhibiting cell cycle progression and the DNA replication machinery. These findings suggest that RTKN inhibition may be a novel therapeutic strategy for lung adenocarcinoma. PMID:26935528

  2. Sphingosylphosphorylcholine inhibits macrophage adhesion to vascular smooth muscle cells.

    PubMed

    Wirrig, Christiane; McKean, Jenny S; Wilson, Heather M; Nixon, Graeme F

    2016-09-01

    Inflammation in de-endothelialised arteries contributes to the development of cardiovascular diseases. The process that initiates this inflammatory response is the adhesion of monocytes/macrophages to exposed vascular smooth muscle cells, typically stimulated by cytokines such as tumour necrosis factor-α (TNF). The aim of this study was to determine the effect of the sphingolipid sphingosylphosphorylcholine (SPC) on the interaction of monocytes/macrophages with vascular smooth muscle cells. Rat aortic smooth muscle cells and rat bone marrow-derived macrophages were co-cultured using an in vitro assay following incubation with sphingolipids to assess inter-cellular adhesion. We reveal that SPC inhibits the TNF-induced adhesion of macrophages to smooth muscle cells. This anti-adhesive effect was the result of SPC-induced changes to the smooth muscle cells (but not the macrophages) and was mediated, at least partly, via the sphingosine 1-phosphate receptor subtype 2. Lipid raft domains were also required. Although SPC did not alter expression or membrane distribution of the adhesion proteins intercellular adhesion molecule-1 and vascular cellular adhesion protein-1 in smooth muscle cells, SPC preincubation inhibited the TNF-induced increase in inducible nitric oxide synthase (NOS2) resulting in a subsequent decrease in nitric oxide production. Inhibiting NOS2 activation in smooth muscle cells led to a decrease in the adhesion of macrophages to smooth muscle cells. This study has therefore delineated a novel pathway which can inhibit the interaction between macrophages and vascular smooth muscle cells via SPC-induced repression of NOS2 expression. This mechanism could represent a potential drug target in vascular disease. PMID:27402344

  3. Inhibition of REST Suppresses Proliferation and Migration in Glioblastoma Cells.

    PubMed

    Zhang, Dianbao; Li, Ying; Wang, Rui; Li, Yunna; Shi, Ping; Kan, Zhoumi; Pang, Xining

    2016-01-01

    Glioblastoma (GBM) is the most common primary brain tumor, with poor prognosis and a lack of effective therapeutic options. The aberrant expression of transcription factor REST (repressor element 1-silencing transcription factor) had been reported in different kinds of tumors. However, the function of REST and its mechanisms in GBM remain elusive. Here, REST expression was inhibited by siRNA silencing in U-87 and U-251 GBM cells. Then CCK-8 assay showed significantly decreased cell proliferation, and the inhibition of migration was verified by scratch wound healing assay and transwell assay. Using cell cycle analysis and Annexin V/PI straining assay, G1 phase cell cycle arrest was found to be a reason for the suppression of cell proliferation and migration upon REST silencing, while apoptosis was not affected by REST silencing. Further, the detection of REST-downstream genes involved in cytostasis and migration inhibition demonstrated that CCND1 and CCNE1 were reduced; CDK5R1, BBC3, EGR1, SLC25A4, PDCD7, MAPK11, MAPK12, FADD and DAXX were enhanced, among which BBC3 and DAXX were direct targets of REST, as verified by ChIP (chromatin immunoprecipitation) and Western blotting. These data suggested that REST is a master regulator that maintains GBM cells proliferation and migration, partly through regulating cell cycle by repressing downstream genes, which might represent a potential target for GBM therapy. PMID:27153061

  4. Inhibition of REST Suppresses Proliferation and Migration in Glioblastoma Cells

    PubMed Central

    Zhang, Dianbao; Li, Ying; Wang, Rui; Li, Yunna; Shi, Ping; Kan, Zhoumi; Pang, Xining

    2016-01-01

    Glioblastoma (GBM) is the most common primary brain tumor, with poor prognosis and a lack of effective therapeutic options. The aberrant expression of transcription factor REST (repressor element 1-silencing transcription factor) had been reported in different kinds of tumors. However, the function of REST and its mechanisms in GBM remain elusive. Here, REST expression was inhibited by siRNA silencing in U-87 and U-251 GBM cells. Then CCK-8 assay showed significantly decreased cell proliferation, and the inhibition of migration was verified by scratch wound healing assay and transwell assay. Using cell cycle analysis and Annexin V/PI straining assay, G1 phase cell cycle arrest was found to be a reason for the suppression of cell proliferation and migration upon REST silencing, while apoptosis was not affected by REST silencing. Further, the detection of REST-downstream genes involved in cytostasis and migration inhibition demonstrated that CCND1 and CCNE1 were reduced; CDK5R1, BBC3, EGR1, SLC25A4, PDCD7, MAPK11, MAPK12, FADD and DAXX were enhanced, among which BBC3 and DAXX were direct targets of REST, as verified by ChIP (chromatin immunoprecipitation) and Western blotting. These data suggested that REST is a master regulator that maintains GBM cells proliferation and migration, partly through regulating cell cycle by repressing downstream genes, which might represent a potential target for GBM therapy. PMID:27153061

  5. Pumpkin seed extract: Cell growth inhibition of hyperplastic and cancer cells, independent of steroid hormone receptors.

    PubMed

    Medjakovic, Svjetlana; Hobiger, Stefanie; Ardjomand-Woelkart, Karin; Bucar, Franz; Jungbauer, Alois

    2016-04-01

    Pumpkin seeds have been known in folk medicine as remedy for kidney, bladder and prostate disorders since centuries. Nevertheless, pumpkin research provides insufficient data to back up traditional beliefs of ethnomedical practice. The bioactivity of a hydro-ethanolic extract of pumpkin seeds from the Styrian pumpkin, Cucurbita pepo L. subsp. pepo var. styriaca, was investigated. As pumpkin seed extracts are standardized to cucurbitin, this compound was also tested. Transactivational activity was evaluated for human androgen receptor, estrogen receptor and progesterone receptor with in vitro yeast assays. Cell viability tests with prostate cancer cells, breast cancer cells, colorectal adenocarcinoma cells and a hyperplastic cell line from benign prostate hyperplasia tissue were performed. As model for non-hyperplastic cells, effects on cell viability were tested with a human dermal fibroblast cell line (HDF-5). No transactivational activity was found for human androgen receptor, estrogen receptor and progesterone receptor, for both, extract and cucurbitin. A cell growth inhibition of ~40-50% was observed for all cell lines, with the exception of HDF-5, which showed with ~20% much lower cell growth inhibition. Given the receptor status of some cell lines, a steroid-hormone receptor independent growth inhibiting effect can be assumed. The cell growth inhibition for fast growing cells together with the cell growth inhibition of prostate-, breast- and colon cancer cells corroborates the ethnomedical use of pumpkin seeds for a treatment of benign prostate hyperplasia. Moreover, due to the lack of androgenic activity, pumpkin seed applications can be regarded as safe for the prostate.

  6. Fungal Cell Wall Septation and Cytokinesis Are Inhibited by Bleomycins

    PubMed Central

    Moore, Carol W.; McKoy, Judith; Del Valle, Robert; Armstrong, Donald; Bernard, Edward M.; Katz, Norman; Gordon, Ronald E.

    2003-01-01

    When the essential and distinctive cell walls of either pathogenic or nonpathogenic fungi break, cytoplasmic membranes rupture and fungi die. This fungicidal activity was discovered previously on nonproliferating Saccharomyces cerevisiae cells treated briefly with the oxidative tool and anticancer drug family of bleomycins. The present studies investigated effects of bleomycin on growing fungal organisms. These included the medically important Aspergillus fumigatus and Cryptococcus neoformans, as well as the emerging human pathogen and fungal model, S. cerevisiae. Bleomycin had its highest potency against A. fumigatus. Scanning electron microscopy and thin-section transmission electron microscopy were used to study morphological growth characteristics. Killing and growth inhibition were also measured. Long, thin, and segmented hyphae were observed when A. fumigatus was grown without bleomycin but were never observed when the mold was grown with the drug. Bleomycin arrested conidial germination, hyphal development, and the progression and completion of cell wall septation. Similarly, the drug inhibited the construction of yeast cell wall septa, preventing cytokinesis and progression in the cell division cycle of S. cerevisiae. Even when cytoplasms of mother and daughter cells separated, septation and cell division did not necessarily occur. Bizarre cell configurations, abnormally thickened cell walls at mother-daughter necks, abnormal polarized growth, large undivided cells, fragmented cells, and empty cell ghosts were also produced. This is the first report of a fungicidal agent that arrests fungal growth and development, septum formation, and cytokinesis and that also preferentially localizes to cell walls and alters isolated cell walls as well as intact cell walls on nongrowing cells. PMID:14506042

  7. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3.

    PubMed

    Nelson, Erik A; Walker, Sarah R; Kepich, Alicia; Gashin, Laurie B; Hideshima, Teru; Ikeda, Hiroshi; Chauhan, Dharminder; Anderson, Kenneth C; Frank, David A

    2008-12-15

    Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126. Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival. PMID:18824601

  8. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3

    PubMed Central

    Nelson, Erik A.; Walker, Sarah R.; Kepich, Alicia; Gashin, Laurie B.; Hideshima, Teru; Ikeda, Hiroshi; Chauhan, Dharminder; Anderson, Kenneth C.

    2008-01-01

    Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126. Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival. PMID:18824601

  9. Cell-Cycle Inhibition by Helicobacter pylori L-Asparaginase

    PubMed Central

    Scotti, Claudia; Sommi, Patrizia; Pasquetto, Maria Valentina; Cappelletti, Donata; Stivala, Simona; Mignosi, Paola; Savio, Monica; Chiarelli, Laurent Roberto; Valentini, Giovanna; Bolanos-Garcia, Victor M.; Merrell, Douglas Scott; Franchini, Silvia; Verona, Maria Luisa; Bolis, Cristina; Solcia, Enrico; Manca, Rachele; Franciotta, Diego; Casasco, Andrea; Filipazzi, Paola; Zardini, Elisabetta; Vannini, Vanio

    2010-01-01

    Helicobacter pylori (H. pylori) is a major human pathogen causing chronic gastritis, peptic ulcer, gastric cancer, and mucosa-associated lymphoid tissue lymphoma. One of the mechanisms whereby it induces damage depends on its interference with proliferation of host tissues. We here describe the discovery of a novel bacterial factor able to inhibit the cell-cycle of exposed cells, both of gastric and non-gastric origin. An integrated approach was adopted to isolate and characterise the molecule from the bacterial culture filtrate produced in a protein-free medium: size-exclusion chromatography, non-reducing gel electrophoresis, mass spectrometry, mutant analysis, recombinant protein expression and enzymatic assays. L-asparaginase was identified as the factor responsible for cell-cycle inhibition of fibroblasts and gastric cell lines. Its effect on cell-cycle was confirmed by inhibitors, a knockout strain and the action of recombinant L-asparaginase on cell lines. Interference with cell-cycle in vitro depended on cell genotype and was related to the expression levels of the concurrent enzyme asparagine synthetase. Bacterial subcellular distribution of L-asparaginase was also analysed along with its immunogenicity. H. pylori L-asparaginase is a novel antigen that functions as a cell-cycle inhibitor of fibroblasts and gastric cell lines. We give evidence supporting a role in the pathogenesis of H. pylori-related diseases and discuss its potential diagnostic application. PMID:21085483

  10. Indomethacin derivatives as tubulin stabilizers to inhibit cancer cell proliferation.

    PubMed

    Chennamaneni, Snigdha; Gan, Chunfang; Lama, Rati; Zhong, Bo; Su, Bin

    2016-01-15

    Cyclooxygenase (COX) inhibitor Indomethacin analogs exhibited more potent cancer cell growth inhibition and apoptosis inducing activities than the parental compound. The anti-proliferative mechanism investigation of the analogs revealed that they inhibited tubulin polymerization at high concentrations whereas enhanced polymerization at low concentrations. The two opposite activities might antagonize each other and impaired the anti-proliferative activity of the derivatives eventually. In this study, we further performed lead optimization based on the structure activity relationship (SAR) generated. One of the new Indomethacin derivatives compound 11 {2-(4-(benzyloxy)phenyl)-N-(1-(4-bromobenzoyl)-3-(2-((2-(dimethylamino)ethyl)amino)-2-oxoethyl)-2-methyl-1H-indol-5-yl)acetamide} inhibited the proliferation of a panel of cancer cell lines with IC50s at the sub-micromole levels. Further study revealed that the compound only enhanced tubulin polymerization and was a tubulin stabilizer.

  11. ATF3 inhibits PPARγ-stimulated transactivation in adipocyte cells

    SciTech Connect

    Jang, Min-Kyung; Jung, Myeong Ho

    2015-01-02

    Highlights: • ATF3 inhibits PPARγ-stimulated transcriptional activation. • ATF3 interacts with PPARγ. • ATF3 suppresses p300-mediated transcriptional coactivation. • ATF3 decreases the binding of PPARγ and recruitment of p300 to PPRE. - Abstract: Previously, we reported that activating transcription factor 3 (ATF3) downregulates peroxisome proliferator activated receptor (PPARγ) gene expression and inhibits adipocyte differentiation in 3T3-L1 cells. Here, we investigated another role of ATF3 on the regulation of PPARγ activity. ATF3 inhibited PPARγ-stimulated transactivation of PPARγ responsive element (PPRE)-containing reporter or GAL4/PPARγ chimeric reporter. Thus, ATF3 effectively repressed rosiglitazone-stimulated expression of adipocyte fatty acid binding protein (aP2), PPARγ target gene, in 3T3-L1 cells. Coimmunoprecipitation and GST pulldown assay demonstrated that ATF3 interacted with PPARγ. Accordingly, ATF3 prevented PPARγ from binding to PPRE on the aP2 promoter. Furthermore, ATF3 suppressed p300-mediated transcriptional coactivation of PPRE-containing reporter. Chromatin immunoprecipitation assay showed that overexpression of ATF3 blocked both binding of PPARγ and recruitment of p300 to PPRE on aP2 promoter induced by rosiglitazone treatment in 3T3-L1 cells. Taken together, these results suggest that ATF3 interacts with PPARγ and represses PPARγ-mediated transactivation through suppression of p300-stimulated coactivation in 3T3-L1 cells, which may play a role in inhibition of adipocyte differentiation.

  12. Lysyl oxidase propeptide inhibits smooth muscle cell signaling and proliferation

    SciTech Connect

    Hurtado, Paola A.; Vora, Siddharth; Sume, Siddika Selva; Yang, Dan; Hilaire, Cynthia St.; Guo Ying; Palamakumbura, Amitha H.; Schreiber, Barbara M.; Ravid, Katya; Trackman, Philip C.

    2008-02-01

    Lysyl oxidase is required for the normal biosynthesis and maturation of collagen and elastin. It is expressed by vascular smooth muscle cells, and its increased expression has been previously found in atherosclerosis and in models of balloon angioplasty. The lysyl oxidase propeptide (LOX-PP) has more recently been found to have biological activity as a tumor suppressor, and it inhibits Erk1/2 Map kinase activation. We reasoned that LOX-PP may have functions in normal non-transformed cells. We, therefore, investigated its effects on smooth muscle cells, focusing on important biological processes mediated by Erk1/2-dependent signaling pathways including proliferation and matrix metalloproteinase-9 (MMP-9) expression. In addition, we investigated whether evidence for accumulation of LOX-PP could be found in vivo in a femoral artery injury model. Recombinant LOX-PP was expressed and purified, and was found to inhibit primary rat aorta smooth muscle cell proliferation and DNA synthesis by more than 50%. TNF-{alpha}-stimulated MMP-9 expression and Erk1/2 activation were both significantly inhibited by LOX-PP. Immunohistochemistry studies carried out with affinity purified anti-LOX-PP antibody showed that LOX-PP epitopes were expressed at elevated levels in vascular lesions of injured arteries. These novel data suggest that LOX-PP may provide a feedback control mechanism that serves to inhibit properties associated with the development of vascular pathology.

  13. Chlorinated englerins with selective inhibition of renal cancer cell growth.

    PubMed

    Akee, Rhone K; Ransom, Tanya; Ratnayake, Ranjala; McMahon, James B; Beutler, John A

    2012-03-23

    The chlorinated englerins (3-9) were isolated from Phyllanthus engleri and shown to selectively inhibit the growth of renal cancer cells. The compounds were shown to be extraction artifacts produced by exposure to chloroform decomposition products during their isolation. The most active compound, 3, was synthesized from englerin A (1). PMID:22280462

  14. Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity

    SciTech Connect

    Nishida, Yoshihiro . E-mail: ynishida@med.nagoya-u.ac.jp; Knudson, Warren; Knudson, Cheryl B.; Ishiguro, Naoki

    2005-07-01

    Osteosarcoma is a common malignant bone tumor associated with childhood and adolescence. The results of numerous studies have suggested that hyaluronan plays an important role in regulating the aggressive behavior of various types of cancer cells. However, no studies have addressed hyaluronan with respect to osteosarcomas. In this investigation, the mRNA expression copy number of three mammalian hyaluronan synthases (HAS) was determined using competitive RT-PCR in the osteoblastic osteosarcoma cell line, MG-63. MG-63 are highly malignant osteosarcoma cells with an abundant hyaluronan-rich matrix. The results demonstrated that HAS-2 is the predominant HAS in MG-63. Accumulation of intracellular hyaluronan increased in association with the proliferative phase of these cells. The selective inhibition of HAS-2 mRNA in MG-63 cells by antisense phosphorothioate oligonucleotides resulted in reduced hyaluronan accumulation by these cells. As expected, the reduction in hyaluronan disrupted the assembly of cell-associated matrices. However, of most interest, coincident with the reduction in hyaluronan, there was a substantial decrease in cell proliferation, a decrease in cell motility and a decrease in cell invasiveness. These data suggest that hyaluronan synthesized by HAS-2 in MG-63 plays a crucial role in osteosarcoma cell proliferation, motility, and invasion.

  15. Tumores carcinoides gastrointestinales—Versión para profesionales de salud

    Cancer.gov

    Información del Instituto Nacional del Cáncer para profesionales de salud sobre el tratamiento del tumor carcinoide gastrointestinal, así como referencias a estudios clínicos y otros temas relacionados.

  16. Maduramicin Inhibits Proliferation and Induces Apoptosis in Myoblast Cells

    PubMed Central

    Chen, Xin; Gu, Ying; Singh, Karnika; Shang, Chaowei; Barzegar, Mansoureh; Jiang, Shanxiang; Huang, Shile

    2014-01-01

    Maduramicin, a polyether ionophore antibiotic derived from the bacterium Actinomadura yumaensis, is currently used as a feed additive against coccidiosis in poultry worldwide. It has been clinically observed that maduramicin can cause skeletal muscle and heart cell damage, resulting in skeletal muscle degeneration, heart failure, and even death in animals and humans, if improperly used. However, the mechanism of its toxic action in myoblasts is not well understood. Using mouse myoblasts (C2C12) and human rhabdomyosarcoma (RD and Rh30) cells as an experimental model for myoblasts, here we found that maduramicin inhibited cell proliferation and induced cell death in a concentration-dependent manner. Further studies revealed that maduramicin induced accumulation of the cells at G0/G1 phase of the cell cycle, and induced apoptosis in the cells. Concurrently, maduramicin downregulated protein expression of cyclin D1, cyclin-dependent kinases (CDK4 and CDK6), and CDC25A, and upregulated expression of the CDK inhibitors (p21Cip1 and p27Kip1), resulting in decreased phosphorylation of Rb. Maduramicin also induced expression of BAK, BAD, DR4, TRADD and TRAIL, leading to activation of caspases 8, 9 and 3 as well as cleavage of poly ADP ribose polymerase (PARP). Taken together, our results suggest that maduramicin executes its toxicity in myoblasts at least by inhibiting cell proliferation and inducing apoptotic cell death. PMID:25531367

  17. Metformin inhibits cell cycle progression of B-cell chronic lymphocytic leukemia cells.

    PubMed

    Bruno, Silvia; Ledda, Bernardetta; Tenca, Claudya; Ravera, Silvia; Orengo, Anna Maria; Mazzarello, Andrea Nicola; Pesenti, Elisa; Casciaro, Salvatore; Racchi, Omar; Ghiotto, Fabio; Marini, Cecilia; Sambuceti, Gianmario; DeCensi, Andrea; Fais, Franco

    2015-09-01

    B-cell chronic lymphocytic leukemia (CLL) was believed to result from clonal accumulation of resting apoptosis-resistant malignant B lymphocytes. However, it became increasingly clear that CLL cells undergo, during their life, iterative cycles of re-activation and subsequent clonal expansion. Drugs interfering with CLL cell cycle entry would be greatly beneficial in the treatment of this disease. 1, 1-Dimethylbiguanide hydrochloride (metformin), the most widely prescribed oral hypoglycemic agent, inexpensive and well tolerated, has recently received increased attention for its potential antitumor activity. We wondered whether metformin has apoptotic and anti-proliferative activity on leukemic cells derived from CLL patients. Metformin was administered in vitro either to quiescent cells or during CLL cell activation stimuli, provided by classical co-culturing with CD40L-expressing fibroblasts. At doses that were totally ineffective on normal lymphocytes, metformin induced apoptosis of quiescent CLL cells and inhibition of cell cycle entry when CLL were stimulated by CD40-CD40L ligation. This cytostatic effect was accompanied by decreased expression of survival- and proliferation-associated proteins, inhibition of signaling pathways involved in CLL disease progression and decreased intracellular glucose available for glycolysis. In drug combination experiments, metformin lowered the apoptotic threshold and potentiated the cytotoxic effects of classical and novel antitumor molecules. Our results indicate that, while CLL cells after stimulation are in the process of building their full survival and cycling armamentarium, the presence of metformin affects this process.

  18. Piperine inhibits cytokine production by human peripheral blood mononuclear cells.

    PubMed

    Chuchawankul, S; Khorana, N; Poovorawan, Y

    2012-01-01

    Piperine, an amide isolated from Piper species (Piperaceae), has been reported to exhibit central nervous system depression, anti-pyretic and anti-inflammatory activity. Immunomodulatory and anti-tumor activity of piperine has been demonstrated in mouse carcinomas. However, there is little information available concerning the effect of piperine on humans. We evaluated the immunopharmacological activity of this compound in human immune cells. Human peripheral blood mononuclear cells (PBMCs) were exposed to piperine, and cell proliferation was determined by the MTS assay. Piperine significantly inhibited phytohemagglutinin-stimulated human PBMC proliferation after exposure for 72 h. This compound inhibited PBMC activity, with an IC(50) of 100.73 ± 11.16 μg/mL. Production of interleukin-2 (IL-2) and interferon-γ (IFN-γ) was measured using an ELISA assay and RT-PCR. Piperine inhibited IL-2 and IFN-γ production in the PBMCs. RT-PCR data indicated that IL-2 and IFN-γ mRNA expression in PBMCs is suppressed by piperine. This compound significantly inhibited the production of these two cytokines by activated PBMCs in a dose-dependent manner. In conclusion, piperine appears to have potential as an immunomodulatory agent for immune system suppression. PMID:22535397

  19. Astaxanthin Inhibits Proliferation and Induces Apoptosis and Cell Cycle Arrest of Mice H22 Hepatoma Cells

    PubMed Central

    Shao, Yiye; Ni, Yanbo; Yang, Jing; Lin, Xutao; Li, Jun; Zhang, Lixia

    2016-01-01

    Background It is widely recognized that astaxanthin (ASX), a member of the carotenoid family, has strong biological activities including antioxidant, anti-inflammation, and immune-modulation activities. Previous studies have confirmed that ASX can effectively inhibit hepatoma cells in vitro. Material/Methods MTT was used to assay proliferation of mice H22 cells, and flow cytometry was used to determine apoptosis and cell cycle arrest of H22 cells in vitro and in vivo. Moreover, anti-tumor activity of ASX was observed in mice. Results ASX inhibited the proliferation of H22 cells, promoted cell necrosis, and induced cell cycle arrest in G2 phase in vitro and in vivo. Conclusions This study indicated that ASX can inhibit proliferation and induce apoptosis and cell cycle arrest in mice H22 hepatoma cells in vitro and in vivo. PMID:27333866

  20. Carbendazim Inhibits Cancer Cell Proliferation by Suppressing Microtubule Dynamics

    PubMed Central

    Yenjerla, Mythili; Cox, Corey; Wilson, Leslie; Jordan, Mary Ann

    2009-01-01

    Carbendazim (methyl 2-benzimidazolecarbamate) is widely used as a systemic fungicide in human food production and appears to act on fungal tubulin. However, it also inhibits proliferation of human cancer cells, including drug- and multidrug-resistant and p53-deficient cell lines. Because of its promising preclinical anti-tumor activity, it has undergone phase I clinical trials and is under further clinical development. Although it weakly inhibits polymerization of brain microtubules and induces G2/M arrest in tumor cells, its mechanism of action in human cells has not been fully elucidated. We examined its mechanism of action in MCF7 human breast cancer cells and found that it inhibits proliferation (IC50, 10 μM) and half-maximally arrests mitosis at a similar concentration (8 μM), in concert with suppression of microtubule dynamic instability without appreciable microtubule depolymerization. It induces mitotic spindle abnormalities and reduces the metaphase intercentromere distance of sister chromatids, indicating reduction of tension on kinetochores, thus leading to metaphase arrest. With microtubules assembled in vitro from pure tubulin, carbendazim also suppresses dynamic instability, reducing the dynamicity by 50% at 10 μM, with only minimal (21%) reduction of polymer mass. Carbendazim binds to mammalian tubulin (Kd, 42.8 ± 4.0 μM). Unlike some benzimidazoles that bind to the colchicine site in tubulin, carbendazim neither competes with colchicine nor competes with vinblastine for binding to brain tubulin. Thus, carbendazim binds to an as yet unidentified site in tubulin and inhibits tumor cell proliferation by suppressing the growing and shortening phases of microtubule dynamic instability, thus inducing mitotic arrest. PMID:19001156

  1. Contact inhibition of locomotion determines cell-cell and cell-substrate forces in tissues.

    PubMed

    Zimmermann, Juliane; Camley, Brian A; Rappel, Wouter-Jan; Levine, Herbert

    2016-03-01

    Cells organized in tissues exert forces on their neighbors and their environment. Those cellular forces determine tissue homeostasis as well as reorganization during embryonic development and wound healing. To understand how cellular forces are generated and how they can influence the tissue state, we develop a particle-based simulation model for adhesive cell clusters and monolayers. Cells are contractile, exert forces on their substrate and on each other, and interact through contact inhibition of locomotion (CIL), meaning that cell-cell contacts suppress force transduction to the substrate and propulsion forces align away from neighbors. Our model captures the traction force patterns of small clusters of nonmotile cells and larger sheets of motile Madin-Darby canine kidney (MDCK) cells. In agreement with observations in a spreading MDCK colony, the cell density in the center increases as cells divide and the tissue grows. A feedback between cell density, CIL, and cell-cell adhesion gives rise to a linear relationship between cell density and intercellular tensile stress and forces the tissue into a nonmotile state characterized by a broad distribution of traction forces. Our model also captures the experimentally observed tissue flow around circular obstacles, and CIL accounts for traction forces at the edge. PMID:26903658

  2. Estrogen inhibits cell cycle progression and retinoblastoma phosphorylation in rhesus ovarian surface epithelial cell culture

    SciTech Connect

    Wright, Jay W.; Stouffer, Richard L.; Rodland, Karin D.

    2003-10-31

    Estrogen promotes the growth of some ovarian cancer cells at nanomolar concentrations, but has been shown to inhibit growth of normal ovarian surface epithelial (OSE) cells at micromolar concentrations (1μg/ml). OSE cells express the estrogen receptor (ER)-α, and are the source of 90% of various cancers. The potential sensitivity of OSE cells to estrogen stresses the importance of understanding the estrogen-dependent mechanisms at play in OSE proliferation and transformation, as well as in anticancer treatment. We investigated the effects of estradiol on cell proliferation in vitro, and demonstrate an intracellular locus of action of estradiol in cultured rhesus ovarian surface epithelial (RhOSE) cells. We show that ovarian and breast cells are growth-inhibited by micromolar concentration of estradiol and that this inhibition correlates with estrogen receptor expression. We further show that normal rhesus OSE cells do not activate ERK or Akt in response to estradiol nor does estradiol block the ability of serum to stimulate ERK or induce cyclin D expression. Contrarily, estradiol inhibits serum-dependent retinoblastoma protein (Rb) phosphorylation and blocks DNA synthesis. This inhibition does not formally arrest cells and is reversible within hours of estrogen withdrawal. Our data are consistent with growth inhibition by activation of Rb and indicate that sensitivity to hormone therapy in anticancer treatment can be modulated by cell cycle regulators downstream of the estrogen receptor.

  3. Apigenin inhibits pancreatic cancer cell proliferation through G2/M cell cycle arrest

    PubMed Central

    Ujiki, Michael B; Ding, Xian-Zhong; Salabat, M Reza; Bentrem, David J; Golkar, Laleh; Milam, Ben; Talamonti, Mark S; Bell, Richard H; Iwamura, Takeshi; Adrian, Thomas E

    2006-01-01

    Background Many chemotherapeutic agents have been used to treat pancreatic cancer without success. Apigenin, a naturally occurring flavonoid, has been shown to inhibit growth in some cancer cell lines but has not been studied in pancreatic cancer. We hypothesized that apigenin would inhibit pancreatic cancer cell growth in vitro. Results Apigenin caused both time- and concentration-dependent inhibition of DNA synthesis and cell proliferation in four pancreatic cancer cell lines. Apigenin induced G2/M phase cell cycle arrest. Apigenin reduced levels of cyclin A, cyclin B, phosphorylated forms of cdc2 and cdc25, which are all proteins required for G2/M transition. Conclusion Apigenin inhibits growth of pancreatic cancer cells through suppression of cyclin B-associated cdc2 activity and G2/M arrest, and may be a valuable drug for the treatment or prevention of pancreatic cancer. PMID:17196098

  4. Givinostat inhibition of hepatic stellate cell proliferation and protein acetylation

    PubMed Central

    Wang, Yu-Gang; Xu, Ling; Wang, Ting; Wei, Jue; Meng, Wen-Ying; Wang, Na; Shi, Min

    2015-01-01

    AIM: To explore the effect of the histone deacetylase inhibitor givinostat on proteins related to regulation of hepatic stellate cell proliferation. METHODS: The cell counting kit-8 assay and flow cytometry were used to observe changes in proliferation, apoptosis, and cell cycle in hepatic stellate cells treated with givinostat. Western blot was used to observe expression changes in p21, p57, CDK4, CDK6, cyclinD1, caspase-3, and caspase-9 in hepatic stellate cells exposed to givinostat. The scratch assay was used to analyze the effect of givinostat on cell migration. Effects of givinostat on the reactive oxygen species profile, mitochondrial membrane potential, and mitochondrial permeability transition pore opening in JS-1 cells were observed by laser confocal microscopy. RESULTS: Givinostat significantly inhibited JS-1 cell proliferation and promoted cell apoptosis, leading to cell cycle arrest in G0/G1 phases. Treatment with givinostat downregulated protein expression of CDK4, CDK6, and cyclin D1, whereas expression of p21 and p57 was significantly increased. The givinostat-induced apoptosis of hepatic stellate cells was mainly mediated through p38 and extracellular signal-regulated kinase 1/2. Givinostat treatment increased intracellular reactive oxygen species production, decreased mitochondrial membrane potential, and promoted mitochondrial permeability transition pore opening. Acetylation of superoxide dismutase (acetyl K68) and nuclear factor-κB p65 (acetyl K310) was upregulated, while there was no change in protein expression. Moreover, the notable beneficial effect of givinostat on liver fibrosis was also confirmed in the mouse models. CONCLUSION: Givinostat has antifibrotic activities via regulating the acetylation of nuclear factor-κB and superoxide dismutase 2, thus inhibiting hepatic stellate cell proliferation and inducing apoptosis. PMID:26217084

  5. Sickle erythrocytes inhibit human endothelial cell DNA synthesis

    SciTech Connect

    Weinstein, R.; Zhou, M.A.; Bartlett-Pandite, A.; Wenc, K. )

    1990-11-15

    Patients with sickle cell anemia experience severe vascular occlusive phenomena including acute pain crisis and cerebral infarction. Obstruction occurs at both the microvascular and the arterial level, and the clinical presentation of vascular events is heterogeneous, suggesting a complex etiology. Interaction between sickle erythrocytes and the endothelium may contribute to vascular occlusion due to alteration of endothelial function. To investigate this hypothesis, human vascular endothelial cells were overlaid with sickle or normal erythrocytes and stimulated to synthesize DNA. The erythrocytes were sedimented onto replicate monolayers by centrifugation for 10 minutes at 17 g to insure contact with the endothelial cells. Incorporation of 3H-thymidine into endothelial cell DNA was markedly inhibited during contact with sickle erythrocytes. This inhibitory effect was enhanced more than twofold when autologous sickle plasma was present during endothelial cell labeling. Normal erythrocytes, with or without autologous plasma, had a modest effect on endothelial cell DNA synthesis. When sickle erythrocytes in autologous sickle plasma were applied to endothelial monolayers for 1 minute, 10 minutes, or 1 hour and then removed, subsequent DNA synthesis by the endothelial cells was inhibited by 30% to 40%. Although adherence of sickle erythrocytes to the endothelial monolayers was observed under these experimental conditions, the effect of sickle erythrocytes on endothelial DNA synthesis occurred in the absence of significant adherence. Hence, human endothelial cell DNA synthesis is partially inhibited by contact with sickle erythrocytes. The inhibitory effect of sickle erythrocytes occurs during a brief (1 minute) contact with the endothelial monolayers, and persists for at least 6 hours of 3H-thymidine labeling.

  6. 5-HTP induced diarrhea as a carcinoid syndrome model in mice?

    PubMed

    Bourin, M; Hascoet, M; Deguiral, P

    1996-01-01

    Serotonin (5-HT) is present in the gastrointestinal tract and is probably one of the compounds responsible for diarrhea in patients presenting with carcinoid syndrome. Intraperitoneal administration of L-5-hydroxytryptophan (L-5-HTP) at doses of 25 to 100 mg/kg dramatically increase defecation in mice. In this new paradigm, counting fecal boli deposited is simple and the appraised or inhibition of diarrhea induced by ip 25 mg/kg of L-5-HIP is very clear, with a good reproducibility of scores. L-5-HTP needs to be metabolized into 5-HT to be active; benserazide, an inhibitor of decarboxylase, antagonized the diarrhea induced by 5-HT. Among the 5-HT antagonists used in interaction with 5-HT, only these of the 5-HT3 type (ondansetron, granisetron, tropisetron) and, to a lesser extent 5-HT2 type (ritanserin), decreased the diarrhea induced by 5-HTP. The 5-HT4 receptor agonists from the benzamide family (metoclopramide and zacopride) increased defecation in mice but the effect failed to reach statistical significance.

  7. Ethylene Inhibits Cell Proliferation of the Arabidopsis Root Meristem.

    PubMed

    Street, Ian H; Aman, Sitwat; Zubo, Yan; Ramzan, Aleena; Wang, Xiaomin; Shakeel, Samina N; Kieber, Joseph J; Schaller, G Eric

    2015-09-01

    The root system of plants plays a critical role in plant growth and survival, with root growth being dependent on both cell proliferation and cell elongation. Multiple phytohormones interact to control root growth, including ethylene, which is primarily known for its role in controlling root cell elongation. We find that ethylene also negatively regulates cell proliferation at the root meristem of Arabidopsis (Arabidopsis thaliana). Genetic analysis indicates that the inhibition of cell proliferation involves two pathways operating downstream of the ethylene receptors. The major pathway is the canonical ethylene signal transduction pathway that incorporates CONSTITUTIVE TRIPLE RESPONSE1, ETHYLENE INSENSITIVE2, and the ETHYLENE INSENSITIVE3 family of transcription factors. The secondary pathway is a phosphorelay based on genetic analysis of receptor histidine kinase activity and mutants involving the type B response regulators. Analysis of ethylene-dependent gene expression and genetic analysis supports SHORT HYPOCOTYL2, a repressor of auxin signaling, as one mediator of the ethylene response and furthermore, indicates that SHORT HYPOCOTYL2 is a point of convergence for both ethylene and cytokinin in negatively regulating cell proliferation. Additional analysis indicates that ethylene signaling contributes but is not required for cytokinin to inhibit activity of the root meristem. These results identify key elements, along with points of cross talk with cytokinin and auxin, by which ethylene negatively regulates cell proliferation at the root apical meristem.

  8. Chloroquine inhibits cell growth and induces cell death in A549 lung cancer cells.

    PubMed

    Fan, Chuandong; Wang, Weiwei; Zhao, Baoxiang; Zhang, Shangli; Miao, Junying

    2006-05-01

    To investigate the effects of chloroquine diphosphate (CQ) on lung cancer cell growth, we treated A549 cells, a lung cancer cell line, with the drug at various concentrations (0.25-128 microM) for 24-72 h. The results showed that, at lower concentrations (from 0.25 to 32 microM), CQ inhibited the growth of A549 cells and, at the same time, it induced vacuolation with increased volume of acidic compartments (VAC). On the other hand, at higher concentrations (64-128 microM), CQ induced apoptosis at 24 h, while its effect of inducing vacuolation declined. The lactate dehydrogenase (LDH) assay showed that with the treatment of CQ 32-64 microM for 72 h or 128 microM for 48 h, CQ induced necrosis of A549 cells. To understand the possible mechanism by which CQ acts in A549 cells, we further incubated the cells with this drug at the concentrations of 32 or 128 microM in the presence of D609, a specific inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC). The results showed that D609 (50 microM) could inhibit the effects of CQ 32 microM on the viability and VAC, but it could not change the effects of CQ 128 microM on the same. Our data suggested that CQ inhibited A549 lung cancer cell growth at lower concentrations by increasing the volume of lysosomes and that PC-PLC might be involved in this process. The data also indicated that, at higher concentrations, CQ induced apoptosis and necrosis, but at this time its ability to increase the volume of lysosome gradually declined, and PC-PLC might not be implicated in the process. PMID:16413786

  9. CD101 inhibits the expansion of colitogenic T cells

    PubMed Central

    Schey, Regina; Dornhoff, Heike; Baier, Julia L.C.; Purtak, Martin; Opoka, Robert; Koller, Anna Katharina; Atreya, Raya; Rau, Tilman T.; Daniel, Christoph; Amann, Kerstin; Bogdan, Christian; Mattner, Jochen

    2015-01-01

    CD101 exerts negative-costimulatory effects in vitro, but its function in vivo remains poorly defined. CD101 is abundantly expressed on lymphoid and myeloid cells in intestinal tissues, but absent from naïve splenic T cells. Here, we assessed the impact of CD101 on the course of inflammatory bowel disease (IBD). Using a T cell transfer model of chronic colitis, we found that in recipients of naïve T cells from CD101+/+ donors up to 30% of the recovered lymphocytes expressed CD101, correlating with an increased IL-2-mediated FoxP3-expression. Transfer of CD101−/− T cells caused more severe colitis and was associated with an expansion of IL-17-producing T cells and an enhanced expression of IL-2Rα/β independently of FoxP3. The co-transfer of naïve and regulatory T cells (Treg) protected most effectively from colitis, when both donor and recipient mice expressed CD101. While the expression of CD101 on T cells was sufficient for Treg-function and the inhibition of T cell proliferation, sustained IL-10-production required additional CD101-expression by myeloid cells. Finally, in patients with IBD a reduced CD101-expression on peripheral and intestinal monocytes and CD4+ T cells correlated with enhanced IL-17-production and disease activity. Thus, CD101-deficiency is a novel marker for progressive colitis and potential target for therapeutic intervention. PMID:26813346

  10. Rapamycin inhibits poly(ADP-ribosyl)ation in intact cells

    SciTech Connect

    Fahrer, Joerg; Wagner, Silvia; Buerkle, Alexander; Koenigsrainer, Alfred

    2009-08-14

    Rapamycin is an immunosuppressive drug, which inhibits the mammalian target of rapamycin (mTOR) kinase activity inducing changes in cell proliferation. Synthesis of poly(ADP-ribose) (PAR) is an immediate cellular response to genotoxic stress catalyzed mostly by poly(ADP-ribose) polymerase 1 (PARP-1), which is also controlled by signaling pathways. Therefore, we investigated whether rapamycin affects PAR production. Strikingly, rapamycin inhibited PAR synthesis in living fibroblasts in a dose-dependent manner as monitored by immunofluorescence. PARP-1 activity was then assayed in vitro, revealing that down-regulation of cellular PAR production by rapamycin was apparently not due to competitive PARP-1 inhibition. Further studies showed that rapamycin did not influence the cellular NAD pool and the activation of PARP-1 in extracts of pretreated fibroblasts. Collectively, our data suggest that inhibition of cellular PAR synthesis by rapamycin is mediated by formation of a detergent-sensitive complex in living cells, and that rapamycin may have a potential as therapeutic PARP inhibitor.

  11. Erianin inhibits the proliferation of T47D cells by inhibiting cell cycles, inducing apoptosis and suppressing migration.

    PubMed

    Sun, Jing; Fu, Xueqi; Wang, Yongsen; Liu, Ye; Zhang, Yu; Hao, Tian; Hu, Xin

    2016-01-01

    Erianin is a natural product extracted from Dendrobiumchrysotoxum. To investigate the antitumor activity of Erianin in estrogen receptor (ER) positive breast cancer, we treated T47D cells with Erianin and evaluated the effects of Erianin treatment on multiple cancer-associated pathways. Erianin inhibited the proliferation of T47D cells effectively. Erianin induced apoptosis in T47D cells through reducing Bcl-2 expression and activating caspase signaling. Furthermore, it also suppressed the expression of CDKs and caused cell cycle arrest. In addition, Erianin treatment suppressed the migration of T47D cells, most likely through regulating the homeostatic expression of MPP and TIMP. Meanwhile, Erianin did not affect the proliferation of normal breast epithelial cell line MCF10A. Together, these results demonstrated that Erianin might have the potential to be an effective drug to treat the ER positive breast cancer. PMID:27508028

  12. Erianin inhibits the proliferation of T47D cells by inhibiting cell cycles, inducing apoptosis and suppressing migration

    PubMed Central

    Sun, Jing; Fu, Xueqi; Wang, Yongsen; Liu, Ye; Zhang, Yu; Hao, Tian; Hu, Xin

    2016-01-01

    Erianin is a natural product extracted from Dendrobiumchrysotoxum. To investigate the antitumor activity of Erianin in estrogen receptor (ER) positive breast cancer, we treated T47D cells with Erianin and evaluated the effects of Erianin treatment on multiple cancer-associated pathways. Erianin inhibited the proliferation of T47D cells effectively. Erianin induced apoptosis in T47D cells through reducing Bcl-2 expression and activating caspase signaling. Furthermore, it also suppressed the expression of CDKs and caused cell cycle arrest. In addition, Erianin treatment suppressed the migration of T47D cells, most likely through regulating the homeostatic expression of MPP and TIMP. Meanwhile, Erianin did not affect the proliferation of normal breast epithelial cell line MCF10A. Together, these results demonstrated that Erianin might have the potential to be an effective drug to treat the ER positive breast cancer. PMID:27508028

  13. Curcumin inhibits bovine herpesvirus type 1 entry into MDBK cells.

    PubMed

    Zhu, L; Ding, X; Zhang, D; Yuan, Ch; Wang, J; Ndegwa, E; Zhu, G

    2015-09-01

    The generation of antiviral drugs from herbs and other natural resources with traditionally long-confirmed effects is an efficient approach. So far, no herb or components from herbs that could inhibit bovine herpesvirus type 1 (BoHV-1) replication have been described. In this study, the antiviral effect of curcumin, a natural phenolic constituent of the spice turmeric, on BoHV-1 replication was evaluated in cell culture. We demonstrated that curcumin impairs BoHV-1 viral particles and affects the virus post-binding entry process. Furthermore, curcumin upregulated the proportion of the plasma membrane adopting a lipid raft conformation in MDBK cells, which supported the previous reports that curcumin can modulate the lipid bilayer. Though the antiviral mechanism of curcumin on BoHV-1 needs further study, we identified for the first time a component from herb that could inhibit BoHV-1 replication, in vitro.

  14. Mast cells aggravate sepsis by inhibiting peritoneal macrophage phagocytosis

    PubMed Central

    Dahdah, Albert; Gautier, Gregory; Attout, Tarik; Fiore, Frédéric; Lebourdais, Emeline; Msallam, Rasha; Daëron, Marc; Monteiro, Renato C.; Benhamou, Marc; Charles, Nicolas; Davoust, Jean; Blank, Ulrich; Malissen, Bernard; Launay, Pierre

    2014-01-01

    Controlling the overwhelming inflammatory reaction associated with polymicrobial sepsis remains a prevalent clinical challenge with few treatment options. In septic peritonitis, blood neutrophils and monocytes are rapidly recruited into the peritoneal cavity to control infection, but the role of resident sentinel cells during the early phase of infection is less clear. In particular, the influence of mast cells on other tissue-resident cells remains poorly understood. Here, we developed a mouse model that allows both visualization and conditional ablation of mast cells and basophils to investigate the role of mast cells in severe septic peritonitis. Specific depletion of mast cells led to increased survival rates in mice with acute sepsis. Furthermore, we determined that mast cells impair the phagocytic action of resident macrophages, thereby allowing local and systemic bacterial proliferation. Mast cells did not influence local recruitment of neutrophils and monocytes or the release of inflammatory cytokines. Phagocytosis inhibition by mast cells involved their ability to release prestored IL-4 within 15 minutes after bacterial encounter, and treatment with an IL-4–neutralizing antibody prevented this inhibitory effect and improved survival of septic mice. Our study uncovers a local crosstalk between mast cells and macrophages during the early phase of sepsis development that aggravates the outcome of severe bacterial infection. PMID:25180604

  15. Ivermectin inhibits growth of Chlamydia trachomatis in epithelial cells.

    PubMed

    Pettengill, Matthew A; Lam, Verissa W; Ollawa, Ikechukwu; Marques-da-Silva, Camila; Ojcius, David M

    2012-01-01

    Ivermectin is currently approved for treatment of both clinical and veterinary infections by nematodes, including Onchocerca cervicalis in horses and Onchocerca volvulus in humans. However, ivermectin has never been shown to be effective against bacterial pathogens. Here we show that ivermectin also inhibits infection of epithelial cells by the bacterial pathogen, Chlamydia trachomatis, at doses that could be envisioned clinically for sexually-transmitted or ocular infections by Chlamydia. PMID:23119027

  16. Clonal cell populations unresponsive to radiosensitization induced by telomerase inhibition

    SciTech Connect

    Ju, Yeun-Jin; Shin, Hyun-Jin; Park, Jeong-Eun; Juhn, Kyoung-Mi; Woo, Seon Rang; Kim, Hee-Young; Han, Young-Hoon; Hwang, Sang-Gu; Hong, Sung-Hee; Kang, Chang-Mo; Yoo, Young-Do; Park, Won-Bong; Cho, Myung-Haing; Park, Gil Hong; Lee, Kee-Ho

    2010-11-12

    Research highlights: {yields} In our present manuscript, we have clearly showed an interesting but problematic obstacle of a radiosensitization strategy based on telomerase inhibition by showing that: Clonal population unresponsive to this radiosensitization occasionally arise. {yields} The telomere length of unsensitized clones was reduced, as was that of most sensitized clones. {yields} The unsensitized clones did not show chromosome end fusion which was noted in all sensitized clones. {yields} P53 status is not associated with the occurrence of unsensitized clone. {yields} Telomere end capping in unsensitized clone is operative even under telomerase deficiency. -- Abstract: A combination of a radiotherapeutic regimen with telomerase inhibition is valuable when tumor cells are to be sensitized to radiation. Here, we describe cell clones unresponsive to radiosensitization after telomere shortening. After extensive division of individual transformed clones of mTERC{sup -/-} cells, about 22% of clones were unresponsive to radiosensitization even though telomerase action was inhibited. The telomere lengths of unsensitized mTERC{sup -/-} clones were reduced, as were those of most sensitized clones. However, the unsensitized clones did not exhibit chromosomal end-to-end fusion to the extent noted in all sensitized clones. Thus, a defense mechanism preventing telomere erosion is operative even when telomeres become shorter under conditions of telomerase deficiency, and results in unresponsiveness to the radiosensitization generally mediated by telomere shortening.

  17. Disulfide linked pyrazole derivatives inhibit phagocytosis of opsonized blood cells.

    PubMed

    Purohit, Meena K; Scovell, Iain; Neschadim, Anton; Katsman, Yulia; Branch, Donald R; Kotra, Lakshmi P

    2013-04-15

    Immune thrombocytopenia (ITP) is caused by production of an autoantibody to autologous platelets. ITP can be treated either by reducing platelet destruction or by increasing platelet production. Fcγ receptor mediated phagocytosis of the opsonized blood cells is a well-accepted mechanism for the underlying pathogenesis of ITP and inhibition of this phagocytosis process with small molecules is a potential strategy for the development of drugs against ITP. A broad screen indicated that 4-methyl-1-phenyl-pyrazole derivative (1) could inhibit the phagocytosis of opsonized blood cells with weak potency. We reveal here the discovery of the polysulfide products, synthesis of various 1-phenyl-pyrazole derivatives, and the biological evaluation of pyrazole derivatives as inhibitors of phagocytosis for potential use as therapeutics for ITP. Substitution at C4 of the pyrazole moiety in the disulfide-bridged dimers influenced the potency in the increasing order of 10 ~/= 11~/= 16 < 19 < 20. A novel scaffold, 20 with an IC(50) of 100 nM inhibiting opsonized blood cell phagocytosis was identified as a potential candidate for further studies. Confirmation of the disulfide bridge additionally provides clues for the non-thiol or non-disulfide bridge carrying ligands targeting ITP and other similar disorders.

  18. Fucoidan inhibits angiogenesis induced by multiple myeloma cells.

    PubMed

    Liu, Fen; Luo, Guoping; Xiao, Qing; Chen, Liping; Luo, Xiaohua; Lv, Jinglong; Chen, Lixue

    2016-10-01

    Multiple myeloma (MM) remains an incurable hematological neoplasms. Our previous studies showed that Fucoidan possessed anti-myeloma effect by inducing apoptosis and inhibiting invasion of myeloma cells. In this study, we evaluated the effect of Fucoidan on angiogenesis induced by human myeloma cells and elucidated its possible mechanisms. Multiple myeloma cells were treated with Fucoidan at different concentrations, then the conditioned medium (CM) was collected. The levels of VEGF in the CM were tested by ELISA. The results showed that Fucoidan significantly decreased VEGF secretion by RPMI-8226 and U266 cells. The tube formation assay and migration test on human umbilical vein endothelial cells (HUVECs) were used to examine the effect of Fucoidan on angiogenesis induced by human myeloma cells. The results showed that Fucoidan decreased HUVECs formed tube structures and inhibited HUVECs migration, and suppressed the angiogenic ability of multiple myeloma RPMI-8226 and U266 cells in a dose-dependent manner. The study also showed that Fucoidan downregulated the expression of several kinds of proteins, which may be correlated with the reduction of angiogenesis induced by myeloma cells. Moreover, results were compared from normoxic and hypoxic conditions, they showed that Fucoidan had anti-angiogenic activity. Furthermore, in a multiple myeloma xenograft mouse model, it indicated that Fucoidan negatively affected tumor growth and angiogenesis in vivo. In conclusion, our results demonstrate that Fucoidan was able to interfere with angiogenesis of multiple myeloma cells both in vitro and in vivo and may have a substantial potential in the treatment of MM.

  19. Radiosensitization by Inhibiting STAT1 in Renal Cell Carcinoma

    SciTech Connect

    Hui Zhouguang; Tretiakova, Maria; Zhang Zhongfa; Li Yan; Wang Xiaozhen; Zhu, Julie Xiaohong; Gao Yuanhong; Mai Weiyuan; Furge, Kyle; Qian Chaonan; Amato, Robert; Butler, E. Brian

    2009-01-01

    Purpose: Renal cell carcinoma (RCC) has been historically regarded as a radioresistant malignancy, but the molecular mechanism underlying its radioresistance is not understood. This study investigated the role of signal transducer and activator of transcription 1 (STAT1), a transcription factor downstream of the interferon-signaling pathway, in radioresistant RCC. Methods and Materials: The expressions of STAT1 and STAT3 in 164 human clear cell RCC samples, 47 papillary RCC samples, and 15 normal kidney tissue samples were examined by microarray expression profiling and immunohistochemistry. Western blotting was performed to evaluate the total and phosphorylated STAT1 expression in CRL-1932 (786-O) (human clear cell RCC), SKRC-39 (human papillary RCC), CCL-116 (human fibroblast), and CRL-1441 (G-401) (human Wilms tumor). STAT1 was reduced or inhibited by fludarabine and siRNA, respectively, and the effects on radiation-induced cell death were investigated using clonogenic assays. Results: STAT1 expression, but not STAT3 expression, was significantly greater in human RCC samples (p = 1.5 x 10{sup -8} for clear cell; and p = 3.6 x 10{sup -4} for papillary). Similarly, the expression of STAT1 was relatively greater in the two RCC cell lines. STAT1 expression was reduced by both fludarabine and siRNA, significantly increasing the radiosensitivity in both RCC cell lines. Conclusion: This is the first study reporting the overexpression of STAT1 in human clear cell and papillary RCC tissues. Radiosensitization in RCC cell lines was observed by a reduction or inhibition of STAT1 signaling, using fludarabine or siRNA. Our data suggest that STAT1 may play a key role in RCC radioresistance and manipulation of this pathway may enhance the efficacy of radiotherapy.

  20. Barium inhibits arsenic-mediated apoptotic cell death in human squamous cell carcinoma cells.

    PubMed

    Yajima, Ichiro; Uemura, Noriyuki; Nizam, Saika; Khalequzzaman, Md; Thang, Nguyen D; Kumasaka, Mayuko Y; Akhand, Anwarul A; Shekhar, Hossain U; Nakajima, Tamie; Kato, Masashi

    2012-06-01

    Our fieldwork showed more than 1 μM (145.1 μg/L) barium in about 3 μM (210.7 μg/L) arsenic-polluted drinking well water (n = 72) in cancer-prone areas in Bangladesh, while the mean concentrations of nine other elements in the water were less than 3 μg/L. The types of cancer include squamous cell carcinomas (SCC). We hypothesized that barium modulates arsenic-mediated biological effects, and we examined the effect of barium (1 μM) on arsenic (3 μM)-mediated apoptotic cell death of human HSC-5 and A431 SCC cells in vitro. Arsenic promoted SCC apoptosis with increased reactive oxygen species (ROS) production and JNK1/2 and caspase-3 activation (apoptotic pathway). In contrast, arsenic also inhibited SCC apoptosis with increased NF-κB activity and X-linked inhibitor of apoptosis protein (XIAP) expression level and decreased JNK activity (antiapoptotic pathway). These results suggest that arsenic bidirectionally promotes apoptotic and antiapoptotic pathways in SCC cells. Interestingly, barium in the presence of arsenic increased NF-κB activity and XIAP expression and decreased JNK activity without affecting ROS production, resulting in the inhibition of the arsenic-mediated apoptotic pathway. Since the anticancer effect of arsenic is mainly dependent on cancer apoptosis, barium-mediated inhibition of arsenic-induced apoptosis may promote progression of SCC in patients in Bangladesh who keep drinking barium and arsenic-polluted water after the development of cancer. Thus, we newly showed that barium in the presence of arsenic might inhibit arsenic-mediated cancer apoptosis with the modulation of the balance between arsenic-mediated promotive and suppressive apoptotic pathways.

  1. Autophagy contributes to gefitinib-induced glioma cell growth inhibition

    SciTech Connect

    Chang, Cheng-Yi; Kuan, Yu-Hsiang; Ou, Yen-Chuan; Li, Jian-Ri; Wu, Chih-Cheng; Pan, Pin-Ho; Chen, Wen-Ying; Huang, Hsuan-Yi; Chen, Chun-Jung

    2014-09-10

    Epidermal growth factor receptor tyrosine kinase inhibitors, including gefitinib, have been evaluated in patients with malignant gliomas. However, the molecular mechanisms involved in gefitinib-mediated anticancer effects against glioma are incompletely understood. In the present study, the cytostatic potential of gefitinib was demonstrated by the inhibition of glioma cell growth, long-term clonogenic survival, and xenograft tumor growth. The cytostatic consequences were accompanied by autophagy, as evidenced by monodansylcadaverine staining of acidic vesicle formation, conversion of microtubule-associated protein-1 light chain 3-II (LC3-II), degradation of p62, punctate pattern of GFP-LC3, and conversion of GFP-LC3 to cleaved-GFP. Autophagy inhibitor 3-methyladenosine and chloroquine and genetic silencing of LC3 or Beclin 1 attenuated gefitinib-induced growth inhibition. Gefitinib-induced autophagy was not accompanied by the disruption of the Akt/mammalian target of rapamycin signaling. Instead, the activation of liver kinase-B1/AMP-activated protein kinase (AMPK) signaling correlated well with the induction of autophagy and growth inhibition caused by gefitinib. Silencing of AMPK suppressed gefitinib-induced autophagy and growth inhibition. The crucial role of AMPK activation in inducing glioma autophagy and growth inhibition was further supported by the actions of AMP mimetic AICAR. Gefitinib was shown to be capable of reducing the proliferation of glioma cells, presumably by autophagic mechanisms involving AMPK activation. - Highlights: • Gefitinib causes cytotoxic and cytostatic effect on glioma. • Gefitinib induces autophagy. • Gefitinib causes cytostatic effect through autophagy. • Gefitinib induces autophagy involving AMPK.

  2. Oxidative stress inhibits distant metastasis by human melanoma cells

    PubMed Central

    Piskounova, Elena; Agathocleous, Michalis; Murphy, Malea M.; Hu, Zeping; Huddlestun, Sara E.; Zhao, Zhiyu; Leitch, A. Marilyn; Johnson, Timothy M.; DeBerardinis, Ralph J.; Morrison, Sean J.

    2015-01-01

    Solid cancer cells commonly enter the blood and disseminate systemically but are highly inefficient at forming distant metastases for poorly understood reasons. We studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NSG mice. All melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficient metastasizers. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established subcutaneous tumours. Successfully metastasizing melanomas underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress, including increased dependence upon NADPH-generating enzymes in the folate pathway. Anti-oxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumors in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo. PMID:26466563

  3. Inhibition of cell adhesion by high molecular weight kininogen

    PubMed Central

    1992-01-01

    An anti-cell adhesion globulin was purified from human plasma by heparin-affinity chromatography. The purified globulin inhibited spreading of osteosarcoma and melanoma cells on vitronectin, and of endothelial cells, platelets, and mononuclear blood cells on vitronectin or fibrinogen. It did not inhibit cell spreading on fibronectin. The protein had the strongest antiadhesive effect when preadsorbed onto the otherwise adhesive surfaces. Amino acid sequence analysis revealed that the globulin is cleaved (kinin-free) high molecular weight kininogen (HKa). Globulin fractions from normal plasma immunodepleted of high molecular weight kininogen (HK) or from an individual deficient of HK lacked adhesive activity. Uncleaved single- chain HK preadsorbed at neutral pH, HKa preadsorbed at pH greater than 8.0, and HKa degraded further to release its histidine-rich domain had little anti-adhesive activity. These results indicate that the cationic histidine-rich domain is critical for anti-adhesive activity and is somehow mobilized upon cleavage. Vitronectin was not displaced from the surface by HKa. Thus, cleavage of HK by kallikrein results in both release of bradykinin, a potent vasoactive and growth-promoting peptide, and formation of a potent anti-adhesive protein. PMID:1370494

  4. Murine cytotoxic activated macrophages inhibit aconitase in tumor cells. Inhibition involves the iron-sulfur prosthetic group and is reversible.

    PubMed

    Drapier, J C; Hibbs, J B

    1986-09-01

    Previous studies show that cytotoxic activated macrophages cause inhibition of DNA synthesis, inhibition of mitochondrial respiration, and loss of intracellular iron from tumor cells. Here we examine aconitase, a citric acid cycle enzyme with a catalytically active iron-sulfur cluster, to determine if iron-sulfur clusters are targets for activated macrophage-induced iron removal. Results show that aconitase activity declines dramatically in target cells after 4 h of co-cultivation with activated macrophages. Aconitase inhibition occurs simultaneously with arrest of DNA synthesis, another early activated macrophage-induced metabolic change in target cells. Dithionite partially prevents activated macrophage induced aconitase inhibition. Furthermore, incubation of injured target cells in medium supplemented with ferrous ion plus a reducing agent causes near-complete reconstitution of aconitase activity. The results show that removal of a labile iron atom from the [4Fe-4S] cluster, by a cytotoxic activated macrophage-mediated mechanism, is causally related to aconitase inhibition. PMID:3745439

  5. Simulated microgravity inhibits cell wall regeneration of Penicillium decumbens protoplasts

    NASA Astrophysics Data System (ADS)

    Zhao, C.; Sun, Y.; Yi, Z. C.; Rong, L.; Zhuang, F. Y.; Fan, Y. B.

    2010-09-01

    This work compares cell wall regeneration from protoplasts of the fungus Penicillium decumbens under rotary culture (simulated microgravity) and stationary cultures. Using an optimized lytic enzyme mixture, protoplasts were successfully released with a yield of 5.3 × 10 5 cells/mL. Under simulated microgravity conditions, the protoplast regeneration efficiency was 33.8%, lower than 44.9% under stationary conditions. Laser scanning confocal microscopy gave direct evidence for reduced formation of polysaccharides under simulated conditions. Scanning electron microscopy showed the delayed process of cell wall regeneration by simulated microgravity. The delayed regeneration of P. decumbens cell wall under simulated microgravity was likely caused by the inhibition of polysaccharide synthesis. This research contributes to the understanding of how gravitational loads affect morphological and physiological processes of fungi.

  6. Ozone Inhibits Guard Cell K+ Channels Implicated in Stomatal Opening

    NASA Astrophysics Data System (ADS)

    Torsethaugen, Gro; Pell, Eva J.; Assmann, Sarah M.

    1999-11-01

    Ozone (O3) deleteriously affects organisms ranging from humans to crop plants, yet little is understood regarding the underlying mechanisms. In plants, O3 decreases CO2 assimilation, but whether this could result from direct O3 action on guard cells remained unknown. Potassium flux causes osmotically driven changes in guard cell volume that regulate apertures of associated microscopic pores through which CO2 is supplied to the photosynthetic mesophyll tissue. We show in Vicia faba that O3 inhibits (i) guard cell K+ channels that mediate K+ uptake that drives stomatal opening; (ii) stomatal opening in isolated epidermes; and (iii) stomatal opening in leaves, such that CO2 assimilation is reduced without direct effects of O3 on photosynthetic capacity. Direct O3 effects on guard cells may have ecological and agronomic implications for plant productivity and for response to other environmental stressors including drought.

  7. Pumpkin seed extract: Cell growth inhibition of hyperplastic and cancer cells, independent of steroid hormone receptors.

    PubMed

    Medjakovic, Svjetlana; Hobiger, Stefanie; Ardjomand-Woelkart, Karin; Bucar, Franz; Jungbauer, Alois

    2016-04-01

    Pumpkin seeds have been known in folk medicine as remedy for kidney, bladder and prostate disorders since centuries. Nevertheless, pumpkin research provides insufficient data to back up traditional beliefs of ethnomedical practice. The bioactivity of a hydro-ethanolic extract of pumpkin seeds from the Styrian pumpkin, Cucurbita pepo L. subsp. pepo var. styriaca, was investigated. As pumpkin seed extracts are standardized to cucurbitin, this compound was also tested. Transactivational activity was evaluated for human androgen receptor, estrogen receptor and progesterone receptor with in vitro yeast assays. Cell viability tests with prostate cancer cells, breast cancer cells, colorectal adenocarcinoma cells and a hyperplastic cell line from benign prostate hyperplasia tissue were performed. As model for non-hyperplastic cells, effects on cell viability were tested with a human dermal fibroblast cell line (HDF-5). No transactivational activity was found for human androgen receptor, estrogen receptor and progesterone receptor, for both, extract and cucurbitin. A cell growth inhibition of ~40-50% was observed for all cell lines, with the exception of HDF-5, which showed with ~20% much lower cell growth inhibition. Given the receptor status of some cell lines, a steroid-hormone receptor independent growth inhibiting effect can be assumed. The cell growth inhibition for fast growing cells together with the cell growth inhibition of prostate-, breast- and colon cancer cells corroborates the ethnomedical use of pumpkin seeds for a treatment of benign prostate hyperplasia. Moreover, due to the lack of androgenic activity, pumpkin seed applications can be regarded as safe for the prostate. PMID:26976217

  8. Inhibition of regulated cell death by cell-penetrating peptides.

    PubMed

    Krautwald, Stefan; Dewitz, Christin; Fändrich, Fred; Kunzendorf, Ulrich

    2016-06-01

    Development of the means to efficiently and continuously renew missing and non-functional proteins in diseased cells remains a major goal in modern molecular medicine. While gene therapy has the potential to achieve this, substantial obstacles must be overcome before clinical application can be considered. A promising alternative approach is the direct delivery of non-permeant active biomolecules, such as oligonucleotides, peptides and proteins, to the affected cells with the purpose of ameliorating an advanced disease process. In addition to receptor-mediated endocytosis, cell-penetrating peptides are widely used as vectors for rapid translocation of conjugated molecules across cell membranes into intracellular compartments and the delivery of these therapeutic molecules is generally referred to as novel prospective protein therapy. As a broad coverage of the enormous amount of published data in this field is unrewarding, this review will provide a brief, focused overview of the technology and a summary of recent studies of the most commonly used protein transduction domains and their potential as therapeutic agents for the treatment of cellular damage and the prevention of regulated cell death. PMID:27048815

  9. Isoliquiritigenin inhibits cell proliferation and induces apoptosis in human hepatoma cells.

    PubMed

    Hsu, Ya-Ling; Kuo, Po-Lin; Lin, Liang-Tzung; Lin, Chun-Ching

    2005-02-01

    Isoliquiritigenin (4,2',4'-trihydroxychalcone, ISL) is a natural pigment with a simple chalcone structure. In this study, we report the ISL-induced inhibition on the growth of human hepatoma cells (Hep G2) for the first time. The cell growth inhibition achieved by ISL treatment resulted in programmed cell death in a caspase activation-dependent manner, with an IC50 of 10.51 microg/mL. Outcomes of ISL treatment included the up-regulation of IkappaBalpha expression in the cytoplasm, and the decrease of NF-kappaB level as well as its activity in the nucleus. In addition, ISL also suppressed the expression of Bcl-XL and c-IAP1/2 protein, the downstream target molecule of NF-kappaB. These results demonstrated that ISL treatment inhibited the NF-kappaB cell survival-signaling pathway and induced apoptotic cell death in Hep G2 cells.

  10. Depolarization counteracts glucocorticoid inhibition of adenohypophysical corticotroph cells

    PubMed Central

    Lim, M C; Shipston, M J; Antoni, F A

    1998-01-01

    In AtT20 mouse corticotroph tumour cells large conductance Ca2+-activated K+-channels (BK-channels) have an essential role in the early glucocorticoid inhibition of adrenocorticotrophin (ACTH) secretion evoked by corticotrophin-releasing factor. The present study examined whether or not BK-channels are also pivotal to glucocorticoid inhibition of normal rat anterior pituitary cells. A membrane-permeant, non-metabolizable cyclic AMP analogue, 8-(4-Chlorophenylthio)adenosine-3′,5′-cyclic-monophosphate (CPT-cAMP) was used as the primary secretagogue stimulus, as this mimics the increase of intracellular cyclic AMP caused by corticotrophin-releasing factor, but is not subject to the complex Ca2+-dependent regulation of cyclic AMP metabolism that is evident in corticotroph cells. Experiments in AtT20 cells showed that ACTH secretion stimulated by 1 mM CPT-cAMP was suppressed to 34±1.5% (n=12) of the control stimulus by a maximal dose of 100 nM dexamethasone. The ACTH secretion evoked by the combination of 1 mM CPT-cAMP with either 5 μM (−)BayK8644 (L-type Ca2+-channel activator) or 5 mM TEA (K+-channel blocker) was respectively 69.1±7.6% and 69.3±11.8% of control after 2 h preincubation with 100 nM dexamethasone (P<0.05 vs CPT-cAMP). The ACTH response elicited by 5 μM (−)BayK8644 and 5 mM TEA given together was completely resistant to inhibition by 100 nM dexamethasone. Furthermore, TEA and (−)BayK8644 given together synergistically stimulated ACTH release in combination with 0.1 mM or 1 mM CPT-cAMP, and these ACTH responses were not inhibited by 100 nM dexamethasone. In primary cultures of rat anterior pituitary cells, TEA (up to 20 mM), charybdotoxin (30 nM) or apamin (100 nM) failed to modify the glucocorticoid inhibition of 0.1 mM CPT-cAMP-induced ACTH release. The combination of 5 mM TEA and 5 μM (−)BayK8644 elicited a small but significant increase in ACTH secretion but did not modify the inhibition of 0.3

  11. The Traditional Chinese Medicine Baicalein Potently Inhibits Gastric Cancer Cells

    PubMed Central

    Mu, Jiasheng; Liu, Tianrun; Jiang, Lin; Wu, Xiangsong; Cao, Yang; Li, Maolan; Dong, Qian; Liu, Yingbin; Xu, Haineng

    2016-01-01

    Baicalein, a traditional Chinese medicine, is a member of the flavone subclass of flavonoids. It has been reported to have anticancer activities in several human cancer cell lines in vitro. However, the therapeutic effects of baicalein on human gastric cancer and the mechanisms of action of baicalein have not been extensively studied. In the present study, we utilized a cell viability assay and an in vivo tumor growth assay to test the inhibitory effects of baicalein on gastric cancer. Analyses of the cell cycle, apoptosis and alterations in protein levels were performed to elucidate how baicalein functions in gastric cancer. We found that baicalein could potently inhibit gastric cancer cell growth and colony formation. Baicalein robustly induced arrest at the S phase in the gastric cancer cell line SGC-7901. It induced SGC-7901 cell apoptosis and disrupted the mitochondrial membrane potential (ΔΨm) in a dose-dependent manner. Analysis of protein expression levels in SGC-7901 cells showed downregulation of Bcl-2 and upregulation of Bax in response to baicalein treatment. These results indicate that baicalein induces apoptosis of gastric cancer cells through the mitochondrial pathway. In an in vivo subcutaneous xenograft model, baicalein exhibited excellent tumor inhibitory effects. These results indicate that baicalein may be a potential drug for gastric cancer therapy. PMID:26918059

  12. The Traditional Chinese Medicine Baicalein Potently Inhibits Gastric Cancer Cells.

    PubMed

    Mu, Jiasheng; Liu, Tianrun; Jiang, Lin; Wu, Xiangsong; Cao, Yang; Li, Maolan; Dong, Qian; Liu, Yingbin; Xu, Haineng

    2016-01-01

    Baicalein, a traditional Chinese medicine, is a member of the flavone subclass of flavonoids. It has been reported to have anticancer activities in several human cancer cell lines in vitro. However, the therapeutic effects of baicalein on human gastric cancer and the mechanisms of action of baicalein have not been extensively studied. In the present study, we utilized a cell viability assay and an in vivo tumor growth assay to test the inhibitory effects of baicalein on gastric cancer. Analyses of the cell cycle, apoptosis and alterations in protein levels were performed to elucidate how baicalein functions in gastric cancer. We found that baicalein could potently inhibit gastric cancer cell growth and colony formation. Baicalein robustly induced arrest at the S phase in the gastric cancer cell line SGC-7901. It induced SGC-7901 cell apoptosis and disrupted the mitochondrial membrane potential (ΔΨm) in a dose-dependent manner. Analysis of protein expression levels in SGC-7901 cells showed downregulation of Bcl-2 and upregulation of Bax in response to baicalein treatment. These results indicate that baicalein induces apoptosis of gastric cancer cells through the mitochondrial pathway. In an in vivo subcutaneous xenograft model, baicalein exhibited excellent tumor inhibitory effects. These results indicate that baicalein may be a potential drug for gastric cancer therapy.

  13. Cell growth inhibition by sequence-specific RNA minihelices.

    PubMed Central

    Hipps, D; Schimmel, P

    1995-01-01

    RNA minihelices which reconstruct the 12 base pair acceptor-T psi C domains of transfer RNAs interact with their cognate tRNA synthetases. These substrates lack the anticodons of the genetic code and, therefore, cannot participate in steps of protein synthesis subsequent to aminoacylation. We report here that expression in Escherichia coli of either of two minihelices, each specific for a different amino acid, inhibited cell growth. Inhibition appears to be due to direct competition between the minihelix and its related tRNA for binding to their common synthetase. This competition, in turn, sharply lowers the pool of the specific charged tRNA for protein synthesis. Inhibition is relieved by single nucleotide changes which disrupt the minihelix-synthetase interaction. The results suggest that sequence-specific RNA minihelix substrates bind to cognate synthetases in vivo and can, in principle, act as cell growth regulators. Naturally occurring non-tRNA substrates for aminoacylation may serve a similar purpose. Images PMID:7664744

  14. Shikonin Suppresses Skin Carcinogenesis via Inhibiting Cell Proliferation.

    PubMed

    Li, Wenjuan; Zhang, Chunjing; Ren, Amy; Li, Teena; Jin, Rong; Li, Guohong; Gu, Xin; Shi, Runhua; Zhao, Yunfeng

    2015-01-01

    The M2 isoform of pyruvate kinase M2 (PKM2) has been shown to be up-regulated in human skin cancers. To test whether PKM2 may be a target for chemoprevention, shikonin, a natural product from the root of Lithospermum erythrorhizon and a specific inhibitor of PKM2, was used in a chemically-induced mouse skin carcinogenesis study. The results revealed that shikonin treatment suppressed skin tumor formation. Morphological examinations and immunohistochemical staining of the skin epidermal tissues suggested that shikonin inhibited cell proliferation without inducing apoptosis. Although shikonin alone suppressed PKM2 activity, it did not suppress tumor promoter-induced PKM2 activation in the skin epidermal tissues at the end of the skin carcinogenesis study. To reveal the potential chemopreventive mechanism of shikonin, an antibody microarray analysis was performed, and the results showed that the transcription factor ATF2 and its downstream target Cdk4 were up-regulated by chemical carcinogen treatment; whereas these up-regulations were suppressed by shikonin. In a promotable skin cell model, the nuclear levels of ATF2 were increased during tumor promotion, whereas this increase was inhibited by shikonin. Furthermore, knockdown of ATF2 decreased the expression levels of Cdk4 and Fra-1 (a key subunit of the activator protein 1. In summary, these results suggest that shikonin, rather than inhibiting PKM2 in vivo, suppresses the ATF2 pathway in skin carcinogenesis. PMID:25961580

  15. Shikonin Suppresses Skin Carcinogenesis via Inhibiting Cell Proliferation.

    PubMed

    Li, Wenjuan; Zhang, Chunjing; Ren, Amy; Li, Teena; Jin, Rong; Li, Guohong; Gu, Xin; Shi, Runhua; Zhao, Yunfeng

    2015-01-01

    The M2 isoform of pyruvate kinase M2 (PKM2) has been shown to be up-regulated in human skin cancers. To test whether PKM2 may be a target for chemoprevention, shikonin, a natural product from the root of Lithospermum erythrorhizon and a specific inhibitor of PKM2, was used in a chemically-induced mouse skin carcinogenesis study. The results revealed that shikonin treatment suppressed skin tumor formation. Morphological examinations and immunohistochemical staining of the skin epidermal tissues suggested that shikonin inhibited cell proliferation without inducing apoptosis. Although shikonin alone suppressed PKM2 activity, it did not suppress tumor promoter-induced PKM2 activation in the skin epidermal tissues at the end of the skin carcinogenesis study. To reveal the potential chemopreventive mechanism of shikonin, an antibody microarray analysis was performed, and the results showed that the transcription factor ATF2 and its downstream target Cdk4 were up-regulated by chemical carcinogen treatment; whereas these up-regulations were suppressed by shikonin. In a promotable skin cell model, the nuclear levels of ATF2 were increased during tumor promotion, whereas this increase was inhibited by shikonin. Furthermore, knockdown of ATF2 decreased the expression levels of Cdk4 and Fra-1 (a key subunit of the activator protein 1. In summary, these results suggest that shikonin, rather than inhibiting PKM2 in vivo, suppresses the ATF2 pathway in skin carcinogenesis.

  16. Substituted oxines inhibit endothelial cell proliferation and angiogenesis†

    PubMed Central

    Bhat, Shridhar; Shim, Joong Sup; Zhang, Feiran; Chong, Curtis Robert; Liu, Jun O.

    2013-01-01

    Two substituted oxines, nitroxoline (5) and 5-chloroquinolin-8-yl phenylcarbamate (22), were identified as hits in a high-throughput screen aimed at finding new anti-angiogenic agents. In a previous study, we have elucidated the molecular mechanism of antiproliferative activity of nitroxoline in endothelial cells, which comprises of a dual inhibition of type 2 human methionine aminopeptidase (MetAP2) and sirtuin 1 (SIRT1). Structure–activity relationship study (SAR) of nitroxoline offered many surprises where minor modifications yielded oxine derivatives with increased potency against human umbilical vein endothelial cells (HUVEC), but with entirely different as yet unknown mechanisms. For example, 5-nitrosoquinolin-8-ol (33) inhibited HUVEC growth with sub-micromolar IC50, but did not affect MetAP2 or MetAP1, and it only showed weak inhibition against SIRT1. Other sub-micromolar inhibitors were derivatives of 5-aminoquinolin-8-ol (34) and 8-sulfonamidoquinoline (32). A sulfamate derivative of nitroxoline (48) was found to be more potent than nitroxoline with the retention of activities against MetAP2 and SIRT1. The bioactivity of the second hit, micromolar HUVEC and MetAP2 inhibitor carbamate 22 was improved further with an SAR study culminating in carbamate 24 which is a nanomolar inhibitor of HUVEC and MetAP2. PMID:22391578

  17. Bortezomib inhibits bone marrow-derived dendritic cells.

    PubMed

    Wang, Ying; Liang, Yong; Zhang, Yanming; Wu, Depei; Liu, Haiyan

    2015-01-01

    Graft versus-host disease (GVHD) severely limits the application of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in treating leukemia. Dendritic cells (DCs) are critical for the development. Here, we examined the effect of proteasome inhibitor Bortezomib on DCs in vitro. Primary cultured mouse DCs were treated with Bortezomib and their proliferation was observed. The expression of CD80 and CD86 and cytokine secretion of LPS-activated DCs was also quantified under Bortezomib. The ability of DCs to activate T cells was also measured by the mixed lymphocyte reaction assay. Finally the effect of Bortezomib on nuclear translocation of NF-κB was measured by EMSA. Bortezomib can inhibit the proliferation of DCs in a dose- and time-dependent manner. It also blocked the expression of co-receptors CD80 and CD86 and secretion of cytokines IL-12 and TNF-α in DCs treated with LPS. Mixed lymphocyte reaction assay suggested Bortezomib reduced the ability of DCs to activate T cells. Finally, we found Bortezomib can inhibit the nuclear translocation of NF-κB in DCs. Our findings indicated that Bortezomib blocked the functions of DCs in various aspects, and is a potential drug candidate for GVHD.

  18. Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

    SciTech Connect

    Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T.; Aftab, Blake T.; Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John; Rudin, Charles M.; Tran, Phuoc T.; Hales, Russell K.

    2013-05-01

    Purpose: Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials: We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of Kras{sup G12D}-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results: In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radiosensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions: Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer.

  19. Inhibition of steroidogenesis in Leydig cells by Müllerian-inhibiting substance.

    PubMed

    Fynn-Thompson, Eric; Cheng, Henry; Teixeira, Jose

    2003-12-15

    Müllerian-inhibiting substance (MIS), a member of the transforming growth factor-beta family of cytokines that signal through a heteromeric complex of single-transmembrane serine/threonine kinase receptors, is required for Müllerian duct regression and normal reproductive tract development in the male embryo. However, the continued expression of MIS at high levels in males until puberty and its induction in females after birth suggested other roles for MIS. Additionally, Leydig cell development and steroidogenic capacity and ovarian follicle recruitment were abnormal in MIS-knockout or MIS-overexpressing mice. We have shown that MIS inhibits the cAMP-induced expression of cytochrome P450 C17alpha-hydroxylase/C17-20 lyase (Cyp17) mRNA both in vitro and in vivo. Our current efforts are to understand the molecular mechanisms regulating both MIS type II receptor (MISRII) expression and its signaling in rodent Leydig cell lines. MISRII expression in R2C cells requires both steroidogenic factor-1 and an unknown protein to bind to its proximal promoter in the context of 1.6 kb 5'-flanking DNA. When bound by MIS, signaling by the receptor in MA-10 cells blocks the protein kinase A-mediated induction of Cyp17 expression by a cAMP regulatory element-binding protein independent mechanism. We continue to investigate the molecular mechanisms of MISRII expression and possible interactions between MIS-regulated SMAD activation and cAMP signaling. These studies will provide a better understanding of the role played by MIS during postnatal life.

  20. GATA3 inhibits GCM1 activity and trophoblast cell invasion

    PubMed Central

    Chiu, Yueh Ho; Chen, Hungwen

    2016-01-01

    Development of human placenta involves the invasion of trophoblast cells from anchoring villi into the maternal decidua. Placental transcription factor GCM1 regulates trophoblast cell invasion via transcriptional activation of HtrA4 gene, which encodes a serine protease enzyme. The GATA3 transcription factor regulates trophoblast cell differentiation and is highly expressed in invasive murine trophoblast giant cells. The regulation of trophoblastic invasion by GCM1 may involve novel cellular factors. Here we show that GATA3 interacts with GCM1 and inhibits its activity to suppress trophoblastic invasion. Immunohistochemistry demonstrates that GATA3 and GCM1 are coexpressed in villous cytotrophoblast cells, syncytiotrophoblast layer, and extravillous trophoblast cells of human placenta. Interestingly, GATA3 interacts with GCM1, but not the GCM2 homologue, through the DNA-binding domain and first transcriptional activation domain in GCM1 and the transcriptional activation domains and zinc finger 1 domain in GATA3. While GATA3 did not affect DNA-binding activity of GCM1, it suppressed transcriptional activity of GCM1 and therefore HtrA4 promoter activity. Correspondingly, GATA3 knockdown elevated HtrA4 expression in BeWo and JEG-3 trophoblast cell lines and enhanced the invasion activities of both lines. This study uncovered a new GATA3 function in placenta as a negative regulator of GCM1 activity and trophoblastic invasion. PMID:26899996

  1. A triterpenoid from wild bitter gourd inhibits breast cancer cells

    NASA Astrophysics Data System (ADS)

    Bai, Li-Yuan; Chiu, Chang-Fang; Chu, Po-Chen; Lin, Wei-Yu; Chiu, Shih-Jiuan; Weng, Jing-Ru

    2016-03-01

    The antitumor activity of 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (TCD), a triterpenoid isolated from wild bitter gourd, in breast cancer cells was investigated. TCD suppressed the proliferation of MCF-7 and MDA-MB-231 breast cancer cells with IC50 values at 72 h of 19 and 23 μM, respectively, via a PPARγ-independent manner. TCD induced cell apoptosis accompanied with pleiotrophic biological modulations including down-regulation of Akt-NF-κB signaling, up-regulation of p38 mitogen-activated protein kinase and p53, increased reactive oxygen species generation, inhibition of histone deacetylases protein expression, and cytoprotective autophagy. Together, these findings provided the translational value of TCD and wild bitter gourd as an antitumor agent for patients with breast cancer.

  2. A triterpenoid from wild bitter gourd inhibits breast cancer cells

    PubMed Central

    Bai, Li-Yuan; Chiu, Chang-Fang; Chu, Po-Chen; Lin, Wei-Yu; Chiu, Shih-Jiuan; Weng, Jing-Ru

    2016-01-01

    The antitumor activity of 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (TCD), a triterpenoid isolated from wild bitter gourd, in breast cancer cells was investigated. TCD suppressed the proliferation of MCF-7 and MDA-MB-231 breast cancer cells with IC50 values at 72 h of 19 and 23 μM, respectively, via a PPARγ−independent manner. TCD induced cell apoptosis accompanied with pleiotrophic biological modulations including down-regulation of Akt-NF-κB signaling, up-regulation of p38 mitogen-activated protein kinase and p53, increased reactive oxygen species generation, inhibition of histone deacetylases protein expression, and cytoprotective autophagy. Together, these findings provided the translational value of TCD and wild bitter gourd as an antitumor agent for patients with breast cancer. PMID:26926586

  3. A triterpenoid from wild bitter gourd inhibits breast cancer cells.

    PubMed

    Bai, Li-Yuan; Chiu, Chang-Fang; Chu, Po-Chen; Lin, Wei-Yu; Chiu, Shih-Jiuan; Weng, Jing-Ru

    2016-01-01

    The antitumor activity of 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (TCD), a triterpenoid isolated from wild bitter gourd, in breast cancer cells was investigated. TCD suppressed the proliferation of MCF-7 and MDA-MB-231 breast cancer cells with IC50 values at 72 h of 19 and 23 μM, respectively, via a PPARγ-independent manner. TCD induced cell apoptosis accompanied with pleiotrophic biological modulations including down-regulation of Akt-NF-κB signaling, up-regulation of p38 mitogen-activated protein kinase and p53, increased reactive oxygen species generation, inhibition of histone deacetylases protein expression, and cytoprotective autophagy. Together, these findings provided the translational value of TCD and wild bitter gourd as an antitumor agent for patients with breast cancer. PMID:26926586

  4. Beta-interferon inhibits cell infection by Trypanosoma cruzi

    NASA Technical Reports Server (NTRS)

    Kierszenbaum, F.; Sonnenfeld, G.

    1984-01-01

    Beta interferon has been shown to inhibit the capacity of bloodstream forms of the flagellate Trypanosoma cruzi, the causative agent of Chagas' disease, to associate with and infect mouse peritoneal macrophages and rat heart myoblasts. The inhibitory effect was abrogated in the presence of specific antibodies to the interferon. Pretreatment of the parasites with interferon reduced their infectivity for untreated host cells, whereas pretreament of either type of host cell did not affect the interaction. The effect of interferon on the trypanosomes was reversible; the extent of the inhibitory effect was significantly reduced afer 20 min, and was undetectable after 60 min when macrophages were used as host cells. For the myoblasts, 60 min elapsed before the inhibitory effect began to subside and 120 min elapsed before it became insignificant or undetectable.

  5. Polydatin Inhibits Formation of Macrophage-Derived Foam Cells

    PubMed Central

    Wu, Min; Liu, Meixia; Guo, Gang; Zhang, Wengao; Liu, Longtao

    2015-01-01

    Rhizoma Polygoni Cuspidati, a Chinese herbal medicine, has been widely used in traditional Chinese medicine for a long time. Polydatin, one of the major active ingredients in Rhizoma Polygoni Cuspidati, has been recently shown to possess extensive cardiovascular pharmacological activities. In present study, we examined the effects of Polydatin on the formation of peritoneal macrophage-derived foam cells in Apolipoprotein E gene knockout mice (ApoE−/−) and explored the potential underlying mechanisms. Peritoneal macrophages were collected from ApoE−/− mice and cultured in vitro. These cells sequentially were divided into four groups: Control group, Model group, Lovastatin group, and Polydatin group. Our results demonstrated that Polydatin significantly inhibits the formation of foam cells derived from peritoneal macrophages. Further studies indicated that Polydatin regulates the metabolism of intracellular lipid and possesses anti-inflammatory effects, which may be regulated through the PPAR-γ signaling pathways. PMID:26557864

  6. A triterpenoid from wild bitter gourd inhibits breast cancer cells

    NASA Astrophysics Data System (ADS)

    Bai, Li-Yuan; Chiu, Chang-Fang; Chu, Po-Chen; Lin, Wei-Yu; Chiu, Shih-Jiuan; Weng, Jing-Ru

    2016-03-01

    The antitumor activity of 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (TCD), a triterpenoid isolated from wild bitter gourd, in breast cancer cells was investigated. TCD suppressed the proliferation of MCF-7 and MDA-MB-231 breast cancer cells with IC50 values at 72 h of 19 and 23 μM, respectively, via a PPARγ‑independent manner. TCD induced cell apoptosis accompanied with pleiotrophic biological modulations including down-regulation of Akt-NF-κB signaling, up-regulation of p38 mitogen-activated protein kinase and p53, increased reactive oxygen species generation, inhibition of histone deacetylases protein expression, and cytoprotective autophagy. Together, these findings provided the translational value of TCD and wild bitter gourd as an antitumor agent for patients with breast cancer.

  7. Bronchial carcinoid tumors metastatic to the sella turcica and review of the literature.

    PubMed

    Moshkin, Olga; Rotondo, Fabio; Scheithauer, Bernd W; Soares, Mark; Coire, Claire; Smyth, Harley S; Goth, Miklos; Horvath, Eva; Kovacs, Kalman

    2012-06-01

    We review here the literature on neuroendocrine neoplasms metastatic to the pituitary and present an example of the disease. Metastasis of bronchial carcinoid tumors to the sellar region are rare. Herein, we describe the case of a 63-year-old woman who presented with constant cough and headaches. She had previously been operated for carcinoid tumor of the lung. During the preoperative investigation, a CT scan of the head revealed a sellar mass. Six months after a left lower lobectomy, the sellar lesion was removed by transsphenoidal surgery. The two tumors were evaluated by histology, immunohistochemistry and electron microscopy. Both showed identical morphologic features, those of carcinoid tumor. Immunohistochemistry revealed immunoreactivity for the endocrine markers, synaptophysin and chromogranin, as well as CD-56, serotonin, bombesin and vascular endothelial growth factor. The sellar neoplasm showed nuclear immunopositivity for thyroid transcription factor-1, supporting the diagnosis of a metastatic bronchial carcinoid tumor. In conclusion, this is the first report of a serotonin- and bombesin-immunopositive atypical bronchial carcinoid tumor metastatic to the sella. PMID:22485018

  8. Minute liver metastases from a rectal carcinoid: A case report and review

    PubMed Central

    Yamamoto, Hirofumi; Hemmi, Hideyuki; Gu, Jin-Yu; Sekimoto, Mitsugu; Doki, Yuichiro; Mori, Masaki

    2010-01-01

    We here report a 43-year-old male patient with minute liver metastases from a rectal carcinoid. Hepatic nodules were diagnosed during surgery, although they were not diagnosed by preoperative computed tomography or ultrasound examination. The rectal carcinoid was resected together with liver metastases and the patient has had no disease recurrence for 5 years following postoperative treatment of hepatic arterial infusion chemotherapy (HAIC) using 5-fluorouracil (5-FU) and oral administration of 1-hexylcarbamoyl-5-fluorouracil (HCFU). In 2003, a health check examination indicated presence of occult blood in his stool. Barium enema study revealed a rectal tumor in the lower rectum and colonoscopy showed a yellowish lesion with a size of 30 mm in diameter. Pathological examination of the biopsy specimen indicated that the rectal tumor was carcinoid. Although preoperative imaging examinations failed to detect liver metastases, 2 min nodules were found on the surface of liver during surgery. A rapid pathological examination revealed that they were metastatic tumors from the rectal carcinoid. Low anterior resection was performed for the rectal tumor and the pathological report indicated that there were 4 metastatic lymph nodes in the rectal mesentery. The patient received treatment by HAIC using 5-FU plus oral administration of HCFU and survived for 5 years. We also review world-wide current treatments and their efficacy for hepatic metastases of carcinoid tumors. PMID:21160856

  9. [Perioperative Management of Emergency Operation for a Patient with Carcinoid Syndrome].

    PubMed

    Oishi, Yuri; Kawanoue, Naoya; Minami, Eriko; Ishikawa, Tomoki; Shin, Yoshiaki; Mieda, Hideyuki; Ishii, Mizue; Iwasaki, Etsu; Fukushima, Tomihiro; Tokioka, Hiroaki

    2015-12-01

    We report a case of carcinoid syndrome requiring an emergency operation for an upper gastrointestinal perforation. A 46-year-old man had undergone left lower lobectomy for a lung carcinoid tumor seven years previously, and liver metastasis was found five years previously. He developed cutaneous flushing and watery diarrhea, and was diagnosed with carcinoid syndrome one year previously. Although he was treated with octreotid, his symptoms became worse and he was admitted to our hospital. During the hospital stay, he underwent an emergency operation for an upper gastrointestinal perforation. Before the operation, hemodynamics were unstable. Anesthesia was induced with sevoflurane and propofol, and maintained with sevoflurane and remifentanil. Only vasopressin was used for the treatment of hypotension. Landiolol was used for perioperative tachyarrythmia. During anesthesia, there was no severe hypotension or hypertension. After the operation, he was managed with intubation in the ICU. Octreotid was administered again for the carcinoid syndrome. Vasopressin was necessary for the treatment of hypotension in the ICU. After improvement of hemodynamics, extubation was performed on the 3rd ICU day and he was discharged from the ICU on the 4th ICU day. In conclusion, we were able to perform good perioperative management of carcinoid syndrome accompanied by hemodynamic instability. PMID:26790329

  10. Murine macrophage heparanase: inhibition and comparison with metastatic tumor cells

    SciTech Connect

    Savion, N.; Disatnik, M.H.; Nevo, Z.

    1987-01-01

    Circulating macrophages and metastatic tumor cells can penetrate the vascular endothelium and migrate from the circulatory system to extravascular compartments. Both activated murine macrophages and different metastatic tumor cells attach, invade, and penetrate confluent vascular endothelial cell monolayer in vitro, by degrading heparan sulfate proteoglycans in the subendothelial extracellular matrix. The sensitivity of the enzymes from the various sources degrading the heparan sulfate proteoglycan was challenged and compared by a series of inhibitors. Activated macrophages demonstrate a heparanase with an endoglycosidase activity that cleaves from the (/sup 35/S)O/sub 4//sup -/-labeled heparan sulfate proteoglycans of the extracellular matrix 10 kDa glycosaminoglycan fragments. The degradation of (/sup 35/S)O/sub 4//sup -/-labeled extracellular matrix proteoglycans by the macrophages' heparanase is significantly inhibited in the presence of heparan sulfate (10..mu..g/ml), arteparon (10..mu..g/ml), and heparin at a concentration of 3 ..mu..g/ml. Degradation of this heparan sulfate proteoglycan is a two-step sequential process involving protease activity followed by heparanase activity. B16-BL6 metastatic melanoma cell heparanase, which is also a cell-associated enzyme, was inhibited by heparin to the same extent as the macrophage haparanase. On the other hand, heparanase of the highly metastatic variant (ESb) of a methylcholanthrene-induced T lymphoma, which is an extracellular enzyme released by the cells to the incubation medium, was more sensitive to heparin and arteparon than the macrophages' heparanase. These results may indicate the potential use of heparin or other glycosaminoglycans as specific and differential inhibitors for the formation in certain cases of blood-borne tumor metastasis.

  11. PF-04691502 triggers cell cycle arrest, apoptosis and inhibits the angiogenesis in hepatocellular carcinoma cells.

    PubMed

    Wang, Feng-Ze; Peng-Jiao; Yang, Na-Na; Chuang-Yuan; Zhao, Ya-Li; Liu, Qiang-Qiang; Fei, Hong-Rong; Zhang, Ji-Guo

    2013-07-01

    Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality in the world. The aim of the present study is to determine the antitumor effect of PF-04691502, a potent inhibitor of PI3K and mTOR kinases, on the apoptosis and angiogenesis of the hepatoma cancer cells. Our results indicate that treatment of cancer cells with PF-04691502 reduces cell viability and inhibits cell growth in a dose-dependent manner. PF-04691502 triggers apoptosis via a mitochondrial pathway, accompanied by activation of caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP). Pre-treatment of hepatoma cells with the caspase-3 inhibitor (z-DEVD-fmk) blocks the PF-04691502-induced death of these cells. In addition, growth factors-induced tube formation and the migration of HUVECs are markedly inhibited by PF-04691502 treatment. The mechanisms of anti-angiogenesis of PF-04691502 are associated with inhibiting the expression of VEGF and HIF-1α. Based on the overall results, we suggest that PF-04691502 reduces hepatocellular carcinoma cell viability, induces cell apoptosis, and inhibits cell growth and tumor angiogenesis, implicating its potential therapeutic value in the treatment of HCC.

  12. RNA interference targeting raptor inhibits proliferation of gastric cancer cells

    SciTech Connect

    Wu, William Ka Kei; Lee, Chung Wa; Cho, Chi Hin; Chan, Francis Ka Leung; Yu, Jun; Sung, Joseph Jao Yiu

    2011-06-10

    Mammalian target of rapamycin complex 1 (mTORC1) is dysregulated in gastric cancer. The biologic function of mTORC1 in gastric carcinogenesis is unclear. Here, we demonstrate that disruption of mTORC1 function by RNA interference-mediated downregulation of raptor substantially inhibited gastric cancer cell proliferation through induction of G{sub 0}/G{sub 1}-phase cell cycle arrest. The anti-proliferative effect was accompanied by concomitant downregulation of activator protein-1 and upregulation of Smad2/3 transcriptional activities. In addition, the expression of cyclin D{sub 3} and p21{sup Waf1}, which stabilizes cyclin D/cdk4 complex for G{sub 1}-S transition, was reduced by raptor knockdown. In conclusion, disruption of mTORC1 inhibits gastric cancer cell proliferation through multiple pathways. This discovery may have an implication in the application of mTORC1-directed therapy for the treatment of gastric cancer.

  13. Matrix metalloproteinase inhibition negatively affects muscle stem cell behavior.

    PubMed

    Bellayr, Ian; Holden, Kyle; Mu, Xiaodong; Pan, Haiying; Li, Yong

    2013-01-01

    Skeletal muscle is a large and complex system that is crucial for structural support, movement and function. When injured, the repair of skeletal muscle undergoes three phases: inflammation and degeneration, regeneration and fibrosis formation in severe injuries. During fibrosis formation, muscle healing is impaired because of the accumulation of excess collagen. A group of zinc-dependent endopeptidases that have been found to aid in the repair of skeletal muscle are matrix metalloproteinases (MMPs). MMPs are able to assist in tissue remodeling through the regulation of extracellular matrix (ECM) components, as well as contributing to cell migration, proliferation, differentiation and angiogenesis. In the present study, the effect of GM6001, a broad-spectrum MMP inhibitor, on muscle-derived stem cells (MDSCs) is investigated. We find that MMP inhibition negatively impacts skeletal muscle healing by impairing MDSCs in migratory and multiple differentiation abilities. These results indicate that MMP signaling plays an essential role in the wound healing of muscle tissue because their inhibition is detrimental to stem cells residing in skeletal muscle. PMID:23329998

  14. Ratite oils promote keratinocyte cell growth and inhibit leukocyte activation

    PubMed Central

    Bennett, Darin C.; Leung, Gigi; Wang, Eddy; Ma, Sam; Lo, Blanche K. K.; McElwee, Kevin J.; Cheng, Kimberly M.

    2015-01-01

    Traditionally, native Australian aborigines have used emu oil for the treatment of inflammation and to accelerate wound healing. Studies on mice suggest that topically applied emu oil may have anti-inflammatory properties and may promote wound healing. We investigated the effects of ratite oils (6 emu, 3 ostrich, 1 rhea) on immortalized human keratinocytes (HaCaT cells) in vitro by culturing the cells in media with oil concentrations of 0%, 0.5%, and 1.0%. Peking duck, tea tree, and olive oils were used as comparative controls. The same oils at 0.5% concentration were evaluated for their influence on peripheral blood mononuclear cell (PBMC) survival over 48 hr and their ability to inhibit IFNγ production in PBMCs activated by phytohemagglutinin (PHA) in ELISpot assays. Compared to no oil control, significantly shorter population doubling time durations were observed for HaCaT cells cultured in emu oil (1.51 × faster), ostrich oil (1.46 × faster), and rhea oil (1.64 × faster). Tea tree oil demonstrated significant antiproliferative activity and olive oil significantly prolonged (1.35 × slower) cell population doubling time. In contrast, almost all oils, particularly tea tree oil, significantly reduced PBMC viability. Different oils had different levels of inhibitory effect on IFNγ production with individual emu, ostrich, rhea, and duck oil samples conferring full inhibition. This preliminary investigation suggests that emu oil might promote wound healing by accelerating the growth rate of keratinocytes. Combined with anti-inflammatory properties, ratite oil may serve as a useful component in bandages and ointments for the treatment of wounds and inflammatory skin conditions. PMID:26217022

  15. Ratite oils promote keratinocyte cell growth and inhibit leukocyte activation.

    PubMed

    Bennett, Darin C; Leung, Gigi; Wang, Eddy; Ma, Sam; Lo, Blanche K K; McElwee, Kevin J; Cheng, Kimberly M

    2015-09-01

    Traditionally, native Australian aborigines have used emu oil for the treatment of inflammation and to accelerate wound healing. Studies on mice suggest that topically applied emu oil may have anti-inflammatory properties and may promote wound healing. We investigated the effects of ratite oils (6 emu, 3 ostrich, 1 rhea) on immortalized human keratinocytes (HaCaT cells) in vitro by culturing the cells in media with oil concentrations of 0%, 0.5%, and 1.0%. Peking duck, tea tree, and olive oils were used as comparative controls. The same oils at 0.5% concentration were evaluated for their influence on peripheral blood mononuclear cell (PBMC) survival over 48 hr and their ability to inhibit IFNγ production in PBMCs activated by phytohemagglutinin (PHA) in ELISpot assays. Compared to no oil control, significantly shorter population doubling time durations were observed for HaCaT cells cultured in emu oil (1.51×faster), ostrich oil (1.46×faster), and rhea oil (1.64×faster). Tea tree oil demonstrated significant antiproliferative activity and olive oil significantly prolonged (1.35×slower) cell population doubling time. In contrast, almost all oils, particularly tea tree oil, significantly reduced PBMC viability. Different oils had different levels of inhibitory effect on IFNγ production with individual emu, ostrich, rhea, and duck oil samples conferring full inhibition. This preliminary investigation suggests that emu oil might promote wound healing by accelerating the growth rate of keratinocytes. Combined with anti-inflammatory properties, ratite oil may serve as a useful component in bandages and ointments for the treatment of wounds and inflammatory skin conditions. PMID:26217022

  16. EGFR inhibition in glioma cells modulates Rho signaling to inhibit cell motility and invasion and cooperates with temozolomide to reduce cell growth.

    PubMed

    Ramis, Guillem; Thomàs-Moyà, Elena; Fernández de Mattos, Silvia; Rodríguez, José; Villalonga, Priam

    2012-01-01

    Enforced EGFR activation upon gene amplification and/or mutation is a common hallmark of malignant glioma. Small molecule EGFR tyrosine kinase inhibitors, such as erlotinib (Tarceva), have shown some activity in a subset of glioma patients in recent trials, although the reported data on the cellular basis of glioma cell responsiveness to these compounds have been contradictory. Here we have used a panel of human glioma cell lines, including cells with amplified or mutant EGFR, to further characterize the cellular effects of EGFR inhibition with erlotinib. Dose-response and cellular growth assays indicate that erlotinib reduces cell proliferation in all tested cell lines without inducing cytotoxic effects. Flow cytometric analyses confirm that EGFR inhibition does not induce apoptosis in glioma cells, leading to cell cycle arrest in G(1). Interestingly, erlotinib also prevents spontaneous multicellular tumour spheroid growth in U87MG cells and cooperates with sub-optimal doses of temozolomide (TMZ) to reduce multicellular tumour spheroid growth. This cooperation appears to be schedule-dependent, since pre-treatment with erlotinib protects against TMZ-induced cytotoxicity whereas concomitant treatment results in a cooperative effect. Cell cycle arrest in erlotinib-treated cells is associated with an inhibition of ERK and Akt signaling, resulting in cyclin D1 downregulation, an increase in p27(kip1) levels and pRB hypophosphorylation. Interestingly, EGFR inhibition also perturbs Rho GTPase signaling and cellular morphology, leading to Rho/ROCK-dependent formation of actin stress fibres and the inhibition of glioma cell motility and invasion.

  17. miR-1 Inhibits Cell Growth, Migration, and Invasion by Targeting VEGFA in Osteosarcoma Cells

    PubMed Central

    Niu, Junjie; Guo, Qiaoge; Niu, Dongju; Liu, Bo

    2016-01-01

    microRNAs (miRNAs) are small noncoding RNAs and have been shown to play a crucial role in the osteosarcoma (OS) tumorigenesis and progression. VEGFA is a key regulator of angiogenesis and plays an important role in regulation of tumor metastasis. The objective of this study was to determine whether VEGFA was involved in miR-1-mediated suppression of proliferation, migration, and invasion of OS cells. The expression levels of miR-1 were significantly lower in OS tumor tissues than those in adjacent normal tissues and in SAOS-2 and U2OS cell lines compared to a normal osteoblast (NHOst) cell line. VEGFA was upregulated in OS tumor tissues and SAOS-2 and U2OS cell lines. The results of CCK-8 assay and transwell assay showed that miR-1 acted as a tumor suppressor by inhibiting cell proliferation, migration, and invasion in U2OS cells. Dual luciferase reporter assay demonstrated that VEGFA was a direct and functional target gene of miR-1. miR-1 directly inhibits the protein expression of VEGFA via its 3′-UTR. Knockdown of VEGFA by siRNA inhibited proliferation, migration, and invasion of U2OS cells. Our study suggested the potential inhibitory function of miR-1 in OS cell proliferation, migration, and invasion via inhibiting VEGFA. PMID:27777493

  18. Antibiotic drug tigecycline inhibited cell proliferation and induced autophagy in gastric cancer cells

    SciTech Connect

    Tang, Chunling; Yang, Liqun; Jiang, Xiaolan; Xu, Chuan; Wang, Mei; Wang, Qinrui; Zhou, Zhansong; Xiang, Zhonghuai; Cui, Hongjuan

    2014-03-28

    Highlights: • Tigecycline inhibited cell growth and proliferation in human gastric cancer cells. • Tigecycline induced autophagy not apoptosis in human gastric cancer cells. • AMPK/mTOR/p70S6K pathway was activated after tigecycline treatment. • Tigecycline inhibited tumor growth in xenograft model of human gastric cancer cells. - Abstract: Tigecycline acts as a glycylcycline class bacteriostatic agent, and actively resists a series of bacteria, specifically drug fast bacteria. However, accumulating evidence showed that tetracycline and their derivatives such as doxycycline and minocycline have anti-cancer properties, which are out of their broader antimicrobial activity. We found that tigecycline dramatically inhibited gastric cancer cell proliferation and provided an evidence that tigecycline induced autophagy but not apoptosis in human gastric cancer cells. Further experiments demonstrated that AMPK pathway was activated accompanied with the suppression of its downstream targets including mTOR and p70S6K, and ultimately induced cell autophagy and inhibited cell growth. So our data suggested that tigecycline might act as a candidate agent for pre-clinical evaluation in treatment of patients suffering from gastric cancer.

  19. WEHI-3 cells inhibit adipocyte differentiation in 3T3-L1 cells

    SciTech Connect

    Lai, Jing; Liu, Gexiu; Yan, Guoyao; He, Dongmei; Zhou, Ying; Chen, Shengting

    2015-06-26

    By investigating the anti-adipogenic effects of WEHI-3 cells – a murine acute myelomonocytic leukemia cell line – we sought to improve the efficiency of hematopoietic stem cell transplantation (HSCT). Analysis of Oil Red O staining and the expression of adipogenic genes, including PPARγ, C/EBPα, FAS and LPL, indicated that WEHI-3 cells significantly inhibited 3T3-L1 mouse preadipocyte cells from differentiating into adipocytes. In vivo, fat vacuoles in mice injected with WEHI-3 cells were also remarkably reduced in the murine bone marrow pimelosis model. Moreover, the key gene in the Rho signaling pathway, ROCKII, and the key gene in the Wnt signaling pathway, β-catenin, were both upregulated compared with the control group. siRNA-mediated knockdown of ROCKII and β-catenin reversed these WEHI-3-mediated anti-adipogenic effects. Taken together, these data suggest that WEHI-3 cells exert anti-adipogenic effects and that both ROCKII and β-catenin are involved in this process. - Highlights: • WEHI-3, an acute myelomonocytic leukemia cell line, inhibited 3T3-L1 preadipocyte from differentiating into adipocyte. • WEHI-3 cells can arrest 3T3-L1 cells in G0/G1 phase by secreting soluble factors and thus inhibit their proliferation. • WEHI-3 cells reduced bone marrow pimelosis in the murine model. • Both ROCKII and β-catenin were involved in the WEHI-3-mediated anti-adipogenic effects.

  20. Transoral robotic surgery for atypical carcinoid tumor of the larynx.

    PubMed

    Muderris, Togay; Bercin, Sami; Sevil, Ergun; Acar, Baran; Kiris, Muzaffer

    2013-11-01

    In recent years, transoral robotic surgery has been introduced as an efficient and a reliable method for excision of selected oral cavity, tongue base, and supraglottic tumors in otolaryngology. In this case report, a 39-year-old woman with a history of hoarseness and dysphagia for approximately 6 months is presented. The patient was diagnosed with atypical carcinoid tumor on the laryngeal aspect of the epiglottis, and excision of the tumor was performed through transoral robotic surgery using the robotic da Vinci surgical system, a 0-degree three-dimensional endoscope, 5-mm microinstruments compatible with the da Vinci robot, and a Feyh-Kastenbauer/Weinstein-O'Malley retractor. The mass was removed completely, and no complications occurred. The patient recovered without a need for tracheotomy. Findings of the 1-year clinical follow-up revealed no locoregional recurrence or distant metastasis. This case shows, once again, that transoral robotic surgery could be used safely and effectively regardless of pathologic diagnosis in the supraglottic region tumors. PMID:24220389

  1. Renshaw cells are inactive during motor inhibition elicited by the pontine microinjection of carbachol.

    PubMed

    Morales, F R; Engelhardt, J K; Pereda, A E; Yamuy, J; Chase, M H

    1988-04-12

    The present study was undertaken to determine whether the postsynaptic inhibition of motoneurons that occurs following the pontine microinjection of carbachol in the decerebrate cat is due to the activity of Renshaw cells. Thirty-two out of 37 Renshaw cells (86%) were spontaneously active prior to the administration of carbachol, whereas only 2 out of 13 Renshaw cells (15%) discharged during carbachol-induced motor inhibition. In addition, discrete inhibitory synaptic potentials were observed in 33% of the Renshaw cells from which intracellular recordings were obtained after carbachol administration, indicating that these cells were actively inhibited. The finding that a population of Renshaw cells, which inhibit motoneurons, were themselves inhibited during a period of profound motoneuron inhibition was quite unexpected. These results support the conclusion that Renshaw cells are not the inhibitory interneurons that are responsible for the powerful inhibition of motoneurons that occurs following the pontine microinjection of carbachol. PMID:3380320

  2. [A case of laparoscopic surgery for a rectal carcinoid after ALTA therapy for an internal hemorrhoid].

    PubMed

    Aomatsu, Naoki; Nakamura, Masanori; Hasegawa, Tsuyoshi; Nakao, Shigetomi; Uchima, Yasutake; Aomatsu, Keiho

    2014-11-01

    We report a case of laparoscopic surgery for a rectal carcinoid after aluminum potassium and tannic acid (ALTA) therapy for an internal hemorrhoid. A 66-year-old man was admitted to our hospital because of bleeding during defecation. He was diagnosed via anoscopy with Goligher grade II internal hemorrhoids. Examination via colonoscopy revealed 2 yellowish submucosal tumors in the lower rectum that were 5mm and 10mm in diameter. A rectal carcinoid tumor was diagnosed based on histopathology. Abdominal computed tomography demonstrated no metastases to the liver or lymph nodes. First, we performed ALTA therapy for the internal hemorrhoids. Two weeks later, we performed laparoscopic-assisted low anterior resection (D2) for the rectal carcinoid. The patient was discharged without complications and has not experienced recurrence during the 2 years of follow-up care.

  3. [A case of laparoscopic surgery for a rectal carcinoid after ALTA therapy for an internal hemorrhoid].

    PubMed

    Aomatsu, Naoki; Nakamura, Masanori; Hasegawa, Tsuyoshi; Nakao, Shigetomi; Uchima, Yasutake; Aomatsu, Keiho

    2014-11-01

    We report a case of laparoscopic surgery for a rectal carcinoid after aluminum potassium and tannic acid (ALTA) therapy for an internal hemorrhoid. A 66-year-old man was admitted to our hospital because of bleeding during defecation. He was diagnosed via anoscopy with Goligher grade II internal hemorrhoids. Examination via colonoscopy revealed 2 yellowish submucosal tumors in the lower rectum that were 5mm and 10mm in diameter. A rectal carcinoid tumor was diagnosed based on histopathology. Abdominal computed tomography demonstrated no metastases to the liver or lymph nodes. First, we performed ALTA therapy for the internal hemorrhoids. Two weeks later, we performed laparoscopic-assisted low anterior resection (D2) for the rectal carcinoid. The patient was discharged without complications and has not experienced recurrence during the 2 years of follow-up care. PMID:25731340

  4. Primary renal carcinoid tumor: case report and review of the literature

    PubMed Central

    Li, Bin; Cui, Tongyue; Ban, Ziqin; Luo, Lei; Sun, Lijiang

    2016-01-01

    Objective The aim of this case report is to discuss the clinicopathological features of a patient with a primary renal carcinoid tumor. Methods We report on the clinical and pathological information of one case of a patient with a primary renal carcinoid tumor as well as review relative literature. Results The patient was diagnosed with a renal tumor when she received physical examination, and exhibited no positive symptoms. The diameter of tumor was 5 cm, the cross surface of the tumor was light yellow and firm, and the central part was soft with hemorrhage and necrosis. Immunohistochemical staining revealed strong and diffuse staining with synaptophysin, chromogranin A, and neuron-specific enolase. Conclusion A primary renal carcinoid tumor is extremely rare. Surgical resection is a preferred therapeutic method. PMID:26966374

  5. Mouse bone marrow stromal cells differentiate to neuron-like cells upon inhibition of BMP signaling.

    PubMed

    Saxena, Monika; Prashar, Paritosh; Yadav, Prem Swaroop; Sen, Jonaki

    2016-01-01

    Bone marrow stromal cells (BMSCs) are a source of autologous stem cells that have the potential for undergoing differentiation into multiple cell types including neurons. Although the neuronal differentiation of mesenchymal stem cells has been studied for a long time, the molecular players involved are still not defined. Here we report that the genetic deletion of two members of the bone morphogenetic protein (Bmp) family, Bmp2 and Bmp4 in mouse BMSCs causes their differentiation into cells with neuron-like morphology. Surprisingly these cells expressed certain markers characteristic of both neuronal and glial cells. Based on this observation, we inhibited BMP signaling in mouse BMSCs through a brief exposure to Noggin protein which also led to their differentiation into cells expressing both neuronal and glial markers. Such cells seem to have the potential for further differentiation into subtypes of neuronal and glial cells and thus could be utilized for cell-based therapeutic applications.

  6. Downregulation of CCR1 inhibits human hepatocellular carcinoma cell invasion

    SciTech Connect

    Wu Xiaofeng; Fan Jia; E-mail: jiafan99@yahoo.com; Wang Xiaoying; Zhou Jian; Qiu Shuangjian; Yu Yao; Liu Yinkun; Tang Zhaoyou

    2007-04-20

    CC chemokine receptor 1 (CCR1) has an important role in the recruitment of leukocytes to the site of inflammation. The migration and metastasis of tumor cells shares many similarities with leukocyte trafficking, which is mainly regulated by chemokine receptor-ligand interactions. CCR1 is highly expressed in hepatocellular carcinoma (HCC) cells and tissues with unknown functions. In this study, we silenced CCR1 expression in the human HCC cell line HCCLM3 using artificial microRNA (miRNA)-mediated RNA interference (RNAi) and examined the invasiveness and proliferation of CCR1-silenced HCCLM3 cells and the matrix metalloproteinase (MMP) activity. The miRNA-mediated knockdown expression of CCR1 significantly inhibited the invasive ability of HCCLM3 cells, but had only a minor effect on the cellular proliferation rate. Moreover, CCR1 knockdown significantly reduced the secretion of MMP-2. Together, these findings indicate that CCR1 has an important role in HCCLM3 invasion and that CCR1 might be a new target of HCC treatment.

  7. Curcumin associated magnetite nanoparticles inhibit in vitro melanoma cell growth.

    PubMed

    de Souza, Fernanda França; dos Santos, Michelly Christine; dos Passos, Debora Cristina Silva; Lima, Emilia Celma de Oliveira; Guillo, Lidia Andreu

    2011-09-01

    Curcumin is a natural product possessing therapeutic properties but the low water solubility of this compound limits its use. We have successfully incorporated curcumin into a bilayer of dodecanoic acid attached to magnetite nanoparticles in an effort to maximize solubility and delivery efficiency. Curcumin/magnetite nanoparticles were characterized using diffused reflectance infra-red fourier transform spectroscopy (DRIFTS) and X-ray powder diffraction (XRD). Moreover curcumin associated magnetite nanoparticles inhibited in vitro melanoma cell growth. An inhibitory concentration (IC50) of 66.0 +/- 3.0 microM (48 +/- 2.2 microg-iron/mL) was observed for the curcumin/magnetite nanoparticles. Fluorescent microscopy revealed that curcumin associated magnetite nanoparticles were internalized by the melanoma cells and remained in the cytoplasm. The curcumin/magnetic nanoparticles synthesized in this study possess magnetic and water solubility properties making this a novel curcumin formulation with therapeutic potential.

  8. Current concepts in diagnosis and perioperative management of carcinoid heart disease.

    PubMed

    Castillo, Javier G; Silvay, George; Solís, Jorge

    2013-09-01

    Carcinoid tumors are neuroendocrine tumors with a very unpredictable clinical behavior. In the setting of hepatic metastases, the tumor's release of bioactive substances into the systemic circulation results in carcinoid syndrome: a constellation of symptoms among which cutaneous flushing, gastrointestinal hypermotility, and cardiac involvement are the most prominent. Cardiac manifestations, also known as carcinoid heart disease, are secondary to a severe fibrotic reaction which frequently involves the right-sided valves and may extend towards the subvalvular apparatus leading to valve thickening and retraction. Left-sided involvement is rare and mostly observed in the presence of an interatrial shunt, endobronchial tumor localization, and high tumor activity. Echocardiographic techniques often reveal noncoaptation of the valves, which are fixed in a semiopen position. In patients with advanced lesions and severe valvular dysfunction, surgery is currently the only definitive treatment to potentially improve quality of life and provide survival benefit. Although cardiac surgery has been traditionally reserved for those patients with symptomatic right ventricular failure, a significant trend towards improved surgical outcomes has triggered a more liberal referral for valve replacement. Carcinoid heart disease poses two distinct challenges for the anesthesiologist: carcinoid crisis and low cardiac output syndrome secondary to right ventricular failure. Carcinoid crisis, characterized by flushing, hypotension, and bronchospasm, may be precipitated by catecholamines and histamine releasing drugs used routinely in patients undergoing valve surgery. Although a broader utilization of octreotide have significantly simplified the anesthetic and perioperative management of these patients, a very balanced anesthetic technique is required to identify and manage low cardiac output syndrome.

  9. Curcumin Inhibits Rift Valley Fever Virus Replication in Human Cells*

    PubMed Central

    Narayanan, Aarthi; Kehn-Hall, Kylene; Senina, Svetlana; Lundberg, Lindsay; Van Duyne, Rachel; Guendel, Irene; Das, Ravi; Baer, Alan; Bethel, Laura; Turell, Michael; Hartman, Amy Lynn; Das, Bhaskar; Bailey, Charles; Kashanchi, Fatah

    2012-01-01

    Rift Valley fever virus (RVFV) is an arbovirus that is classified as a select agent, an emerging infectious virus, and an agricultural pathogen. Understanding RVFV-host interactions is imperative to the design of novel therapeutics. Here, we report that an infection by the MP-12 strain of RVFV induces phosphorylation of the p65 component of the NFκB cascade. We demonstrate that phosphorylation of p65 (serine 536) involves phosphorylation of IκBα and occurs through the classical NFκB cascade. A unique, low molecular weight complex of the IKK-β subunit can be observed in MP-12-infected cells, which we have labeled IKK-β2. The IKK-β2 complex retains kinase activity and phosphorylates an IκBα substrate. Inhibition of the IKK complex using inhibitors impairs viral replication, thus alluding to the requirement of an active IKK complex to the viral life cycle. Curcumin strongly down-regulates levels of extracellular infectious virus. Our data demonstrated that curcumin binds to and inhibits kinase activity of the IKK-β2 complex in infected cells. Curcumin partially exerts its inhibitory influence on RVFV replication by interfering with IKK-β2-mediated phosphorylation of the viral protein NSs and by altering the cell cycle of treated cells. Curcumin also demonstrated efficacy against ZH501, the fully virulent version of RVFV. Curcumin treatment down-regulated viral replication in the liver of infected animals. Our data point to the possibility that RVFV infection may result in the generation of novel versions of host components (such as IKK-β2) that, by virtue of altered protein interaction and function, qualify as unique therapeutic targets. PMID:22847000

  10. T-705 (favipiravir) inhibition of arenavirus replication in cell culture.

    PubMed

    Mendenhall, Michelle; Russell, Andrew; Juelich, Terry; Messina, Emily L; Smee, Donald F; Freiberg, Alexander N; Holbrook, Michael R; Furuta, Yousuke; de la Torre, Juan-Carlos; Nunberg, Jack H; Gowen, Brian B

    2011-02-01

    A number of New World arenaviruses (Junín [JUNV], Machupo [MACV], and Guanarito [GTOV] viruses) can cause human disease ranging from mild febrile illness to a severe and often fatal hemorrhagic fever syndrome. These highly pathogenic viruses and the Old World Lassa fever virus pose a significant threat to public health and national security. The only licensed antiviral agent with activity against these viruses, ribavirin, has had mixed success in treating severe arenaviral disease and is associated with significant toxicities. A novel pyrazine derivative currently in clinical trials for the treatment of influenza virus infections, T-705 (favipiravir), has demonstrated broad-spectrum activity against a number of RNA viruses, including arenaviruses. T-705 has also been shown to be effective against Pichinde arenavirus infection in a hamster model. Here, we demonstrate the robust antiviral activity of T-705 against authentic highly pathogenic arenaviruses in cell culture. We show that T-705 disrupts an early or intermediate stage in viral replication, distinct from absorption or release, and that its antiviral activity in cell culture is reversed by the addition of purine bases and nucleosides, but not with pyrimidines. Specific inhibition of viral replication/transcription by T-705 was demonstrated using a lymphocytic choriomeningitis arenavirus replicon system. Our findings indicate that T-705 acts to inhibit arenavirus replication/transcription and may directly target the viral RNA-dependent RNA polymerase.

  11. Broadly neutralizing antibodies that inhibit HIV-1 cell to cell transmission

    PubMed Central

    Malbec, Marine; Porrot, Françoise; Rua, Rejane; Horwitz, Joshua; Klein, Florian; Halper-Stromberg, Ari; Scheid, Johannes F.; Eden, Caroline; Mouquet, Hugo; Nussenzweig, Michel C.

    2013-01-01

    The neutralizing activity of anti–HIV-1 antibodies is typically measured in assays where cell-free virions enter reporter cell lines. However, HIV-1 cell to cell transmission is a major mechanism of viral spread, and the effect of the recently described broadly neutralizing antibodies (bNAbs) on this mode of transmission remains unknown. Here we identify a subset of bNAbs that inhibit both cell-free and cell-mediated infection in primary CD4+ lymphocytes. These antibodies target either the CD4-binding site (NIH45-46 and 3BNC60) or the glycan/V3 loop (10-1074 and PGT121) on HIV-1 gp120 and act at low concentrations by inhibiting multiple steps of viral cell to cell transmission. These antibodies accumulate at virological synapses and impair the clustering and fusion of infected and target cells and the transfer of viral material to uninfected T cells. In addition, they block viral cell to cell transmission to plasmacytoid DCs and thereby interfere with type-I IFN production. Thus, only a subset of bNAbs can efficiently prevent HIV-1 cell to cell transmission, and this property should be considered an important characteristic defining antibody potency for therapeutic or prophylactic antiviral strategies. PMID:24277152

  12. Cushing's like syndrome in typical bronchial carcinoid a case report and review of the literature.

    PubMed

    Pedicelli, Ilaria; Patriciello, Giuseppina; Scala, Giovanni; Sorrentino, Antonietta; Gravino, Gennaro; Patriciello, Pasquale; Zeppa, Pio; Di Crescenzo, Vincenzo; Vatrella, Alessandro

    2016-01-01

    Cushing's syndrome occurred in 1-5% of cases of bronchial carcinoids. In this paper we describe a case of typical bronchial carcinoid in a nonsmoker young male with clinical manifestations mimicking a Cushing's syndrome. The patient performed chest radiograph and computed tomography. Fiberoptic bronchoscopy revealed the presence of an endobronchial mass occluding the bronchus intermedius. A rigid bronchoscopy was necessary for the conclusive diagnosis and for partial resection of the intraluminal tumor. Despite of the presence of Cushingoid features, the normal blood levels of ACTH and cortisol excluded the coexistence of a Cushing's syndrome. PMID:26923475

  13. Photodynamic therapy for bronchial carcinoid tumours: complete response over a 10-year follow-up.

    PubMed

    Moghissi, Keyvan; Dixon, Kate; Gibbins, Sally

    2013-06-01

    A 63-year old woman diagnosed in September 2001 with a typical bronchial carcinoid of the left upper lobe bronchus extending into the left main stem bronchus is presented. The patient was unsuitable for standard surgical treatment, and the topography was not amenable for a parenchyma-saving bronchoplastic procedure. Two cycles of bronchoscopic photodynamic therapy (PDT) were undertaken at 6 monthly intervals. The patient has now been followed up regularly for over 10 years without signs of recurrence bronchoscopically or radiologically. To our knowledge, this is the first case of a carcinoid tumour treated solely by PDT. PMID:23284100

  14. Cushing's like syndrome in typical bronchial carcinoid a case report and review of the literature.

    PubMed

    Pedicelli, Ilaria; Patriciello, Giuseppina; Scala, Giovanni; Sorrentino, Antonietta; Gravino, Gennaro; Patriciello, Pasquale; Zeppa, Pio; Di Crescenzo, Vincenzo; Vatrella, Alessandro

    2016-01-01

    Cushing's syndrome occurred in 1-5% of cases of bronchial carcinoids. In this paper we describe a case of typical bronchial carcinoid in a nonsmoker young male with clinical manifestations mimicking a Cushing's syndrome. The patient performed chest radiograph and computed tomography. Fiberoptic bronchoscopy revealed the presence of an endobronchial mass occluding the bronchus intermedius. A rigid bronchoscopy was necessary for the conclusive diagnosis and for partial resection of the intraluminal tumor. Despite of the presence of Cushingoid features, the normal blood levels of ACTH and cortisol excluded the coexistence of a Cushing's syndrome.

  15. Salidroside inhibits endogenous hydrogen peroxide induced cytotoxicity of endothelial cells.

    PubMed

    Zhao, Xingyu; Jin, Lianhai; Shen, Nan; Xu, Bin; Zhang, Wei; Zhu, Hongli; Luo, Zhengli

    2013-01-01

    Salidroside, a phenylpropanoid glycoside isolated from Rhodiola rosea L., shows potent antioxidant property. Herein, we investigated the protective effects of salidroside against hydrogen peroxide (H2O2)-induced oxidative damage in human endothelial cells (EVC-304). EVC-304 cells were incubated in the presence or absence of low steady states of H2O2 (3-4 µM) generated by glucose oxidase (GOX) with or without salidroside. 3(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) assays were performed, together with Hoechst 33258 staining and flow cytometric analysis using Annexin-V and propidium iodide (PI) label. The results indicated that salidroside pretreatment attenuated endogenous H2O2 induced apoptotic cell death in EVC-304 cells in a dose-dependent pattern. Furthermore, Western blot data revealed that salidroside inhibited activation of caspase-3, 9 and cleavage of poly(ADP-ribose) polymerase (PARP) induced by endogenous H2O2. It also decreased the expression of Bax and rescued the balance of pro- and anti-apoptotic proteins. All these results demonstrated that salidroside may present a potential therapy for oxidative stress in cardiovascular and cerebrovascular diseases.

  16. Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2.

    PubMed

    Deshane, Jessy; Garner, Craig C; Sontheimer, Harald

    2003-02-01

    Primary brain tumors (gliomas) have the unusual ability to diffusely infiltrate the normal brain thereby evading surgical treatment. Chlorotoxin is a scorpion toxin that specifically binds to the surface of glioma cells and impairs their ability to invade. Using a recombinant His-Cltx we isolated and identified the principal Cltx receptor on the surface of glioma cells as matrix metalloproteinase-2 (MMP-2). MMP-2 is specifically up-regulated in gliomas and related cancers, but is not normally expressed in brain. We demonstrate that Cltx specifically and selectively interacts with MMP-2 isoforms, but not with MMP-1, -3, and -9, which are also expressed in malignant glioma cells. Importantly, we show that the anti-invasive effect of Cltx on glioma cells can be explained by its interactions with MMP-2. Cltx exerts a dual effect on MMP-2: it inhibits the enzymatic activity of MMP-2 and causes a reduction in the surface expression of MMP-2. These findings suggest that Cltx is a specific MMP-2 inhibitor with significant therapeutic potential for gliomas and other diseases that invoke the activity of MMP-2.

  17. Dextromethorphan Inhibits Activations and Functions in Dendritic Cells

    PubMed Central

    Chen, Der-Yuan; Song, Pei-Shan; Hong, Jau-Shyong; Chu, Ching-Liang; Pan, I-Horng; Chen, Yi-Ming; Lin, Ching-Hsiung; Lin, Sheng-Hao; Lin, Chi-Chen

    2013-01-01

    Dendritic cells (DCs) play an important role in connecting innate and adaptive immunity. Thus, DCs have been regarded as a major target for the development of immunomodulators. In this study, we examined the effect of dextromethorphan (DXM), a common cough suppressant with a high safety profile, on the activation and function of DCs. In the presence of DXM, the LPS-induced expression of the costimulatory molecules in murine bone marrow-derived dendritic cells (BMDCs) was significantly suppressed. In addition, DXM treatment reduced the production of reactive oxygen species (ROS), proinflammatory cytokines, and chemokines in maturing BMDCs that were activated by LPS. Therefore, DXM abrogated the ability of LPS-stimulated DCs to induce Ag-specific T-cell activation, as determined by their decreased proliferation and IFN-γ secretion in mixed leukocyte cultures. Moreover, the inhibition of LPS-induced MAPK activation and NF-κB translocation may contribute to the suppressive effect of DXM on BMDCs. Remarkably, DXM decreased the LPS-induced surface expression of CD80, CD83, and HLA-DR and the secretion of IL-6 and IL-12 in human monocyte-derived dendritic cells (MDDCs). These findings provide a new insight into the impact of DXM treatment on DCs and suggest that DXM has the potential to be used in treating DC-related acute and chronic diseases. PMID:23781253

  18. Dextromethorphan inhibits activations and functions in dendritic cells.

    PubMed

    Chen, Der-Yuan; Song, Pei-Shan; Hong, Jau-Shyong; Chu, Ching-Liang; Pan, I-Horng; Chen, Yi-Ming; Lin, Ching-Hsiung; Lin, Sheng-Hao; Lin, Chi-Chen

    2013-01-01

    Dendritic cells (DCs) play an important role in connecting innate and adaptive immunity. Thus, DCs have been regarded as a major target for the development of immunomodulators. In this study, we examined the effect of dextromethorphan (DXM), a common cough suppressant with a high safety profile, on the activation and function of DCs. In the presence of DXM, the LPS-induced expression of the costimulatory molecules in murine bone marrow-derived dendritic cells (BMDCs) was significantly suppressed. In addition, DXM treatment reduced the production of reactive oxygen species (ROS), proinflammatory cytokines, and chemokines in maturing BMDCs that were activated by LPS. Therefore, DXM abrogated the ability of LPS-stimulated DCs to induce Ag-specific T-cell activation, as determined by their decreased proliferation and IFN- γ secretion in mixed leukocyte cultures. Moreover, the inhibition of LPS-induced MAPK activation and NF- κ B translocation may contribute to the suppressive effect of DXM on BMDCs. Remarkably, DXM decreased the LPS-induced surface expression of CD80, CD83, and HLA-DR and the secretion of IL-6 and IL-12 in human monocyte-derived dendritic cells (MDDCs). These findings provide a new insight into the impact of DXM treatment on DCs and suggest that DXM has the potential to be used in treating DC-related acute and chronic diseases. PMID:23781253

  19. ABCB5-Targeted Chemoresistance Reversal Inhibits Merkel Cell Carcinoma Growth.

    PubMed

    Kleffel, Sonja; Lee, Nayoung; Lezcano, Cecilia; Wilson, Brian J; Sobolewski, Kristine; Saab, Karim R; Mueller, Hansgeorg; Zhan, Qian; Posch, Christian; Elco, Christopher P; DoRosario, Andrew; Garcia, Sarah S; Thakuria, Manisha; Wang, Yaoyu E; Wang, Linda C; Murphy, George F; Frank, Markus H; Schatton, Tobias

    2016-04-01

    Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with profound but poorly understood resistance to chemotherapy, which poses a significant barrier to clinical MCC treatment. Here we show that ATP-binding cassette member B5 (ABCB5) confers resistance to standard-of-care MCC chemotherapeutic agents and provide proof-of-principle that ABCB5 blockade can inhibit human MCC tumor growth through sensitization to drug-induced cell cytotoxicity. ABCB5 expression was detected in both established MCC lines and clinical MCC specimens at levels significantly higher than those in normal skin. Carboplatin- and etoposide-resistant MCC cell lines exhibited increased expression of ABCB5, along with enhanced ABCB1 and ABCC3 transcript expression. ABCB5-expressing MCC cells in heterogeneous cancers preferentially survived treatment with carboplatin and etoposide in vitro and in human MCC xenograft-bearing mice in vivo. Moreover, patients with MCC also exhibited enhanced ABCB5 positivity after carboplatin- and etoposide-based chemotherapy, pointing to clinical significance of this chemoresistance mechanism. Importantly, ABCB5 blockade reversed MCC drug resistance and impaired tumor growth in xenotransplantation models in vivo. Our results establish ABCB5 as a chemoresistance mechanism in MCC and suggest utility of this molecular target for improved MCC therapy. PMID:26827764

  20. Vasoactive intestinal peptide (VIP) inhibits human renal cell carcinoma proliferation.

    PubMed

    Vacas, Eva; Fernández-Martínez, Ana B; Bajo, Ana M; Sánchez-Chapado, Manuel; Schally, Andrew V; Prieto, Juan C; Carmena, María J

    2012-10-01

    Clear renal cell carcinoma (cRCC) is an aggressive and fatal neoplasm. The present work was undertaken to investigate the antiproliferative potential of vasoactive intestinal peptide (VIP) exposure on non-tumoral (HK2) and tumoral (A498, cRCC) human proximal tubular epithelial cell lines. Reverse transcription and semiquantitative PCR was used at the VIP mRNA level whereas enzyme immunoanalysis was performed at the protein level. Both renal cell lines expressed VIP as well as VIP/pituitary adenylate cyclase-activating peptide (VPAC) receptors whereas only HK2 cells expressed formyl peptide receptor-like 1 (FPRL-1). Receptors were functional, as shown by VIP stimulation of adenylyl cyclase activity. Treatment with 0.1μM VIP (24h) inhibited proliferation of A498 but not HK2 cells as based on a reduction in the incorporation of [(3)H]-thymidine and BrdU (5'-Br-2'-deoxyuridine), PCNA (proliferating-cell nuclear antigen) expression and STAT3 (signal transducer and activator of transcription 3) expression and activation. VPAC(1)-receptor participation was established using JV-1-53 antagonist and siRNA transfection. Growth-inhibitory response to VIP was related to the cyclic adenosine monophosphate (cAMP)/exchange protein directly activated by cAMP (EPAC)/phosphoinositide 3-kinase (PI3-K) signaling systems as shown by studies on adenylate cyclase stimulation, and using the EPAC-specific compound 8CPT-2Me-cAMP and specific kinase inhibitors such as H89, wortmannin and PD98059. The efficacy of VIP on the prevention of tumor progression was confirmed in vivo using xenografted athymic mouse. These actions support a potential role of this peptide and its agonists in new therapies for cRCC.

  1. Phloroglucinol suppresses metastatic ability of breast cancer cells by inhibition of epithelial-mesenchymal cell transition.

    PubMed

    Kim, Rae-Kwon; Suh, Yongjoon; Yoo, Ki-Chun; Cui, Yan-Hong; Hwang, Eunji; Kim, Hyun-Jin; Kang, Ju-Seop; Kim, Min-Jung; Lee, Young Yiul; Lee, Su-Jae

    2015-01-01

    Metastasis is a challenging clinical problem and the primary cause of death in breast cancer patients. However, there is no therapeutic agent against metastasis of breast cancer cells. Here we report that phloroglucinol, a natural phlorotannin component of brown algae suppresses metastatic ability of breast cancer cells. Treatment with phloroglucinol effectively inhibited mesenchymal phenotypes of basal type breast cancer cells through downregulation of SLUG without causing a cytotoxic effect. Importantly, phloroglucinol decreased SLUG through inhibition of PI3K/AKT and RAS/RAF-1/ERK signaling. In agreement with in vitro data, phloroglucinol was also effective against in vivo metastasis of breast cancer cells, drastically suppressing their metastatic ability to lungs, and extending the survival time of mice. Collectively, our findings demonstrate a novel anticancer activity of phloroglucinol against metastasis of breast cancer cells, implicating its clinical relevance. PMID:25456733

  2. The marine-derived fungal metabolite, terrein, inhibits cell proliferation and induces cell cycle arrest in human ovarian cancer cells.

    PubMed

    Chen, Yi-Fei; Wang, Shu-Ying; Shen, Hong; Yao, Xiao-Fen; Zhang, Feng-Li; Lai, Dongmei

    2014-12-01

    The difficulties faced in the effective treatment of ovarian cancer are multifactorial, but are mainly associated with relapse and drug resistance. Cancer stem-like cells have been reported to be an important contributor to these hindering factors. In this study, we aimed to investigate the anticancer activities of a bioactive fungal metabolite, namely terrein, against the human epithelial ovarian cancer cell line, SKOV3, primary human ovarian cancer cells and ovarian cancer stem-like cells. Terrein was separated and purified from the fermentation metabolites of the marine sponge-derived fungus, Aspergillus terreus strain PF26. Its anticancer activities against ovarian cancer cells were investigated by cell proliferation assay, cell migration assay, cell apoptosis and cell cycle assays. The ovarian cancer stem-like cells were enriched and cultured in a serum-free in vitro suspension system. Terrein inhibited the proliferation of the ovarian cancer cells by inducing G2/M phase cell cycle arrest. The underlying mechanisms involved the suppression of the expression of LIN28, an important marker gene of stemness in ovarian cancer stem cells. Of note, our study also demonstrated the ability of terrein to inhibit the proliferation of ovarian cancer stem-like cells, in which the expression of LIN28 was also downregulated. Our findings reveal that terrein (produced by fermention) may prove to be a promising drug candidate for the treatment of ovarian cancer by inhibiting the proliferation of cancer stem-like cells.

  3. Chlorpyrifos inhibits cell proliferation through ERK1/2 phosphorylation in breast cancer cell lines.

    PubMed

    Ventura, Clara; Venturino, Andrés; Miret, Noelia; Randi, Andrea; Rivera, Elena; Núñez, Mariel; Cocca, Claudia

    2015-02-01

    It is well known the participation of oxidative stress in the induction and development of different pathologies including cancer, diabetes, neurodegeneration and respiratory disorders among others. It has been reported that oxidative stress may be induced by pesticides and it could be the cause of health alteration mediated by pollutants exposure. Large number of registered products containing chlorpyrifos (CPF) is used to control pest worldwide. We have previously reported that 50 μM CPF induces ROS generation and produces cell cycle arrest followed by cell death. The present investigation was designed to identify the pathway involved in CPF-inhibited cell proliferation in MCF-7 and MDA-MB-231 breast cancer cell lines. In addition, we determined if CPF-induced oxidative stress is related to alterations in antioxidant defense system. Finally we studied the molecular mechanisms underlying in the cell proliferation inhibition produced by the pesticide. In this study we demonstrate that CPF (50 μM) induces redox imbalance altering the antioxidant defense system in breast cancer cells. Furthermore, we found that the main mechanism involved in the inhibition of cell proliferation induced by CPF is an increment of p-ERK1/2 levels mediated by H2O2 in breast cancer cells. As PD98059 could not abolish the increment of ROS induced by CPF, we concluded that ERK1/2 phosphorylation is subsequent to ROS production induced by CPF but not the inverse. PMID:25180937

  4. A Novel Small Molecular STAT3 Inhibitor, LY5, Inhibits Cell Viability, Cell Migration, and Angiogenesis in Medulloblastoma Cells*

    PubMed Central

    Xiao, Hui; Bid, Hemant Kumar; Jou, David; Wu, Xiaojuan; Yu, Wenying; Li, Chenglong; Houghton, Peter J.; Lin, Jiayuh

    2015-01-01

    Signal transducers and activators of transcription 3 (STAT3) signaling is persistently activated and could contribute to tumorigenesis of medulloblastoma. Numerous studies have demonstrated that inhibition of the persistent STAT3 signaling pathway results in decreased proliferation and increased apoptosis in human cancer cells, indicating that STAT3 is a viable molecular target for cancer therapy. In this study, we investigated a novel non-peptide, cell-permeable small molecule, named LY5, to target STAT3 in medulloblastoma cells. LY5 inhibited persistent STAT3 phosphorylation and induced apoptosis in human medulloblastoma cell lines expressing constitutive STAT3 phosphorylation. The inhibition of STAT3 signaling by LY5 was confirmed by down-regulating the expression of the downstream targets of STAT3, including cyclin D1, bcl-XL, survivin, and micro-RNA-21. LY5 also inhibited the induction of STAT3 phosphorylation by interleukin-6 (IL-6), insulin-like growth factor (IGF)-1, IGF-2, and leukemia inhibitory factor in medulloblastoma cells, but did not inhibit STAT1 and STAT5 phosphorylation stimulated by interferon-γ (IFN-γ) and EGF, respectively. In addition, LY5 blocked the STAT3 nuclear localization induced by IL-6, but did not block STAT1 and STAT5 nuclear translocation mediated by IFN-γ and EGF, respectively. A combination of LY5 with cisplatin or x-ray radiation also showed more potent effects than single treatment alone in the inhibition of cell viability in human medulloblastoma cells. Furthermore, LY5 demonstrated a potent inhibitory activity on cell migration and angiogenesis. Taken together, these findings indicate LY5 inhibits persistent and inducible STAT3 phosphorylation and suggest that LY5 is a promising therapeutic drug candidate for medulloblastoma by inhibiting persistent STAT3 signaling. PMID:25313399

  5. Aptamers Binding to c-Met Inhibiting Tumor Cell Migration.

    PubMed

    Piater, Birgit; Doerner, Achim; Guenther, Ralf; Kolmar, Harald; Hock, Bjoern

    2015-01-01

    The human receptor tyrosine kinase c-Met plays an important role in the control of critical cellular processes. Since c-Met is frequently over expressed or deregulated in human malignancies, blocking its activation is of special interest for therapy. In normal conditions, the c-Met receptor is activated by its bivalent ligand hepatocyte growth factor (HGF). Also bivalent antibodies can activate the receptor by cross linking, limiting therapeutic applications. We report the generation of the RNA aptamer CLN64 containing 2'-fluoro pyrimidine modifications by systematic evolution of ligands by exponential enrichment (SELEX). CLN64 and a previously described single-stranded DNA (ssDNA) aptamer CLN3 exhibited high specificities and affinities to recombinant and cellular expressed c-Met. Both aptamers effectively inhibited HGF-dependent c-Met activation, signaling and cell migration. We showed that these aptamers did not induce c-Met activation, revealing an advantage over bivalent therapeutic molecules. Both aptamers were shown to bind overlapping epitopes but only CLN3 competed with HGF binding to cMet. In addition to their therapeutic and diagnostic potential, CLN3 and CLN64 aptamers exhibit valuable tools to further understand the structural and functional basis for c-Met activation or inhibition by synthetic ligands and their interplay with HGF binding. PMID:26658271

  6. Astaxanthin Inhibits Proliferation of Human Gastric Cancer Cell Lines by Interrupting Cell Cycle Progression

    PubMed Central

    Kim, Jung Ha; Park, Jong-Jae; Lee, Beom Jae; Joo, Moon Kyung; Chun, Hoon Jai; Lee, Sang Woo; Bak, Young-Tae

    2016-01-01

    Background/Aims Astaxanthin is a carotenoid pigment that has antioxidant, antitumoral, and anti-inflammatory properties. In this in vitro study, we investigated the mechanism of anticancer effects of astaxanthin in gastric carcinoma cell lines. Methods The human gastric adenocarcinoma cell lines AGS, KATO-III, MKN-45, and SNU-1 were treated with various concentrations of astaxanthin. A cell viability test, cell cycle analysis, and immunoblotting were performed. Results The viability of each cancer cell line was suppressed by astaxanthin in a dose-dependent manner with significantly decreased proliferation in KATO-III and SNU-1 cells. Astaxanthin increased the number of cells in the G0/G1 phase but reduced the proportion of S phase KATO-III and SNU-1 cells. Phosphorylated extracellular signal-regulated kinase (ERK) was decreased in an inverse dose-dependent correlation with astaxanthin concentration, and the expression of p27kip-1 increased the KATO-III and SNU-1 cell lines in an astaxanthin dose-dependent manner. Conclusions Astaxanthin inhibits proliferation by interrupting cell cycle progression in KATO-III and SNU-1 gastric cancer cells. This may be caused by the inhibition of the phosphorylation of ERK and the enhanced expression of p27kip-1. PMID:26470770

  7. Resveratrol induces cell death and inhibits human herpesvirus 8 replication in primary effusion lymphoma cells.

    PubMed

    Tang, Feng-Yi; Chen, Chang-Yu; Shyu, Huey-Wen; Hong, Shin; Chen, Hung-Ming; Chiou, Yee-Hsuan; Lin, Kuan-Hua; Chou, Miao-Chen; Wang, Lin-Yu; Wang, Yi-Fen

    2015-12-01

    Resveratrol (3,4',5-trihydroxy-trans-stilbene) has been reported to inhibit proliferation of various cancer cells. However, the effects of resveratrol on the human herpesvirus 8 (HHV8) harboring primary effusion lymphoma (PEL) cells remains unclear. The anti-proliferation effects and possible mechanisms of resveratrol in the HHV8 harboring PEL cells were examined in this study. Results showed that resveratrol induced caspase-3 activation and the formation of acidic vacuoles in the HHV8 harboring PEL cells, indicating resveratrol treatment could cause apoptosis and autophagy in PEL cells. In addition, resveratrol treatment increased ROS generation but did not lead to HHV8 reactivation. ROS scavenger (N-acetyl cysteine, NAC) could attenuate both the resveratrol induced caspase-3 activity and the formation of acidic vacuoles, but failed to attenuate resveratrol induced PEL cell death. Caspase inhibitor, autophagy inhibitors and necroptosis inhibitor could not block resveratrol induced PEL cell death. Moreover, resveratrol disrupted HHV8 latent infection, inhibited HHV8 lytic gene expression and decreased virus progeny production. Overexpression of HHV8-encoded viral FLICE inhibitory protein (vFLIP) could partially block resveratrol induced cell death in PEL cells. These data suggest that resveratrol-induced cell death in PEL cells may be mediated by disruption of HHV8 replication. Resveratrol may be a potential anti-HHV8 drug and an effective treatment for HHV8-related tumors.

  8. Glycosylation inhibitors efficiently inhibit P-selectin-mediated cell adhesion to endothelial cells.

    PubMed

    Ghoshal, Pushpankur; Rajendran, Mythilypriya; Odo, Nadine; Ikuta, Tohru

    2014-01-01

    Adhesion molecules play a critical role in the adhesive interactions of multiple cell types in sickle cell disease (SCD). We previously showed that anti-P-selectin aptamer efficiently inhibits cell adhesion to endothelial cells (ECs) and permits SCD mice to survive hypoxic stress. In an effort to discover new mechanisms with which to inhibit P-selectin, we examined the role of glycosylation. P-selectin is a 90 kDa protein but was found to migrate as 90 and 140 kDa bands on gel electrophoresis. When P-selectin isolated from ECs was digested with peptide N-glycosidase F, but not O-glycosidase, the 140 kDa band was lost and the 90 kDa band was enhanced. Treatment of ECs with tunicamycin, an N-glycosylation inhibitor, suppressed CD62P (P-selectin) expression on the cell surface as well as the 140 kDa form in the cytoplasm. These results indicate that the 140 kDa band is N-glycosylated and glycosylation is critical for cell surface expression of P-selectin in ECs. Thrombin, which stimulates P-selectin expression on ECs, induced AKT phosphorylation, whereas tunicamycin inhibited AKT phosphorylation, suggesting that AKT signaling is involved in the tunicamycin-mediated inhibition of P-selectin expression. Importantly, the adhesion of sickle red blood cells (sRBCs) and leukocytes to ECs induced by thrombin or hypoxia was markedly inhibited by two structurally distinct glycosylation inhibitors; the levels of which were comparable to that of a P-selectin monoclonal antibody which most strongly inhibited cell adhesion in vivo. Knockdown studies of P-selectin using short-hairpin RNAs in ECs suppressed sRBC adhesion, indicating a legitimate role for P-selectin in sRBC adhesion. Together, these results demonstrate that P-selectin expression on ECs is regulated in part by glycosylation mechanisms and that glycosylation inhibitors efficiently reduce the adhesion of sRBCs and leukocytes to ECs. Glycosylation inhibitors may lead to a novel therapy which inhibits cell adhesion in SCD.

  9. Contact inhibition of phagocytosis in epithelial sheets: alterations of cell surface properties induced by cell-cell contacts.

    PubMed Central

    Vasiliev, J M; Gelfand, I M; Domnina, L V; Zacharova, O S; Ljubimov, A V

    1975-01-01

    Contact inhibition of phagocytosis was found to be characteristic for epithelial sheets formed in cultures by several cell types: normal and transformed mouse kidney cells, and differentiated mouse hepatoma cells. In these sheets most central cells surrounded by other cells had very low phagocytic activity. In contrast, marginal cells having a free edge were able to perform an active phagocytosis. Contact inhibition of phagocytosis was absent in dense cultures of mouse embryo fibroblasts and in cultures of anaplastic mouse hepatoma 22a. The upper surface of epithelial sheets was nonadhesive for prelabeled epithelial cells and fibroblasts. In contrast, the upper surface of dense cultures of mouse fibroblasts was adhesive for these cells. These and other data strengthen the suggestion that contact inhibition of phagocytosis is a result of different adhesiveness of the upper cell surface and of the surfaces near the free edge. Agents inhibiting cell surface movements at the free edges of marginal epithelial cells (cytochalasin, azide, sorbitol, low temperature) prevented adhesion of particles to these edges. Possibly, the surface of actively moving cytoplasmic processes is the only cell part that has adhesive properties necessary for the formation of attachments with other cellular and noncellular surfaces. In epithelial sheets, in contrast to fibroblast cultures, Colcemid did not activate movements of immobile contacting cell edges. These results indicate that mechanisms of contact immobilization of cell surface may be different in epithelium and fibroblasts. Firm contacts formed between epithelial cells are sufficient for stable immobilization of the surface; additional stabilization of the surface by microtubules is not essential. Fibroblasts do not form firm contacts and the Colcemid-sensitive stabilization process is essential for maintenance of the immobile state of their surfaces. Differences in the stability of cell surface immobilization produced by cell-cell

  10. Lichen Secondary Metabolite, Physciosporin, Inhibits Lung Cancer Cell Motility.

    PubMed

    Yang, Yi; Park, So-Yeon; Nguyen, Thanh Thi; Yu, Young Hyun; Nguyen, Tru Van; Sun, Eun Gene; Udeni, Jayalal; Jeong, Min-Hye; Pereira, Iris; Moon, Cheol; Ha, Hyung-Ho; Kim, Kyung Keun; Hur, Jae-Seoun; Kim, Hangun

    2015-01-01

    Lichens produce various unique chemicals that can be used for pharmaceutical purposes. To screen for novel lichen secondary metabolites showing inhibitory activity against lung cancer cell motility, we tested acetone extracts of 13 lichen samples collected in Chile. Physciosporin, isolated from Pseudocyphellaria coriacea (Hook f. & Taylor) D.J. Galloway & P. James, was identified as an effective compound and showed significant inhibitory activity in migration and invasion assays against human lung cancer cells. Physciosporin treatment reduced both protein and mRNA levels of N-cadherin with concomitant decreases in the levels of epithelial-mesenchymal transition markers such as snail and twist. Physciosporin also suppressed KITENIN (KAI1 C-terminal interacting tetraspanin)-mediated AP-1 activity in both the absence and presence of epidermal growth factor stimulation. Quantitative real-time PCR analysis showed that the expression of the metastasis suppressor gene, KAI1, was increased while that of the metastasis enhancer gene, KITENIN, was dramatically decreased by physciosporin. Particularly, the activity of 3'-untranslated region of KITENIN was decreased by physciosporin. Moreover, Cdc42 and Rac1 activities were decreased by physciosporin. These results demonstrated that the lichen secondary metabolite, physciosporin, inhibits lung cancer cell motility through novel mechanisms of action. PMID:26371759

  11. Homocysteine injures vascular endothelial cells by inhibiting mitochondrial activity

    PubMed Central

    Yang, Fengyong; Qi, Xiujing; Gao, Zheng; Yang, Xingju; Zheng, Xingfeng; Duan, Chonghao; Zheng, Jian

    2016-01-01

    The aim of the present study was to investigate the role of homocysteine (Hcy) in the pathogenesis of pulmonary embolism (PE) and the associated molecular mechanisms in human umbilical vein endothelial cells (HUVECs). Hcy contents were detected with high-performance liquid chromatography. Apoptosis was detected by flow cytometry using Annexin-V staining. Cytochrome c oxidase (COX) activity was assessed with an enzyme activity assay, and the expression levels of COX 17 were determined by western blot analysis. Intracellular reactive oxygen species levels were measured using a microplate reader with a fluorescence probe. The results demonstrated that, compared with the control group, the serum Hcy levels were significantly elevated in the PE group, suggesting that Hcy may be an indicator for PE. Following treatment with Hcy, the apoptosis rate was markedly elevated in HUVECs. Moreover, Hcy decreased COX activity and downregulated the expression of COX 17 in HUVECs. Furthermore, Hcy increased the ROS levels in these endothelial cells. However, all the above-mentioned physiopathological changes induced by Hcy in HUVECs could be restored by folic acid. In conclusion, the results of the present study demonstrated that Hcy inhibited COX activity, downregulated COX 17 expression, increased intracellular ROS levels and enhanced apoptosis in endothelial cells.

  12. Lichen Secondary Metabolite, Physciosporin, Inhibits Lung Cancer Cell Motility

    PubMed Central

    Yang, Yi; Park, So-Yeon; Nguyen, Thanh Thi; Yu, Young Hyun; Nguyen, Tru Van; Sun, Eun Gene; Udeni, Jayalal; Jeong, Min-Hye; Pereira, Iris; Moon, Cheol; Ha, Hyung-Ho; Kim, Kyung Keun; Hur, Jae-Seoun; Kim, Hangun

    2015-01-01

    Lichens produce various unique chemicals that can be used for pharmaceutical purposes. To screen for novel lichen secondary metabolites showing inhibitory activity against lung cancer cell motility, we tested acetone extracts of 13 lichen samples collected in Chile. Physciosporin, isolated from Pseudocyphellaria coriacea (Hook f. & Taylor) D.J. Galloway & P. James, was identified as an effective compound and showed significant inhibitory activity in migration and invasion assays against human lung cancer cells. Physciosporin treatment reduced both protein and mRNA levels of N-cadherin with concomitant decreases in the levels of epithelial-mesenchymal transition markers such as snail and twist. Physciosporin also suppressed KITENIN (KAI1 C-terminal interacting tetraspanin)-mediated AP-1 activity in both the absence and presence of epidermal growth factor stimulation. Quantitative real-time PCR analysis showed that the expression of the metastasis suppressor gene, KAI1, was increased while that of the metastasis enhancer gene, KITENIN, was dramatically decreased by physciosporin. Particularly, the activity of 3’-untranslated region of KITENIN was decreased by physciosporin. Moreover, Cdc42 and Rac1 activities were decreased by physciosporin. These results demonstrated that the lichen secondary metabolite, physciosporin, inhibits lung cancer cell motility through novel mechanisms of action. PMID:26371759

  13. Mitochondrial thiol modification by a targeted electrophile inhibits metabolism in breast adenocarcinoma cells by inhibiting enzyme activity and protein levels.

    PubMed

    Smith, M Ryan; Vayalil, Praveen K; Zhou, Fen; Benavides, Gloria A; Beggs, Reena R; Golzarian, Hafez; Nijampatnam, Bhavitavya; Oliver, Patsy G; Smith, Robin A J; Murphy, Michael P; Velu, Sadanandan E; Landar, Aimee

    2016-08-01

    Many cancer cells follow an aberrant metabolic program to maintain energy for rapid cell proliferation. Metabolic reprogramming often involves the upregulation of glutaminolysis to generate reducing equivalents for the electron transport chain and amino acids for protein synthesis. Critical enzymes involved in metabolism possess a reactive thiolate group, which can be modified by certain oxidants. In the current study, we show that modification of mitochondrial protein thiols by a model compound, iodobutyl triphenylphosphonium (IBTP), decreased mitochondrial metabolism and ATP in MDA-MB 231 (MB231) breast adenocarcinoma cells up to 6 days after an initial 24h treatment. Mitochondrial thiol modification also depressed oxygen consumption rates (OCR) in a dose-dependent manner to a greater extent than a non-thiol modifying analog, suggesting that thiol reactivity is an important factor in the inhibition of cancer cell metabolism. In non-tumorigenic MCF-10A cells, IBTP also decreased OCR; however the extracellular acidification rate was significantly increased at all but the highest concentration (10µM) of IBTP indicating that thiol modification can have significantly different effects on bioenergetics in tumorigenic versus non-tumorigenic cells. ATP and other adenonucleotide levels were also decreased by thiol modification up to 6 days post-treatment, indicating a decreased overall energetic state in MB231 cells. Cellular proliferation of MB231 cells was also inhibited up to 6 days post-treatment with little change to cell viability. Targeted metabolomic analyses revealed that thiol modification caused depletion of both Krebs cycle and glutaminolysis intermediates. Further experiments revealed that the activity of the Krebs cycle enzyme, aconitase, was attenuated in response to thiol modification. Additionally, the inhibition of glutaminolysis corresponded to decreased glutaminase C (GAC) protein levels, although other protein levels were unaffected. This study

  14. Mitochondrial thiol modification by a targeted electrophile inhibits metabolism in breast adenocarcinoma cells by inhibiting enzyme activity and protein levels.

    PubMed

    Smith, M Ryan; Vayalil, Praveen K; Zhou, Fen; Benavides, Gloria A; Beggs, Reena R; Golzarian, Hafez; Nijampatnam, Bhavitavya; Oliver, Patsy G; Smith, Robin A J; Murphy, Michael P; Velu, Sadanandan E; Landar, Aimee

    2016-08-01

    Many cancer cells follow an aberrant metabolic program to maintain energy for rapid cell proliferation. Metabolic reprogramming often involves the upregulation of glutaminolysis to generate reducing equivalents for the electron transport chain and amino acids for protein synthesis. Critical enzymes involved in metabolism possess a reactive thiolate group, which can be modified by certain oxidants. In the current study, we show that modification of mitochondrial protein thiols by a model compound, iodobutyl triphenylphosphonium (IBTP), decreased mitochondrial metabolism and ATP in MDA-MB 231 (MB231) breast adenocarcinoma cells up to 6 days after an initial 24h treatment. Mitochondrial thiol modification also depressed oxygen consumption rates (OCR) in a dose-dependent manner to a greater extent than a non-thiol modifying analog, suggesting that thiol reactivity is an important factor in the inhibition of cancer cell metabolism. In non-tumorigenic MCF-10A cells, IBTP also decreased OCR; however the extracellular acidification rate was significantly increased at all but the highest concentration (10µM) of IBTP indicating that thiol modification can have significantly different effects on bioenergetics in tumorigenic versus non-tumorigenic cells. ATP and other adenonucleotide levels were also decreased by thiol modification up to 6 days post-treatment, indicating a decreased overall energetic state in MB231 cells. Cellular proliferation of MB231 cells was also inhibited up to 6 days post-treatment with little change to cell viability. Targeted metabolomic analyses revealed that thiol modification caused depletion of both Krebs cycle and glutaminolysis intermediates. Further experiments revealed that the activity of the Krebs cycle enzyme, aconitase, was attenuated in response to thiol modification. Additionally, the inhibition of glutaminolysis corresponded to decreased glutaminase C (GAC) protein levels, although other protein levels were unaffected. This study

  15. Mitochondrial thiol modification by a targeted electrophile inhibits metabolism in breast adenocarcinoma cells by inhibiting enzyme activity and protein levels

    PubMed Central

    Smith, M. Ryan; Vayalil, Praveen K.; Zhou, Fen; Benavides, Gloria A.; Beggs, Reena R.; Golzarian, Hafez; Nijampatnam, Bhavitavya; Oliver, Patsy G.; Smith, Robin A.J.; Murphy, Michael P.; Velu, Sadanandan E.; Landar, Aimee

    2016-01-01

    Many cancer cells follow an aberrant metabolic program to maintain energy for rapid cell proliferation. Metabolic reprogramming often involves the upregulation of glutaminolysis to generate reducing equivalents for the electron transport chain and amino acids for protein synthesis. Critical enzymes involved in metabolism possess a reactive thiolate group, which can be modified by certain oxidants. In the current study, we show that modification of mitochondrial protein thiols by a model compound, iodobutyl triphenylphosphonium (IBTP), decreased mitochondrial metabolism and ATP in MDA-MB 231 (MB231) breast adenocarcinoma cells up to 6 days after an initial 24 h treatment. Mitochondrial thiol modification also depressed oxygen consumption rates (OCR) in a dose-dependent manner to a greater extent than a non-thiol modifying analog, suggesting that thiol reactivity is an important factor in the inhibition of cancer cell metabolism. In non-tumorigenic MCF-10A cells, IBTP also decreased OCR; however the extracellular acidification rate was significantly increased at all but the highest concentration (10 µM) of IBTP indicating that thiol modification can have significantly different effects on bioenergetics in tumorigenic versus non-tumorigenic cells. ATP and other adenonucleotide levels were also decreased by thiol modification up to 6 days post-treatment, indicating a decreased overall energetic state in MB231 cells. Cellular proliferation of MB231 cells was also inhibited up to 6 days post-treatment with little change to cell viability. Targeted metabolomic analyses revealed that thiol modification caused depletion of both Krebs cycle and glutaminolysis intermediates. Further experiments revealed that the activity of the Krebs cycle enzyme, aconitase, was attenuated in response to thiol modification. Additionally, the inhibition of glutaminolysis corresponded to decreased glutaminase C (GAC) protein levels, although other protein levels were unaffected. This study

  16. Fermented Viola mandshurica inhibits melanogenesis in B16 melanoma cells.

    PubMed

    Kwak, Yeon-Joo; Kim, Kyoung-Sook; Kim, Kyung-Mi; Yu, Hai Yang; Chung, Eunsook; Kim, Seok-Jo; Cha, Jae-Young; Lee, Young-Choon; Lee, Jai-Heon

    2011-01-01

    We assessed the effects of chloroform extract of fermented Viola mandshurica (CEFV) on melanogenesis B16 melanoma cells. CEFV treatment significantly decreased melanin content and tyrosinase activity in dose-dependent manners. To elucidate the mechanism of the inhibitory effects of CEFV on melanogenesis, we performed RT-PCR and Western blotting for melanogenesis-related genes such as tyrosinase, tyrosinase-related protein-1 (TRP-1), TRP-2, and microphthalmia-associated transcription factor (MITF). CEFV strongly inhibited mRNA as well as the protein expression of tyrosinase and MITF, but had no significant effect on TRP-1 or TRP-2 expressions. It markedly decreased the phosphorylation of cAMP responsive element binding protein (CREB), and induced the duration of extracellular signal-regulated kinase (ERK) activation, leading to reduction of MITF expression and subsequently that of tyrosinase. Therefore, we suggest that CEFV induces downregulation of melanogenesis through decreased CREB phosphorylation and ERK activation.

  17. Inhibition of miR-29c promotes proliferation, and inhibits apoptosis and differentiation in P19 embryonic carcinoma cells

    PubMed Central

    CHEN, BIN; SONG, GUIXIAN; LIU, MING; QIAN, LINGMEI; WANG, LIHUA; GU, HAITAO; SHEN, YAHUI

    2016-01-01

    In our previous study, the upregulation of microRNA (miR)-29c was identified in the mother of a fetus with a congenital heart defect. However, the functional and regulatory mechanisms of miR-29c in the development of the heart remain to be elucidated. In the present study, the role and mechanism of miR-29c inhibition in heart development were investigated in an embryonic carcinoma cell model. Inhibition of miR-29c promoted proliferation, and suppressed the apoptosis and differentiation of P19 cells. It was also demonstrated that Wingless-related MMTV integration site 4 (Wnt4) was a target of miR-29c, determined using bioinformatic analysis combined with luciferase assays. The inhibition of miR-29c stimulated the WNT4/β-catenin pathway, promoting proliferation of the P19 cells, but suppressing their differentiation into cardiomyocytes. Furthermore, the inhibition of miR-29c promoted the expression of B cell lymphoma-2 and inhibited cell apoptosis. These results demonstrate the significance of miR-29c in the process of cardiac development and suggest that miR-29c dysregulation may be associated with the occurrence of CHD. Thus, miR-29c may have therapeutic potential in the future. PMID:26848028

  18. Inhibition of geranylgeranylation mediates sensitivity to CHOP-induced cell death of DLBCL cell lines

    SciTech Connect

    Ageberg, Malin; Rydstroem, Karin; Linden, Ola; Linderoth, Johan; Jerkeman, Mats; Drott, Kristina

    2011-05-01

    Prenylation is a post-translational hydrophobic modification of proteins, important for their membrane localization and biological function. The use of inhibitors of prenylation has proven to be a useful tool in the activation of apoptotic pathways in tumor cell lines. Rab geranylgeranyl transferase (Rab GGT) is responsible for the prenylation of the Rab family. Overexpression of Rab GGTbeta has been identified in CHOP refractory diffuse large B cell lymphoma (DLBCL). Using a cell line-based model for CHOP resistant DLBCL, we show that treatment with simvastatin, which inhibits protein farnesylation and geranylgeranylation, sensitizes DLBCL cells to cytotoxic treatment. Treatment with the farnesyl transferase inhibitor FTI-277 or the geranylgeranyl transferase I inhibitor GGTI-298 indicates that the reduction in cell viability was restricted to inhibition of geranylgeranylation. In addition, treatment with BMS1, a combined inhibitor of farnesyl transferase and Rab GGT, resulted in a high cytostatic effect in WSU-NHL cells, demonstrated by reduced cell viability and decreased proliferation. Co-treatment of BMS1 or GGTI-298 with CHOP showed synergistic effects with regard to markers of apoptosis. We propose that inhibition of protein geranylgeranylation together with conventional cytostatic therapy is a potential novel strategy for treating patients with CHOP refractory DLBCL.

  19. N-Myristoyltransferase Inhibition Induces ER-Stress, Cell Cycle Arrest, and Apoptosis in Cancer Cells

    PubMed Central

    2016-01-01

    N-Myristoyltransferase (NMT) covalently attaches a C14 fatty acid to the N-terminal glycine of proteins and has been proposed as a therapeutic target in cancer. We have recently shown that selective NMT inhibition leads to dose-responsive loss of N-myristoylation on more than 100 protein targets in cells, and cytotoxicity in cancer cells. N-myristoylation lies upstream of multiple pro-proliferative and oncogenic pathways, but to date the complex substrate specificity of NMT has limited determination of which diseases are most likely to respond to a selective NMT inhibitor. We describe here the phenotype of NMT inhibition in HeLa cells and show that cells die through apoptosis following or concurrent with accumulation in the G1 phase. We used quantitative proteomics to map protein expression changes for more than 2700 proteins in response to treatment with an NMT inhibitor in HeLa cells and observed down-regulation of proteins involved in cell cycle regulation and up-regulation of proteins involved in the endoplasmic reticulum stress and unfolded protein response, with similar results in breast (MCF-7, MDA-MB-231) and colon (HCT116) cancer cell lines. This study describes the cellular response to NMT inhibition at the proteome level and provides a starting point for selective targeting of specific diseases with NMT inhibitors, potentially in combination with other targeted agents. PMID:27267252

  20. N-Myristoyltransferase Inhibition Induces ER-Stress, Cell Cycle Arrest, and Apoptosis in Cancer Cells.

    PubMed

    Thinon, Emmanuelle; Morales-Sanfrutos, Julia; Mann, David J; Tate, Edward W

    2016-08-19

    N-Myristoyltransferase (NMT) covalently attaches a C14 fatty acid to the N-terminal glycine of proteins and has been proposed as a therapeutic target in cancer. We have recently shown that selective NMT inhibition leads to dose-responsive loss of N-myristoylation on more than 100 protein targets in cells, and cytotoxicity in cancer cells. N-myristoylation lies upstream of multiple pro-proliferative and oncogenic pathways, but to date the complex substrate specificity of NMT has limited determination of which diseases are most likely to respond to a selective NMT inhibitor. We describe here the phenotype of NMT inhibition in HeLa cells and show that cells die through apoptosis following or concurrent with accumulation in the G1 phase. We used quantitative proteomics to map protein expression changes for more than 2700 proteins in response to treatment with an NMT inhibitor in HeLa cells and observed down-regulation of proteins involved in cell cycle regulation and up-regulation of proteins involved in the endoplasmic reticulum stress and unfolded protein response, with similar results in breast (MCF-7, MDA-MB-231) and colon (HCT116) cancer cell lines. This study describes the cellular response to NMT inhibition at the proteome level and provides a starting point for selective targeting of specific diseases with NMT inhibitors, potentially in combination with other targeted agents. PMID:27267252

  1. Differences in antiproliferative effect of STAT3 inhibition in HCC cells with versus without HBV expression

    SciTech Connect

    Hong, Yun; Zhou, Lin; Xie, Haiyang; Wang, Weilin; Zheng, Shusen

    2015-06-05

    Chronic infection with hepatitis B virus (HBV) plays an important role in the etiology of hepatocellular carcinoma (HCC). Signal transducer and activator of transcription 3 (STAT3) inactivation could inhibit the tumor growth of HCC. In this study, differential antiproliferative effect of STAT3 inhibition was observed with HBV-related HCC cells being more resistant than non-HBV-related HCC cells. Resistance of HBV-related HCC cells to STAT3 inhibition was positively correlated to the expression of HBV. Enhanced ERK activation after STAT3 blockade was detected in HBV-related HCC cells but not in non-HBV-related HCC cells. Combined ERK and STAT3 inhibition eliminates the discrepancy between the two types of HCC cells. Moderate reduced HBV expression was found after STAT3 inhibition. These findings disclose a discrepancy in cellular response to STAT3 inhibition between non-HBV-related and HBV-related HCC cells and underscore the complexity of antiproliferative effect of STAT3 inactivation in HBV-related HCC cells. - Highlights: • HBV endows HCC cells with resistance to STAT3 inactivation on proliferation. • Abnormal ERK activation after STAT3 inhibition in HBV-related HCC cells. • Combined ERK and STAT3 inhibition eliminates the discrepancy. • STAT3 inhibition moderately reduces HBV expression.

  2. Pure bronchoplastic resections of the bronchus without pulmonary resection for endobronchial carcinoid tumours†

    PubMed Central

    Nowak, Kai; Karenovics, Wolfram; Nicholson, Andrew G.; Jordan, Simon; Dusmet, Michael

    2013-01-01

    OBJECTIVES Bronchopulmonary carcinoid tumours are relatively uncommon primary lung neoplasms. A small proportion of these lesions are predominantly endobronchial and do not extend beyond the bronchial wall. Endoscopic resection can be performed, but carries around a one in three risk of local recurrence and, therefore, mandates long-term surveillance. An alternative is complete surgical resection via bronchoplastic resection. We present our experience of surgical resection in patients with endobronchial carcinoids. METHODS From 2000 to 2010, 13 patients (age 45 ± 16 years, 10 males) underwent pure bronchoplastic resection, including systematic nodal dissection, for endobronchial carcinoid tumours, without the resection of lung parenchyma. RESULTS There was no significant operative morbidity or mortality. This is a retrospective review of a consecutive case series. The last follow-up for all patients was obtained in 2011. The mean maximum tumour size was 18 ± 8 mm. No lymph node invasion was observed. The median follow-up was 6.3 ± 3.3 years, with no regional recurrence. In 1 case, a tumourlet was identified at 5 years in the contralateral airway and viewed as a metachronous new lesion. CONCLUSIONS Bronchial sleeve resection is a safe procedure for suitably located endobronchial carcinoid tumours. Endoscopic resection should be reserved for patients who decline, or are unfit, for surgery. PMID:23628650

  3. Management of occult adrenocorticotropin-secreting bronchial carcinoids: limits of endocrine testing and imaging techniques.

    PubMed

    Loli, P; Vignati, F; Grossrubatscher, E; Dalino, P; Possa, M; Zurleni, F; Lomuscio, G; Rossetti, O; Ravini, M; Vanzulli, A; Bacchetta, C; Galli, C; Valente, D

    2003-03-01

    The differential diagnosis and the identification of the source of ACTH in occult ectopic Cushing's syndrome due to a bronchial carcinoid still represents a challenge for the endocrinologist. We report our experience in six patients with occult bronchial carcinoid in whom extensive hormonal, imaging, and scintigraphic evaluation was performed. All patients presented with hypercortisolism associated with high plasma ACTH values. The CRH test and high dose dexamethasone suppression test suggested an ectopic source of ACTH in three of six patients. During bilateral inferior petrosal sinus sampling, none of the patients showed a central to peripheral ACTH gradient. At the time of diagnosis, none of the patients had radiological evidence of the ectopic source of ACTH, whereas pentetreotide scintigraphy identified the lesion in two of four patients. Finally, a chest computed tomography scan revealed the presence of a bronchial lesion in all patients, and pentetreotide scintigraphy identified four of six lesions. In all patients a bronchial carcinoid was found and removed. In one patient with scintigraphic evidence of residual disease after two operations, radioguided surgery, using a hand-held gamma probe after iv administration of radiolabeled pentetreotide, was performed; this allowed detection and removal of residual multiple mediastinal lymph node metastases. In conclusion, our data show that there is not a single endocrine test or imaging procedure accurate enough to diagnose and localize occult ectopic ACTH-secreting bronchial carcinoids. Radioguided surgery appears to be promising in the presence of multiple tumor foci and previous incomplete removal of the tumor. PMID:12629081

  4. Management of occult adrenocorticotropin-secreting bronchial carcinoids: limits of endocrine testing and imaging techniques.

    PubMed

    Loli, P; Vignati, F; Grossrubatscher, E; Dalino, P; Possa, M; Zurleni, F; Lomuscio, G; Rossetti, O; Ravini, M; Vanzulli, A; Bacchetta, C; Galli, C; Valente, D

    2003-03-01

    The differential diagnosis and the identification of the source of ACTH in occult ectopic Cushing's syndrome due to a bronchial carcinoid still represents a challenge for the endocrinologist. We report our experience in six patients with occult bronchial carcinoid in whom extensive hormonal, imaging, and scintigraphic evaluation was performed. All patients presented with hypercortisolism associated with high plasma ACTH values. The CRH test and high dose dexamethasone suppression test suggested an ectopic source of ACTH in three of six patients. During bilateral inferior petrosal sinus sampling, none of the patients showed a central to peripheral ACTH gradient. At the time of diagnosis, none of the patients had radiological evidence of the ectopic source of ACTH, whereas pentetreotide scintigraphy identified the lesion in two of four patients. Finally, a chest computed tomography scan revealed the presence of a bronchial lesion in all patients, and pentetreotide scintigraphy identified four of six lesions. In all patients a bronchial carcinoid was found and removed. In one patient with scintigraphic evidence of residual disease after two operations, radioguided surgery, using a hand-held gamma probe after iv administration of radiolabeled pentetreotide, was performed; this allowed detection and removal of residual multiple mediastinal lymph node metastases. In conclusion, our data show that there is not a single endocrine test or imaging procedure accurate enough to diagnose and localize occult ectopic ACTH-secreting bronchial carcinoids. Radioguided surgery appears to be promising in the presence of multiple tumor foci and previous incomplete removal of the tumor.

  5. Gadolinium metallofullerenol nanoparticles inhibit cancer metastasis through matrix metalloproteinase inhibition: imprisoning instead of poisoning cancer cells

    PubMed Central

    Meng, Huan; Xing, Gengmei; Blanco, Elvin; Song, Yan; Zhao, Lina; Sun, Baoyun; Li, Xiaoda; Wang, Paul C.; Korotcov, Alexandru; Li, Wei; Liang, Xing-Jie; Chen, Chunying; Yuan, Hui; Zhao, Feng; Chen, Zhen; Sun, Tong; Chai, Zhifang; Ferrari, Mauro; Zhao, Yuliang

    2012-01-01

    The purpose of this work is to study the antimetastasis activity of gadolinium metallofullerenol nanoparticles (f-NPs) in malignant and invasive human breast cancer models. We demonstrated that f-NPs inhibited the production of matrix metalloproteinase (MMP) enzymes and further interfered with the invasiveness of cancer cells in tissue culture condition. In the tissue invasion animal model, the invasive primary tumor treated with f-NPs showed significantly less metastasis to the ectopic site along with the decreased MMP expression. In the same animal model, we observed the formation of a fibrous cage that may serve as a physical barrier capable of cancer tissue encapsulation that cuts the communication between cancer- and tumor-associated macrophages, which produce MMP enzymes. In another animal model, the blood transfer model, f-NPs potently suppressed the establishment of tumor foci in lung. Based on these data, we conclude that f-NPs have antimetastasis effects and speculate that utilization of f-NPs may provide a new strategy for the treatment of tumor metastasis. PMID:21930111

  6. Iron depletion results in Src kinase inhibition with associated cell cycle arrest in neuroblastoma cells

    PubMed Central

    Siriwardana, Gamini; Seligman, Paul A

    2015-01-01

    Iron is required for cellular proliferation. Recently, using systematic time studies of neuroblastoma cell growth, we better defined the G1 arrest caused by iron chelation to a point in mid-G1, where cyclin E protein is present, but the cyclin E/CDK2 complex kinase activity is inhibited. In this study, we again used the neuroblastoma SKNSH cells lines to pinpoint the mechanism responsible for this G1 block. Initial studies showed in the presence of DFO, these cells have high levels of p27 and after reversal of iron chelation p27 is degraded allowing for CDK2 kinase activity. The initial activation of CDK2 kinase allows cells to exit G1 and enter S phase. Furthermore, we found that inhibition of p27 degradation by DFO is directly associated with inhibition of Src kinase activity measured by lack of phosphorylation of Src at the 416 residue. Activation of Src kinase occurs very early after reversal from the DFO G1 block and is temporally associated with initiation of cellular proliferation associated with entry into S phase. For the first time therefore we show that iron chelation inhibits Src kinase activity and this activity is a requirement for cellular proliferation. PMID:25825542

  7. Iron depletion results in Src kinase inhibition with associated cell cycle arrest in neuroblastoma cells.

    PubMed

    Siriwardana, Gamini; Seligman, Paul A

    2015-03-01

    Iron is required for cellular proliferation. Recently, using systematic time studies of neuroblastoma cell growth, we better defined the G1 arrest caused by iron chelation to a point in mid-G1, where cyclin E protein is present, but the cyclin E/CDK2 complex kinase activity is inhibited. In this study, we again used the neuroblastoma SKNSH cells lines to pinpoint the mechanism responsible for this G1 block. Initial studies showed in the presence of DFO, these cells have high levels of p27 and after reversal of iron chelation p27 is degraded allowing for CDK2 kinase activity. The initial activation of CDK2 kinase allows cells to exit G1 and enter S phase. Furthermore, we found that inhibition of p27 degradation by DFO is directly associated with inhibition of Src kinase activity measured by lack of phosphorylation of Src at the 416 residue. Activation of Src kinase occurs very early after reversal from the DFO G1 block and is temporally associated with initiation of cellular proliferation associated with entry into S phase. For the first time therefore we show that iron chelation inhibits Src kinase activity and this activity is a requirement for cellular proliferation.

  8. Vitisin A inhibits adipocyte differentiation through cell cycle arrest in 3T3-L1 cells

    SciTech Connect

    Kim, Soon-hee; Park, Hee-Sook; Lee, Myoung-su; Cho, Yong-Jin; Kim, Young-Sup; Hwang, Jin-Taek; Sung, Mi Jeong; Kim, Myung Sunny; Kwon, Dae Young

    2008-07-18

    Inhibition of adipocyte differentiation is one approach among the anti-obesity strategies. This study demonstrates that vitisin A, a resveratrol tetramer, inhibits adipocyte differentiation most effectively of 18 stilbenes tested. Fat accumulation and PPAR{gamma} expression were decreased by vitisin A in a dose-dependent manner. Vitisin A significantly inhibited preadipocyte proliferation and consequent differentiation within the first 2 days of treatment, indicating that the anti-adipogenic effect of vitisin A was derived from anti-proliferation. Based on cell cycle analysis, vitisin A blocked the cell cycle at the G1-S phase transition, causing cells to remain in the preadipocyte state. Vitisin A increased p21 expression, while the Rb phosphorylation level was reduced. Therefore, vitisin A seems to induce G1 arrest through p21- and consequent Rb-dependent suppression of transcription. On the other hand, ERK and Akt signaling pathways were not involved in the anti-mitotic regulation by vitisin A. Taken together, these results suggest that vitisin A inhibits adipocyte differentiation through preadipocyte cell cycle arrest.

  9. Acrylamide inhibits cellular differentiation of human neuroblastoma and glioblastoma cells.

    PubMed

    Chen, Jong-Hang; Chou, Chin-Cheng

    2015-08-01

    This study explores human neuroblastoma (SH-SY5Y) and human glioblastoma (U-1240 MG) cellular differentiation changes under exposure to acrylamide (ACR). Differentiation of SH-SY5Y and U-1240 MG cells were induced by retinoic acid (RA) and butyric acid (BA), respectively. Morphological observations and MTT assay showed that the induced cellular differentiation and cell proliferation were inhibited by ACR in a time- and dose-dependent manner. ACR co-treatment with RA attenuated SH-SY5Y expressions of neurofilament protein-L (NF-L), microtubule-associated protein 1b (MAP1b; 1.2 to 0.7, p < 0.001), MAP2c (2.2 to 0.8, p < 0.05), and Janus kinase1 (JAK1; 1.9 to 0.6, p < 0.001), while ACR co-treatment with BA attenuated U-1240 MG expressions of glial fibrillary acidic protein (GFAP), MAP1b (1.2 to 0.6, p < 0.001), MAP2c (1.5 to 0.7, p < 0.01), and JAK1 (2.1 to 0.5, p < 0.001), respectively. ACR also decreased the phosphorylation of extracellular-signal-regulated kinases (ERK) and c-Jun N-terminal kinases (JNK) in U-1240 MG cells, while caffeine reversed this suppression of ERK and JNK phosphorylation caused by ACR treatment. These results showed that RA-induced neurogenesis of SH-SY5Y and BA-induced astrogliogenesis of U-1240 MG cells were attenuated by ACR and were associated with down-regulation of MAPs expression and JAK-STAT signaling.

  10. Apoptotic cells actively inhibit the expression of CD69 on Con A activated T lymphocytes.

    PubMed

    Sun, E; Zhang, L; Zeng, Y; Ge, Q; Zhao, M; Gao, W

    2000-03-01

    Although apoptosis is commonly viewed as a silent cell death without damage to adjacent tissues, the effect of apoptosis on immunity has been unclear. We have investigated the influence of apoptotic cells on T-cell activation. The K562 or HL-60 human leukemia cell lines that had been induced apoptosis by FTY720 or cycloheximide (CHX) were added into the culture of mouse spleen cells stimulated with Con A. Six to 20 h later, the expression of CD69, an early T-cell activation antigen, was detected using flowcytometry. Living cells and necrotic cells served as control groups. Apoptotic K562 or HL-60 cells induced by either FTY720 or CHX unanimously inhibited CD69 expression on the CD3+ mouse T cells while living and necrotic cells did not. The inhibition was proportional to the number of apoptotic cells and was different in the T-cell subsets, showing a rapid and transient inhibition on the CD3+CD8+ T-cell activation but with a slow and continuous inhibition on CD3+CD8- T-cell activation. In conclusion, the apoptotic cells actively inhibit a T-cell activation that is independent of the cell lines or the apoptotic inducers, indicating that the apoptotic cells dominantly regulate T-cell immunity. PMID:10736091

  11. D-Glucosamine inhibits proliferation of human cancer cells through inhibition of p70S6K

    SciTech Connect

    Oh, Hyun-Ji; Lee, Jason S.; Song, Dae-Kyu; Shin, Dong-Hoon; Jang, Byeong-Churl; Suh, Seong-Il; Park, Jong-Wook; Suh, Min-Ho; Baek, Won-Ki . E-mail: wonki@dsmc.or.kr

    2007-09-07

    Although D-glucosamine has been reported as an inhibitor of tumor growth both in vivo and in vitro, the mechanism for the anticancer effect of D-glucosamine is still unclear. Since there are several reports suggesting D-glucosamine inhibits protein synthesis, we examined whether D-glucosamine affects p70S6 K activity, an important signaling molecule involved in protein translation. In the present study, we found D-glucosamine inhibited the activity of p70S6K and the proliferation of DU145 prostate cancer cells and MDA-MB-231 breast cancer cells. D-Glucosamine decreased phosphorylation of p70S6K, and its downstream substrates RPS6, and eIF-4B, but not mTOR and 4EBP1 in DU145 cells, suggesting that D-glucosamine induced inhibition of p70S6K is not through the inhibition of mTOR. In addition, D-glucosamine enhanced the growth inhibitory effects of rapamycin, a specific inhibitor of mTOR. These findings suggest that D-glucosamine can inhibit growth of cancer cells through dephosphorylation of p70S6K.

  12. Picropodophyllin inhibits proliferation and survival of diffuse large B-cell lymphoma cells.

    PubMed

    Strömberg, Thomas; Feng, Xiaoying; Delforoush, Maryam; Berglund, Mattias; Lin, Yingbo; Axelson, Magnus; Larsson, Olle; Georgii-Hemming, Patrik; Lennartsson, Johan; Enblad, Gunilla

    2015-07-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. Although chemotherapy in combination with anti-CD20 antibodies results in a cure rate of 60-70 %, novel treatment approaches are warranted for the remaining patients. The insulin-like growth factor-1 receptor (IGF-1R) and its principal ligands IGF-1 and IGF-2 have been suggested to play pivotal roles in different cancers. However, in DLBCL the importance of this system is less well understood. To assess whether interference with IGF-1R-mediated signaling may represent a therapeutic option for this malignancy, we used a panel of eight DLBCL cell lines together with primary tumor cells derived from lymph nodes in four DLBCL patients. The cells were treated with the cyclolignan picropodophyllin (PPP), a small molecule compound initially described to selectively inhibit the IGF-1R. PPP dose-dependently inhibited proliferation/survival in all cell lines and primary cell preparations. In parallel experiments, the IGF-1R inhibitor NVP-AEW541 and the microtubule-destabilizing compounds podophyllotoxin (PPT) and colchicine were demonstrated to also inhibit growth of the cell lines. Linear regression analysis showed that the responses of the cell lines to PPP correlated with their responses to the microtubule inhibitors PPT and colchicine, but not with the response to NVP-AEW541 or the expression level of surface IGF-1R. Analysis of cell cycle phase distribution revealed that treatment with PPP for only 1 h induced a clear accumulation of cells in the G2/M-phase with a corresponding depletion of the G0/G1-phase. Interestingly, these cell cycle effects could be closely mimicked by using PPT or colchicine. Treatment with PPP led to increased apoptotic cell death in the SU-DHL-6 and U-2932 cell lines, whereas the DB and U-2940 did not undergo apoptosis. However, the DB cells were still killed by PPP, suggesting another mode of cell death for this cell line. The U-2940 cells responded to PPP mainly by

  13. Inhibition by Tyroserleutide (YSL) on the Invasion and Adhesion of the Mouse Melanoma Cell

    PubMed Central

    Yao, Zhi; Che, Xu-chun; Lu, Rong; Zheng, Min-na; Zhu, Zhi-feng; Li, Jin-ping; Jian, Xu; Shi, Lin-xi; Liu, Jun-yan; Gao, Wen-yuan

    2007-01-01

    Tyroserleutide (YSL) is an active, low-molecular-weight polypeptide, comprised of three amino acids, that has shown antitumor effects on human hepatocarcinoma BEL-7402 in vitro and in vivo. In this study, we evaluated the inhibition of YSL on invasion and adhesion of the mouse B16-F10 melanoma cell line by injecting B16-F10 cells into the tail veins of C57BL/6 mice to establish an experimental lung metastasis model. YSL inhibited B16-F10 cell metastasis to lung, reducing the number and area of metastasis lesions. When we treated B16-F10 cells with YSL (0.01, 0.1, 1, 10, or 100 μg/mL) in vitro, we found that YSL inhibited the proliferation of B16-F10 cells with a 28.11% rate of inhibition. YSL significantly decreased the adhesiveness of B16-F10 cells to Matrigel with a 29.15% inhibition rate; YSL also significantly inhibited the invasion of B16-F10 cells, producing an inhibition of 35.31%. By analyses with Western blot and real-time RT-PCR, we found that YSL markedly inhibited the expression of ICAM-1 in B16-F10 cells. These data suggest that YSL inhibits the growth, invasion, and adhesion of B16-F10 cells. PMID:17515953

  14. Solena amplexicaulis induces cell cycle arrest, apoptosis and inhibits angiogenesis in hepatocarcinoma cells and HUVECs.

    PubMed

    Ren, Jie; Xu, Yuan Yuan; Jiang, He Fei; Yang, Meng; Huang, Qian Hui; Yang, Jie; Hu, Kun; Wei, Kun

    2014-01-01

    Solena amplexicaulis (Lam.) Gandhi (SA) has been used as a traditional medicine for the treatment of dysentery, multiple abscess, gastralgia, urethritis, and eczema in the minority area of China. This study was aimed to examine the cell proliferation inhibitory activity of the SA extract (SACE) and its mechanism of action in human hepatoma cell line (HepG2) and evaluate its anti-angiogenesis activity in human umbilical vein endothelial cell line (HUVEC). SACE could inhibit the growth of HepG2 cells in a dose- and time-dependent manner. FCM analysis showed that SACE could induce G2/M phase arrest, cell apoptosis, the mitochondrial membrane potential loss (ΔΨm) and increase the production of intracellular ROS of HepG2 cells. After treatment with SACE, topical morphological changes of apoptotic body formation, obvious increase of apoptosis-related protein expressions, such as Bax, cytochrome c, caspase-3, PARP-1, and decrease of Bcl-2, procaspase-9 protein expressions were observed at the same time. Moreover, SACE caused the significant inhibition of endothelial cell migration and tube formation in HUVEC cells. The results suggested that SACE could act as an angiogenesis inhibitor and induce cell apoptosis via a caspase-dependent mitochondrial pathway. Therefore, SACE could be a potent candidate for the prevention and treatment of liver cancer. PMID:25547924

  15. Silencing Aurora-A with siRNA inhibits cell proliferation in human lung adenocarcinoma cells.

    PubMed

    Zhong, Ning; Shi, Shunbin; Wang, Hongzhen; Wu, Guangzhou; Wang, Yunliang; Ma, Qiang; Wang, Hongwei; Liu, Yuanhua; Wang, Jinzhi

    2016-09-01

    Aurora kinase A (AURKA) is an oncogenic serine/threonine kinase, it plays important roles in tumorigenesis and chemoresistance. In this study, we investigated the expression of AURKA in lung adenocarcinoma tissues, the role of small interference RNA targeting AURKA on growth, cell cycle, and apoptosis of lung adenocarcinoma cell lines in vitro. The AURKA is highly expressed in lung adenocarcinoma tissues and human lung adenocarcinoma cell lines. Lentivirus-mediated short hairpin RNA (shRNA) was used to knock down AURKA expression in human lung adenocarcinoma cell lines H1299 and A549. The results indicated that depletion of AURKA could inhibit cell growth, cause cell cycle arrest and apoptosis. The potential mechanisms of AURKA inhibition induced cell cycle arrest and apoptosis are associated with downregulated RAF-1, CCND2, CCND3, CDK4, PAK4, EGFR and upregulated WEE1 expression. Furthermore, AURKA knockdown cooperated with vincristine (VCR) to repress A549 cell proliferation. Therefore, AURKA plays important roles in the proliferation of human lung adenocarcinoma cells, which suggests that AURKA could be a promising tool for lung adenocarcinoma therapy. PMID:27571708

  16. Suppression of PAX6 promotes cell proliferation and inhibits apoptosis in human retinoblastoma cells.

    PubMed

    Meng, Bo; Wang, Yisong; Li, Bin

    2014-08-01

    The aim of this study was to investigate the role of the transcription factor, PAX6, in the development of retinoblastoma. The expression of endogenous PAX6 was knocked down using PAX6-specific lentivirus in two human retinoblastoma cell lines, SO-Rb50 and Y79. Cell proliferation functional assays and apoptotic assays were performed on the cells in which PAX6 was knocked down. The results revealed that PAX6 knockdown efficiency was significant (P<0.01, n=3) in the SO-Rb50 and Y79 cells. The inhibition of PAX6 reduced tumor cell apoptosis (P<0.05, n=3), but induced cell cycle S phase arrest (SO-Rb50; P<0.05, n=3) and G2/M phase arrest (Y79; P<0.05, n=3). Western blot analysis indicated that the inhibition of PAX6 increased the levels of the anti-apoptotic proteins, Bcl-2, proliferating cell nuclear antigen (PCNA) and CDK1, but reduced the levels of the pro-apoptotic proteins, BAX and p21. In conclusion, our data demonstrate that the suppression of PAX6 increases proliferation and decreases apoptosis in human retinoblastoma cells by regulating several cell cycle and apoptosis biomarkers. PMID:24939714

  17. Suppression of PAX6 promotes cell proliferation and inhibits apoptosis in human retinoblastoma cells

    PubMed Central

    MENG, BO; WANG, YISONG; LI, BIN

    2014-01-01

    The aim of this study was to investigate the role of the transcription factor, PAX6, in the development of retinoblastoma. The expression of endogenous PAX6 was knocked down using PAX6-specific lentivirus in two human retinoblastoma cell lines, SO-Rb50 and Y79. Cell proliferation functional assays and apoptotic assays were performed on the cells in which PAX6 was knocked down. The results revealed that PAX6 knockdown efficiency was significant (P<0.01, n=3) in the SO-Rb50 and Y79 cells. The inhibition of PAX6 reduced tumor cell apoptosis (P<0.05, n=3), but induced cell cycle S phase arrest (SO-Rb50; P<0.05, n=3) and G2/M phase arrest (Y79; P<0.05, n=3). Western blot analysis indicated that the inhibition of PAX6 increased the levels of the anti-apoptotic proteins, Bcl-2, proliferating cell nuclear antigen (PCNA) and CDK1, but reduced the levels of the pro-apoptotic proteins, BAX and p21. In conclusion, our data demonstrate that the suppression of PAX6 increases proliferation and decreases apoptosis in human retinoblastoma cells by regulating several cell cycle and apoptosis biomarkers. PMID:24939714

  18. Targeting Notch1 inhibits invasion and angiogenesis of human breast cancer cells via inhibition Nuclear Factor-κB signaling.

    PubMed

    Liu, Yuan; Su, Chuanfu; Shan, Yuqing; Yang, Shouxiang; Ma, Guifeng

    2016-01-01

    Notch-1, a type-1 transmembrane protein, plays critical roles in the pathogenesis and progression of human malignancies, including breast cancer; however, the precise mechanism by which Notch-1 causes tumor cell invasion and angiogenesis remain unclear. Nuclear factor-κB (NF-κB), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMP) are critically involved in the processes of tumor cell invasion and metastasis, we investigated whether targeting Notch-1 could be mechanistically associated with the down-regulation of NF-κB, IL-8, VEGF, and MMP-9, resulting in the inhibition of invasion and angiogenesis of breast cancer cells. Our data showed that down-regulation of Notch-1 leads to the inactivation of NF-κB activity and inhibits the expression of its target genes, such as IL-8, VEGF and MMP-9. We also found that down-regulation of Notch-1 decreased cell invasion, and vice versa Consistent with these results, we also found that the down-regulation of Notch-1 not only decreased MMP-9 mRNA and its protein expression but also inhibited MMP-9 active form. Moreover, conditioned medium from Notch-1 siRNA-transfected breast cancer cells showed reduced levels of IL-8 and VEGF and, in turn, inhibited the tube formation of HUVECs, suggesting that down-regulation of Notch-1 leads to the inhibition of angiogenesis. Furthermore, conditioned medium from Notch-1 cDNA-transfected breast cancer cells showed increased levels of IL-8 and VEGF and, in turn, promoted the tube formation of HUVECs, suggesting that Notch-1 overexpression leads to the promotion of angiogenesis.We therefore concluded that down-regulation of Notch-1 leads to the inactivation NF-κB and its target genes (IL-8, MMP-9 and VEGF), resulting in the inhibition of invasion and angiogenesis.

  19. Targeting Notch1 inhibits invasion and angiogenesis of human breast cancer cells via inhibition Nuclear Factor-κB signaling

    PubMed Central

    Liu, Yuan; Su, Chuanfu; Shan, Yuqing; Yang, Shouxiang; Ma, Guifeng

    2016-01-01

    Notch-1, a type-1 transmembrane protein, plays critical roles in the pathogenesis and progression of human malignancies, including breast cancer; however, the precise mechanism by which Notch-1 causes tumor cell invasion and angiogenesis remain unclear. Nuclear factor-κB (NF-κB), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMP) are critically involved in the processes of tumor cell invasion and metastasis, we investigated whether targeting Notch-1 could be mechanistically associated with the down-regulation of NF-κB, IL-8, VEGF, and MMP-9, resulting in the inhibition of invasion and angiogenesis of breast cancer cells. Our data showed that down-regulation of Notch-1 leads to the inactivation of NF-κB activity and inhibits the expression of its target genes, such as IL-8, VEGF and MMP-9. We also found that down-regulation of Notch-1 decreased cell invasion, and vice versa Consistent with these results, we also found that the down-regulation of Notch-1 not only decreased MMP-9 mRNA and its protein expression but also inhibited MMP-9 active form. Moreover, conditioned medium from Notch-1 siRNA-transfected breast cancer cells showed reduced levels of IL-8 and VEGF and, in turn, inhibited the tube formation of HUVECs, suggesting that down-regulation of Notch-1 leads to the inhibition of angiogenesis. Furthermore, conditioned medium from Notch-1 cDNA-transfected breast cancer cells showed increased levels of IL-8 and VEGF and, in turn, promoted the tube formation of HUVECs, suggesting that Notch-1 overexpression leads to the promotion of angiogenesis.We therefore concluded that down-regulation of Notch-1 leads to the inactivation NF-κB and its target genes (IL-8, MMP-9 and VEGF), resulting in the inhibition of invasion and angiogenesis. PMID:27398151

  20. G9a Inhibition Induces Autophagic Cell Death via AMPK/mTOR Pathway in Bladder Transitional Cell Carcinoma.

    PubMed

    Li, Feng; Zeng, Jin; Gao, Yang; Guan, Zhenfeng; Ma, Zhenkun; Shi, Qi; Du, Chong; Jia, Jing; Xu, Shan; Wang, Xinyang; Chang, Luke; He, Dalin; Guo, Peng

    2015-01-01

    G9a has been reported to highly express in bladder transitional cell carcinoma (TCC) and G9a inhibition significantly attenuates cell proliferation, but the underlying mechanism is not fully understood. The present study aimed at examining the potential role of autophagy in the anti-proliferation effect of G9a inhibition on TCC T24 and UMUC-3 cell lines in vitro. We found that both pharmaceutical and genetical G9a inhibition significantly attenuated cell proliferation by MTT assay, Brdu incorporation assay and colony formation assay. G9a inhibition induced autophagy like morphology as determined by transmission electron microscope and LC-3 fluorescence assay. In addition, autophagy flux was induced by G9a inhibition in TCC cells, as determined by p62 turnover assay and LC-3 turnover assay. The autophagy induced positively contributed to the inhibition of cell proliferation because the growth attenuation capacity of G9a inhibition was reversed by autophagy inhibitors 3-MA. Mechanically, AMPK/mTOR pathway was identified to be involved in the regulation of G9a inhibition induced autophagy. Intensively activating mTOR by Rheb overexpression attenuated autophagy and autophagic cell death induced by G9a inhibition. In addition, pre-inhibiting AMPK by Compound C attenuated autophagy together with the anti-proliferation effect induced by G9a inhibition while pre-activating AMPK by AICAR enhanced them. In conclusion, our results indicate that G9a inhibition induces autophagy through activating AMPK/mTOR pathway and the autophagy induced positively contributes to the inhibition of cell proliferation in TCC cells. These findings shed some light on the functional role of G9a in cell metabolism and suggest that G9a might be a therapeutic target in bladder TCC in the future. PMID:26397365

  1. Inhibition of pancreatic tumoral cells by snake venom disintegrins

    PubMed Central

    Lucena, Sara; Castro, Roberto; Lundin, Courtney; Hofstetter, Amanda; Alaniz, Amber; Suntravat, Montamas; Sánchez, Elda Eliza

    2014-01-01

    Pancreatic cancer often has a poor prognosis, even when diagnosed early. Pancreatic cancer typically spreads rapidly and is rarely detected in its early stages, which is a major reason it is a leading cause of cancer death. Signs and symptoms may not appear until pancreatic cancer is quite advanced, and complete surgical removal is not possible. Furthermore, pancreatic cancer responds poorly to most chemotherapeutic agents. The importance of integrins in several cell types that affect tumor progression has made them an appealing target for cancer therapy. Some of the proteins found in the snake venom present a great potential as anti-tumor agents. In this study, we summarize the activity of two integrins antagonist, recombinant disintegrins mojastin 1 and viridistatin 2, on human pancreatic carcinoma cell line (BXPC-3). Both recombinant disintegrins inhibited some essential aspects of the metastasis process such as proliferation, adhesion, migration, and survival through apoptosis, making these proteins prominent candidates for the development of drugs for the treatment of pancreatic cancer. PMID:25450798

  2. Silencing homeobox C6 inhibits colorectal cancer cell proliferation

    PubMed Central

    Tang, Wentao; Lao, Xinyuan; Zhu, Dexiang; Lin, Qi; Xu, Pingping; Wei, Ye; Xu, Jianmin

    2016-01-01

    Homeobox C6 (HOXC6), a member of the homeobox family that encodes highly conserved transcription factors, plays a vital role in various carcinomas. In this study, we used a tissue microarray (TMA) consisting of 462 CRC samples to demonstrate that HOXC6 is more abundantly expressed in colorectal cancer (CRC) tissues than adjacent normal mucosa. Clinicopathological data indicated that higher HOXC6 expression correlated with poor overall survival and was associated with primary tumor location in the right colon, primary tumor (pT) stage 3/4 and primary node (pN) stage 1/2. Multivariate analysis showed that high HOXC6 expression was an independent risk factor for poor CRC patient prognosis. HOXC6 downregulation via lentivirus-mediated expression of HOXC6-targeting shRNA reduced HCT116 cell viability and colony formation in vitro, and reduced growth of subcutaneous xenografts in nude mouse. HOXC6 thus appears to promote CRC cell proliferation and tumorigenesis through autophagy inhibition and mTOR pathway activation. PMID:27081081

  3. Amlodipine inhibits cell proliferation via PKD1-related pathway

    SciTech Connect

    Ohba, Takayoshi; Watanabe, Hiroyuki; Murakami, Manabu; Radovanovic, Milena; Iino, Kenji; Ishida, Masaru; Tosa, Shinya; Ono, Kyoichi; Ito, Hiroshi

    2008-05-02

    Human coronary artery smooth muscle cell (hCASMC) proliferation is involved in the progression of coronary artery disease. Amlodipine, a widely used antihypertensive drug, exerts antiproliferative effects by increasing the expression of p21{sup (Waf1/Cip1)}. Polycystic kidney disease 1 (PKD1) is also involved in cell cycle inhibition via p21{sup (Waf1/Cip1)} up-regulation. We clarified the involvement of PKD1-related signaling on hCASMCs. Cultured hCASMCs, which constitutively express PKD1, were stimulated with 5% serum. Amlodipine increased p21{sup (Waf1/Cip1)} expression in a dose- and time-dependent manner, resulting in reduced hCASMC proliferation. The inhibitory effect of amlodipine was mimicked by overexpression of PKD1 and was reversed by a dominant-negative version of PKD1 (R4227X). Immunoblot analysis showed that phosphorylated JAK2 was increased by amlodipine treatment or PKD1 overexpression. A luciferase assay revealed that the overexpression of PKD1 induced STAT1 enhancer activity. These data suggest that PKD1 contributes to the antiproliferative effect of amlodipine on hCASMCs via JAK/STAT signaling and p21{sup (Waf1/Cip1)} up-regulation.

  4. Argininosuccinate synthetase 1 suppression and arginine restriction inhibit cell migration in gastric cancer cell lines.

    PubMed

    Shan, Yan-Shen; Hsu, Hui-Ping; Lai, Ming-Derg; Yen, Meng-Chi; Chen, Wei-Ching; Fang, Jung-Hua; Weng, Tzu-Yang; Chen, Yi-Ling

    2015-01-01

    Gastric cancer metastasis remains a major cause of cancer-related deaths. There is an urgent need to develop new therapeutic approaches targeting metastatic gastric cancer. Argininosuccinate synthetase 1 (ASS1) expression is increased in gastric cancer. We detected the protein expression of ASS1 in human gastric cancer cell lines (AGS, NCI-N87, and MKN45) and in murine gastric cancer cell lines (3I and 3IB2). We used vector-mediated short hairpin RNA (shRNA) expression to silence ASS1 expression in the MKN45 and 3IB2 cell lines, and analyzed the effects of this protein on cell migration and metastasis. We demonstrated that ASS1 silencing suppressed cell migration in the MKN45 and 3IB2 cell lines. ASS1 knockdown significantly reduced liver metastasis in mice after the intrasplenic implantation of 3IB2 cancer cell clones. To determine whether arginine restriction may represent a therapeutic approach to treat gastric cancer, the sensitivity of tumor cells to arginine depletion was determined in gastric cancer cells. Arginine depletion significantly inhibited cell migration in the gastric cancer cell line. The silencing of ASS1 expression in MKN45 and 3IB2 gastric cancer cells markedly decreased STAT3 protein expression. In conclusion, our results indicate that the ASS1 protein is required for cell migration in gastric cancer cell lines. PMID:25928182

  5. Alpha-tocopherol inhibits agonist-induced monocytic cell adhesion to cultured human endothelial cells.

    PubMed Central

    Faruqi, R; de la Motte, C; DiCorleto, P E

    1994-01-01

    Antioxidants have been proposed to be anti-atherosclerotic agents; however, the mechanisms underlying their beneficial effects are poorly understood. We have examined the effect of alpha-tocopherol (alpha-tcp) on one cellular event in atherosclerotic plaque development, monocyte adhesion to stimulated endothelial cells (ECs). Human umbilical vein ECs were pretreated with alpha-tcp before stimulation with known agonists of monocyte adhesion: IL-1 (10 ng/ml), LPS (10 ng/ml), thrombin (30 U/ml), or PMA (10 nM). Agonist-induced monocytic cell adhesion, but not basal adhesion, was inhibited in a time- and concentration-dependent manner by alpha-tcp. The IC50 of alpha-tcp on an IL-1-induced response was 45 microM. The inhibition correlated with a decrease in steady state levels of E-selectin mRNA and cell surface expression of E-selectin which is consistent with the ability of a monoclonal antibody to E-selectin to inhibit monocytic cell adhesion in this system. Probucol (50 microM) and N-acetylcysteine (20 mM) also inhibited agonist-induced monocytic cell adhesion; whereas, several other antioxidants had no significant effect. Protein kinase C (PKC) does not appear to play a role in the alpha-tcp effect since no suppression of phosphorylation of PKC substrates was observed. Activation of the transcription factor NF-kappa B is reported to be necessary but not sufficient for E-selectin expression in EC. Electrophoretic mobility shift assays failed to show an alpha-tcp-induced decrease in activation of this transcription factor after cytokine stimulation. It has been hypothesized that alpha-tcp acts as an anti-atherosclerotic molecule by inhibiting generation of oxidized LDL--a putative triggering molecule in the atherosclerotic process. Our results point to a novel alternative mechanism of action of alpha-tcp. Images PMID:7518838

  6. Arsenic trioxide inhibits cell proliferation and human papillomavirus oncogene expression in cervical cancer cells

    SciTech Connect

    Wang, Hongtao; Gao, Peng; Zheng, Jie

    2014-09-05

    Highlights: • As{sub 2}O{sub 3} inhibits growth of cervical cancer cells and expression of HPV oncogenes in these cells. • HPV-negative cervical cancer cells are more sensitive to As{sub 2}O{sub 3} than HPV-positive cervical cancer cells. • HPV-18 positive cervical cancer cells are more sensitive to As{sub 2}O{sub 3} than HPV-16 positive cancer cells. • Down-regulation of HPV oncogenes by As{sub 2}O{sub 3} is partially due to the diminished AP-1 binding. - Abstract: Arsenic trioxide (As{sub 2}O{sub 3}) has shown therapeutic effects in some leukemias and solid cancers. However, the molecular mechanisms of its anticancer efficacy have not been clearly elucidated, particularly in solid cancers. Our previous data showed that As{sub 2}O{sub 3} induced apoptosis of human papillomavirus (HPV) 16 DNA-immortalized human cervical epithelial cells and cervical cancer cells and inhibited the expression of HPV oncogenes in these cells. In the present study, we systemically examined the effects of As{sub 2}O{sub 3} on five human cervical cancer cell lines and explored the possible molecular mechanisms. MTT assay showed that HPV-negative C33A cells were more sensitive to growth inhibition induced by As{sub 2}O{sub 3} than HPV-positive cervical cancer cells, and HPV 18-positive HeLa and C4-I cells were more sensitive to As{sub 2}O{sub 3} than HPV 16-positive CaSki and SiHa cells. After As{sub 2}O{sub 3} treatment, both mRNA and protein levels of HPV E6 and E7 obviously decreased in all HPV positive cell lines. In contrast, p53 and Rb protein levels increased in all tested cell lines. Transcription factor AP-1 protein expression decreased significantly in HeLa, CaSki and C33A cells with ELISA method. These results suggest that As{sub 2}O{sub 3} is a potential anticancer drug for cervical cancer.

  7. Inhibition of thromboxane synthase induces lung cancer cell death via increasing the nuclear p27

    SciTech Connect

    Leung, Kin Chung; Hsin, Michael K.Y.; Chan, Joey S.Y.; Yip, Johnson H.Y.; Li, Mingyue; Leung, Billy C.S.; Mok, Tony S.K.; Warner, Timothy D.; Underwood, Malcolm J.; Chen, George G.

    2009-10-15

    The role of thromboxane in lung carcinogenesis is not clearly known, though thromboxane B2 (TXB{sub 2}) level is increased and antagonists of thromboxane receptors or TXA2 can induce apoptosis of lung cancer cells. p27, an atypical tumor suppressor, is normally sequestered in the nucleus. The increased nuclear p27 may result in apoptosis of tumor cells. We hypothesize that the inhibition of thromboxane synthase (TXS) induces the death of lung cancer cells and that such inhibition is associated with the nuclear p27 level. Our experiment showed that the inhibition of TXS significantly induced the death or apoptosis in lung cancer cells. The activity of TXS was increased in lung cancer. The nuclear p27 was remarkably reduced in lung cancer tissues. The inhibition of TXS caused the cell death and apoptosis of lung cancer cells, likely via the elevation of the nuclear p27 since the TXS inhibition promoted the nuclear p27 level and the inhibition of p27 by its siRNA recovered the cell death induced by TXS inhibition. Collectively, lung cancer cells produce high levels of TXB{sub 2} but their nuclear p27 is markedly reduced. The inhibition of TXS results in the p27-related induction of cell death in lung cancer cells.

  8. Inhibition of mitogen stimulated growth of human colon cancer cells by interferon.

    PubMed Central

    Hamburger, A. W.; Condon, M. E.; O'Donnell, K.

    1988-01-01

    Recombinant human interferon alpha inhibits growth of a human colon cancer cell line, Colo 205. To explore the mechanisms of IFN induced growth inhibition, quiescent Colo 205 cells were stimulated to proliferate in serum-free media by defined growth factors. Addition of insulin, transferrin and selenium (ITS) stimulated DNA synthesis, as measured by 3H-thymidine incorporation, in a dose-dependent manner. IFN-alpha (at concentrations greater than 100 U ml-1) inhibited ITS stimulated DNA synthesis by 63%. Inhibition of cell cycle traverse was confirmed by flow cytometric analysis. Although IFN inhibited growth of ITS-treated cells, steady state levels of c-myc mRNA remained above levels observed in unstimulated cells. IFN inhibited DNA synthesis only when added prior to mitogen stimulation. IFN, added 6 h after exposure of quiescent cells to ITS, failed to inhibit cell growth. Addition of increasing concentrations of ITS failed to overcome the IFN-induced growth inhibition. These results suggest IFN may inhibit cell growth in part by antagonizing the action of growth factors. Images Figure 4 PMID:3166905

  9. Simvastatin induces cell cycle arrest and inhibits proliferation of bladder cancer cells via PPARγ signalling pathway

    PubMed Central

    Wang, Gang; Cao, Rui; Wang, Yongzhi; Qian, Guofeng; Dan, Han C.; Jiang, Wei; Ju, Lingao; Wu, Min; Xiao, Yu; Wang, Xinghuan

    2016-01-01

    Simvastatin is currently one of the most common drugs for old patients with hyperlipidemia, hypercholesterolemia and atherosclerotic diseases by reducing cholesterol level and anti-lipid properties. Importantly, simvastatin has also been reported to have anti-tumor effect, but the underlying mechanism is largely unknown. We collected several human bladder samples and performed microarray. Data analysis suggested bladder cancer (BCa) was significantly associated with fatty acid/lipid metabolism via PPAR signalling pathway. We observed simvastatin did not trigger BCa cell apoptosis, but reduced cell proliferation in a dose- and time-dependent manner, accompanied by PPARγ-activation. Moreover, flow cytometry analysis indicated that simvastatin induced cell cycle arrest at G0/G1 phase, suggested by downregulation of CDK4/6 and Cyclin D1. Furthermore, simvastatin suppressed BCa cell metastasis by inhibiting EMT and affecting AKT/GSK3β. More importantly, we found that the cell cycle arrest at G0/G1 phase and the alterations of CDK4/6 and Cyclin D1 triggered by simvastatin could be recovered by PPARγ-antagonist (GW9662), whereas the treatment of PPARα-antagonist (GW6471) shown no significant effects on the BCa cells. Taken together, our study for the first time revealed that simvastatin inhibited bladder cancer cell proliferation and induced cell cycle arrest at G1/G0 phase via PPARγ signalling pathway. PMID:27779188

  10. Oridonin inhibits BxPC-3 cell growth through cell apoptosis.

    PubMed

    Xu, Bin; Shen, Wen; Liu, Xing; Zhang, Ting; Ren, Jun; Fan, Yongjun; Xu, Jian

    2015-03-01

    Oridonin, an ent-kaurene diterpenoid extracted from the traditional Chinese herb Rabdosia rubescens, has multiple biological and pharmaceutical functions and has been used clinically for many years. While the antitumor function of oridonin has been corroborated by numerous lines of evidence, its anticancer mechanism has not been well documented. In this study, the pancreatic cancer cell line BxPC-3 was used as a model to investigate a possible anticancer mechanism of oridonin through examining its effects on cell viability. The results showed that oridonin affected cell viability in a time- and dose-dependent manner. After exposure to different oridonin concentrations, growth rates and cell cycle arrest of BxPC-3 cells were significantly reduced compared with untreated cells, suggesting its effects on proliferation inhibition. Detailed signaling pathway analysis by western blot analysis revealed that low-dose oridonin treatment inhibited BxPC-3 cell proliferation by up-regulating p53 and down-regulating cyclin-dependent kinase 1 (CDK1), which led to cell cycle arrest in the G2/M phase. A high-dose oridonin not only arrested BxPC-3 cells in the G2/M phase but also induced cell accumulation in the S phase, presumably through γH2AX up-regulation and DNA damage. In addition, our results showed that a cell subpopulation was stained with propidium iodide after oridonin treatment. Protein quantification showed that cleaved poly(ADP-ribose) polymerase (PARP) expression was increased after a high-dose oridonin treatment, especially after long-term exposure. Accompanied by the increased level of deactivated PARP in BxPC-3 cells, the apoptosis initiators caspase-3 and caspase-7 expressions were also significantly increased, suggesting that caspase-mediated apoptosis contributed to cell death. PMID:25651847

  11. Inhibition of Snail1-DNA-PKcs protein-protein interface sensitizes cancer cells and inhibits tumor metastasis.

    PubMed

    Kang, Ga-Young; Pyun, Bo-Jeong; Seo, Haeng Ran; Jin, Yeung Bae; Lee, Hae-June; Lee, Yoon-Jin; Lee, Yun-Sil

    2013-11-01

    Our previous study suggested that the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) interacts with Snail1, which affects genomic instability, sensitivity to DNA-damaging agents, and migration of tumor cells by reciprocal regulation between DNA-PKcs and Snail1. Here, we further investigate that a peptide containing 7-amino acid sequences (amino acids 15-21) of Snail1 (KPNYSEL, SP) inhibits the endogenous interaction between DNA-PKcs and Snail1 through primary interaction with DNA-PKcs. SP restored the inhibited DNA-PKcs repair activity and downstream pathways. On the other hand, DNA-PKcs-mediated phosphorylation of Snail1 was inhibited by SP, which resulted in decreased Snail1 stability and Snail1 functions. However, these phenomena were only shown in p53 wild-type cells, not in p53-defective cells. From these results, it is suggested that interfering with the protein interaction between DNA-PKcs and Snail1 might be an effective strategy for sensitizing cancer cells and inhibiting tumor migration, especially in both Snail1-overexpressing and DNA-PKcs-overexpressing cancer cells with functional p53.

  12. Benzyl isothiocyanate inhibits HNSCC cell migration and invasion, and sensitizes HNSCC cells to cisplatin.

    PubMed

    Wolf, M Allison; Claudio, Pier Paolo

    2014-01-01

    Metastasis and chemoresistance represent two detrimental events that greatly hinder the outcome for those suffering with head and neck squamous cell carcinoma (HNSCC). Herein, we investigated benzyl isothiocyanate's (BITC) ability to inhibit HNSCC migration and invasion and enhance chemotherapy. Our data suggests that treatment with BITC 1) induced significant reductions in the viability of multiple HNSCC cell lines tested (HN12, HN8, and HN30) after 24 and 48 h, 2) decreased migration and invasion of the HN12 cells in a dose dependent manner, and 3) inhibited expression and altered localization of the epithelial-mesenchymal transition (EMT) marker, vimentin. We also observed that a pretreatment of BITC followed by cisplatin treatment 1) induced a greater decrease in HN12, HN30, and HN8 cell viability and total cell count than either treatment alone and 2) significantly increased apoptosis when compared to either treatment alone. Taken together these data suggest that BITC has the capacity to inhibit processes involved in metastasis and enhance the effectiveness of chemotherapy. Consequently, the results indicate that further investigation, including in vivo studies, are warranted.

  13. p205, a potential tumor suppressor, inhibits cell proliferation via multiple pathways of cell cycle regulation.

    PubMed

    Asefa, Benyam; Dermott, Jonathan M; Kaldis, Philipp; Stefanisko, Karen; Garfinkel, David J; Keller, Jonathan R

    2006-02-20

    p205 is a member of the interferon-inducible p200 family of proteins that regulate cell proliferation. Over-expression of p205 inhibits cell growth, although its mechanism of action is currently unknown. Therefore, we evaluated the effect of p205 on the p53 and Rb-dependent pathways of cell cycle regulation. p205 expression results in elevated levels of p21, and activates the p21 promoter in vitro in a p53-dependent manner. In addition, p205 induces increased expression of Rb, and binds directly to Rb and p53. Interestingly, p205 also induces growth inhibition independent of p53 and Rb by delaying G2/M progression in proliferating cells, and is a substrate for Cdk2 kinase activity. Finally, we have identified other binding partners of p205 by a yeast two-hybrid screen, including the paired homeodomain protein HoxB2. Taken together, our results indicate that p205 induces growth arrest by interaction with multiple transcription factors that regulate the cell cycle, including but not entirely dependent on the Rb- and p53-mediated pathways of growth inhibition. PMID:16458891

  14. Lycopene inhibits the cell proliferation and invasion of human head and neck squamous cell carcinoma

    PubMed Central

    Ye, Min; Wu, Qundan; Zhang, Min; Huang, Jinbei

    2016-01-01

    Lycopene has been shown to be associated with anticancer effects in numerous tumor types. However, the underlying mechanisms of lycopene in human head and neck squamous cell carcinoma (HNSCC) remain to be determined. The present study aimed to investigate the involvement of lycopene overload and the cytotoxic effects of lycopene on HNSCC cells, and to determine the possible mechanisms involved. Treatment with lycopene at a dose of >10 µM for >24 h inhibited the growth of FaDu and Cal27 cells in a time- and dose-dependent manner. The clearest increase in growth inhibition was due to the apoptotic population being significantly increased. The invasion abilities decreased with 25 µM lycopene exerting significant inhibitory effects (P<0.01). Mechanistic studies revealed that lycopene induced the upregulation of the pro-apoptotic protein, B-cell lymphoma-associated X protein, and therefore, resulted in the inhibition of the protein kinase B and mitogen-activated protein kinase signaling pathway. These data provided insights into the antitumor activity of lycopene in HNSCC cells. PMID:27510325

  15. Downregulation of SENP1 inhibits cell proliferation, migration and promotes apoptosis in human glioma cells

    PubMed Central

    ZHANG, QIU-SHENG; ZHANG, MENG; HUANG, XIAN-JIAN; LIU, XIAO-JIA; LI, WEI-PING

    2016-01-01

    Small ubiquitin-related modifier protein (SUMO) is an evolutionarily conserved protein in a broad range of eukaryotic organisms. De-SUMOylation, the reverse reaction of SUMOylation, is regulated by a family of SUMO-specific proteases (SENPs). SENP1 is a member of the de-SUMOylation protease family involved in the de-SUMOylation of a variety of SUMOylated proteins. The present study demonstrates that small hairpin RNA (shRNA)-mediated downregulation of SENP1 inhibits cell proliferation and migration, and promotes apoptosis in human glioma cells. Firstly, LN-299 cells were transfected with a plasmid expressing SENP1 shRNA (pGenesil-1-SENP1). The messenger RNA and protein expression of SENP1 was detected by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Cell proliferation in vitro was assessed using a methyl thiazolyl tetrazolium assay. Flow cytometry (FCM) was used to detect the apoptosis of LN-299 cells. The effect of the downregulation of SENP1 on cell migration was detected by a Transwell migration system. The present results showed that, compared with the control shRNA group, the expression of SENP1 was significantly reduced in the SENP1 shRNA group. The proliferation was markedly inhibited in the SENP1 shRNA group. FCM findings revealed that apoptosis increased significantly in the SENP1 shRNA group. In addition, it was found that downregulation of SENP1 evidently suppressed tumor cell migration. Downregulation of SENP1 expression inhibited the proliferation and migration and promoted apoptosis in LN-299 cells. These results indirectly demonstrate that SENP1 is likely to play a critical role in human glioma cells. PMID:27347128

  16. Gambogic acid induces apoptosis in diffuse large B-cell lymphoma cells via inducing proteasome inhibition

    PubMed Central

    Shi, Xianping; Lan, Xiaoying; Chen, Xin; Zhao, Chong; Li, Xiaofen; Liu, Shouting; Huang, Hongbiao; Liu, Ningning; Zang, Dan; Liao, Yuning; Zhang, Peiquan; Wang, Xuejun; Liu, Jinbao

    2015-01-01

    Resistance to chemotherapy is a great challenge to improving the survival of patients with diffuse large B-cell lymphoma (DLBCL), especially those with activated B-cell-like DLBCL (ABC-DLBCL). Therefore it is urgent to search for novel agents for the treatment of DLBCL. Gambogic acid (GA), a small molecule derived from Chinese herb gamboges, has been approved for Phase II clinical trial for cancer therapy by Chinese FDA. In the present study, we investigated the effect of GA on cell survival and apoptosis in DLBCL cells including both GCB- and ABC-DLBCL cells. We found that GA induced growth inhibition and apoptosis of both GCB- and ABC-DLBCL cells in vitro and in vivo, which is associated with proteasome malfunction. These findings provide significant pre-clinical evidence for potential usage of GA in DLBCL therapy particularly in ABC-DLBCL treatment. PMID:25853502

  17. Polydatin inhibits growth of lung cancer cells by inducing apoptosis and causing cell cycle arrest.

    PubMed

    Zhang, Yusong; Zhuang, Zhixiang; Meng, Qinghui; Jiao, Yang; Xu, Jiaying; Fan, Saijun

    2014-01-01

    Polydatin (PD), a small natural compound from Polygonum cuspidatum, has a number of biological functions. However, the anticancer activity of PD has been poorly investigated. In the present study, thiazolyl blue tetrazolium bromide assay was used to evaluate the inhibitory effect of PD on cell growth. Cell cycle distribution and apoptosis were investigated by flow cytometry. In addition, the expression of several proteins associated with apoptosis and cell cycle were analyzed by western blot analysis. The results demonstrated that PD significantly inhibits the proliferation of A549 and NCI-H1975 lung cancer cell lines and causes dose-dependent apoptosis. Cell cycle analysis revealed that PD induces S phase cell cycle arrest. Western blot analysis showed that the expression of Bcl-2 decreased as that of Bax increased, and the expression of cyclin D1 was also suppressed. The results suggest that PD has potential therapeutic applications in the treatment of lung cancer. PMID:24348867

  18. Inhibition of Kv channel expression by NSAIDs depolarizes membrane potential and inhibits cell migration by disrupting calpain signaling.

    PubMed

    Silver, Kristopher; Littlejohn, Alaina; Thomas, Laurel; Marsh, Elizabeth; Lillich, James D

    2015-12-15

    Clinical use of non-steroidal anti-inflammatory drugs (NSAIDs) is well known to cause gastrointestinal ulcer formation via several mechanisms that include inhibiting epithelial cell migration and mucosal restitution. The drug-affected signaling pathways that contribute to inhibition of migration by NSAIDs are poorly understood, though previous studies have shown that NSAIDs depolarize membrane potential and suppress expression of calpain proteases and voltage-gated potassium (Kv) channel subunits. Kv channels play significant roles in cell migration and are targets of NSAID activity in white blood cells, but the specific functional effects of NSAID-induced changes in Kv channel expression, particularly on cell migration, are unknown in intestinal epithelial cells. Accordingly, we investigated the effects of NSAIDs on expression of Kv1.3, 1.4, and 1.6 in vitro and/or in vivo and evaluated the functional significance of loss of Kv subunit expression. Indomethacin or NS-398 reduced total and plasma membrane protein expression of Kv1.3 in cultured intestinal epithelial cells (IEC-6). Additionally, depolarization of membrane potential with margatoxin (MgTx), 40mM K(+), or silencing of Kv channel expression with siRNA significantly reduced IEC-6 cell migration and disrupted calpain activity. Furthermore, in rat small intestinal epithelia, indomethacin and NS-398 had significant, yet distinct, effects on gene and protein expression of Kv1.3, 1.4, or 1.6, suggesting that these may be clinically relevant targets. Our results show that inhibition of epithelial cell migration by NSAIDs is associated with decreased expression of Kv channel subunits, and provide a mechanism through which NSAIDs inhibit cell migration and may contribute to NSAID-induced gastrointestinal (GI) toxicity.

  19. Suppression of autophagy augments the radiosensitizing effects of STAT3 inhibition on human glioma cells

    SciTech Connect

    Yuan, Xiaopeng; Du, Jie; Hua, Song; Zhang, Haowen; Gu, Cheng; Wang, Jie; Yang, Lei; Huang, Jianfeng; Yu, Jiahua Liu, Fenju

    2015-01-15

    Radiotherapy is an essential component of the standard therapy for newly diagnosed glioblastoma. To increase the radiosensitivity of glioma cells is a feasible solution to improve the therapeutic effects. It has been suggested that inhibition of signal transducer and activator of transcription 3 (STAT3) can radiosensitize glioma cells, probably via the activation of mitochondrial apoptotic pathway. In this study, human malignant glioma cells, U251 and A172, were treated with an STAT3 inhibitor, WP1066, or a short hairpin RNA plasmid targeting STAT3 to suppress the activation of STAT3 signaling. The radiosensitizing effects of STAT3 inhibition were confirmed in glioma cells. Intriguingly, combination of ionizing radiation exposure and STAT3 inhibition triggered a pronounced increase of autophagy flux. To explore the role of autophagy, glioma cells were treated with 3-methyladenine or siRNA for autophagy-related gene 5, and it was demonstrated that inhibition of autophagy further strengthened the radiosensitizing effects of STAT3 inhibition. Accordingly, more apoptotic cells were induced by the dual inhibition of autophagy and STAT3 signaling. In conclusion, our data revealed a protective role of autophagy in the radiosensitizing effects of STAT3 inhibition, and inhibition of both autophagy and STAT3 might be a potential therapeutic strategy to increase the radiosensitivity of glioma cells. - Highlights: • Inactivation of STAT3 signaling radiosensitizes malignant glioma cells. • STAT3 inhibition triggers a significant increase of autophagy flux induced by ionizing radiation in glioma cells. • Suppression of autophagy further strengthens the radiosensitizing effects of STAT3 inhibition in glioma cells. • Dual inhibition of autophagy and STAT3 induce massive apoptotic cells upon exposure to ionizing radiation.

  20. Transient Inhibition of Cell Proliferation does not Compromise Self-Renewal of Mouse Embryonic Stem Cells

    PubMed Central

    Wang, Ruoxing; Guo, Yan-Lin

    2012-01-01

    Embryonic stem cells (ESCs) have unlimited capacity for self-renewal and can differentiate into various cell types when induced. They also have an unusual cell cycle control mechanism driven by constitutively active cyclin dependent kinases (Cdks). In mouse ESCs (mESCs). It is proposed that the rapid cell proliferation could be a necessary part of mechanisms that maintain mESC self-renewal and pluripotency, but this hypothesis is not in line with the finding in human ESCs (hESCs) that the length of the cell cycle is similar to differentiated cells. Therefore, whether rapid cell proliferation is essential for the maintenance of mESC state remains unclear. We provide insight into this uncertainty through chemical intervention of mESC cell cycle. We report here that inhibition of Cdks with olomoucine II can dramatically slow down cell proliferation of mESCs with concurrent down-regulation of cyclin A, B and E, and the activation of the Rb pathway. However, mESCs display can recover upon the removal of olomoucine II and are able to resume normal cell proliferation without losing self-renewal and pluripotency, as demonstrated by the expression of ESC markers, colony formation, embryoid body formation, and induced differentiation. We provide a mechanistic explanation for these observations by demonstrating that Oct4 and Nanog, two major transcription factors that play critical roles in the maintenance of ESC properties, are up-regulated via de novo protein synthesis when the cells are exposed to olomoucine II. Together, our data suggest that short-term inhibition of cell proliferation does not compromise the basic properties of mESCs. PMID:22705123

  1. M2 receptor activation inhibits cell cycle progression and survival in human glioblastoma cells.

    PubMed

    Ferretti, Michela; Fabbiano, Cinzia; Di Bari, Maria; Conte, Claudia; Castigli, Emilia; Sciaccaluga, Miriam; Ponti, Donatella; Ruggieri, Paola; Raco, Antonino; Ricordy, Ruggero; Calogero, Antonella; Tata, Ada Maria

    2013-04-01

    Muscarinic receptors, expressed in several primary and metastatic tumours, appear to be implicated in their growth and propagation. In this work we have demonstrated that M2 muscarinic receptors are expressed in glioblastoma human specimens and in glioblastoma cell lines. Moreover, we have characterized the effects of the M2 agonist arecaidine on cell growth and survival both in two different glioblastoma cell lines (U251MG and U87MG) and in primary cultures obtained from different human biopsies. Cell growth analysis has demonstrated that the M2 agonist arecaidine strongly decreased cell proliferation in both glioma cell lines and primary cultures. This effect was dose and time dependent. FACS analysis has confirmed cell cycle arrest at G1/S and at G2/M phase in U87 cells and U251 respectively. Cell viability analysis has also shown that arecaidine induced severe apoptosis, especially in U251 cells. Chemosensitivity assays have, moreover, shown arecaidine and temozolomide similar effects on glioma cell lines, although IC50 value for arecaidine was significantly lower than temozolomide. In conclusion, we report for the first time that M2 receptor activation has a relevant role in the inhibition of glioma cell growth and survival, suggesting that M2 may be a new interesting therapeutic target to investigate for glioblastoma therapy.

  2. Transient inhibition of cell proliferation does not compromise self-renewal of mouse embryonic stem cells

    SciTech Connect

    Wang, Ruoxing; Guo, Yan-Lin

    2012-10-01

    Embryonic stem cells (ESCs) have unlimited capacity for self-renewal and can differentiate into various cell types when induced. They also have an unusual cell cycle control mechanism driven by constitutively active cyclin dependent kinases (Cdks). In mouse ESCs (mESCs). It is proposed that the rapid cell proliferation could be a necessary part of mechanisms that maintain mESC self-renewal and pluripotency, but this hypothesis is not in line with the finding in human ESCs (hESCs) that the length of the cell cycle is similar to differentiated cells. Therefore, whether rapid cell proliferation is essential for the maintenance of mESC state remains unclear. We provide insight into this uncertainty through chemical intervention of mESC cell cycle. We report here that inhibition of Cdks with olomoucine II can dramatically slow down cell proliferation of mESCs with concurrent down-regulation of cyclin A, B and E, and the activation of the Rb pathway. However, mESCs display can recover upon the removal of olomoucine II and are able to resume normal cell proliferation without losing self-renewal and pluripotency, as demonstrated by the expression of ESC markers, colony formation, embryoid body formation, and induced differentiation. We provide a mechanistic explanation for these observations by demonstrating that Oct4 and Nanog, two major transcription factors that play critical roles in the maintenance of ESC properties, are up-regulated via de novo protein synthesis when the cells are exposed to olomoucine II. Together, our data suggest that short-term inhibition of cell proliferation does not compromise the basic properties of mESCs. -- Highlights: Black-Right-Pointing-Pointer Inhibition of Cdks slows down mESCs proliferation. Black-Right-Pointing-Pointer mESCs display remarkable recovery capacity from short-term cell cycle interruption. Black-Right-Pointing-Pointer Short-term cell cycle interruption does not compromise mESC self-renewal. Black

  3. G protein γ subunit 7 induces autophagy and inhibits cell division

    PubMed Central

    Liu, Juanjuan; Ji, Xinmiao; Li, Zhiyuan; Yang, Xingxing; Wang, Wenchao; Zhang, Xin

    2016-01-01

    GNG7 (G protein γ subunit 7), a subunit of heterotrimeric G protein, is ubiquitously expressed in multiple tissues but is down-regulated in various cancers. Its expression could reduce tumor volume in mice but the mechanism was not clear. Here we show that GNG7 overexpression inhibits cell proliferation and increases cell death. GNG7 level is cell cycle-dependent and it regulates actin cytoskeleton and cell division. In addition, GNG7 is an autophagy inducer, which is the first reported Gγ protein involved in autophagy. GNG7 knockdown reduces Rapamycin and starvation-induced autophagy. Further analysis reveals that GNG7 inhibits MTOR in cells, a central regulator for autophagy and cell proliferation. In conclusion, GNG7 inhibits MTOR pathway to induce autophagy and cell death, inhibits cell division by regulating actin cytoskeleton. These combined effects lead to the antitumor capacity of GNG7. PMID:27056891

  4. Restoration of WNT4 inhibits cell growth in leukemia-derived cell lines

    PubMed Central

    2013-01-01

    Background WNT signaling pathways are significantly altered during cancer development. Vertebrates possess two classes of WNT signaling pathways: the “canonical” WNT/β-catenin signaling pathway, and the “non-canonical” pathways including WNT/Ca2+ and WNT/Planar cell polarity [PCP] signaling. WNT4 influences hematopoietic progenitor cell expansion and survival; however, WNT4 function in cancer development and the resulting implications for oncogenesis are poorly understood. The aim of this study was twofold: first, to determine the expression of WNT4 in mature peripheral blood cells and diverse leukemia-derived cells including cell lines from hematopoietic neoplasms and cells from patients with leukemia; second, to identify the effect of this ligand on the proliferation and apoptosis of the blast-derived cell lines BJAB, Jurkat, CEM, K562, and HL60. Methods We determined WNT4 expression by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) in peripheral blood mononuclear cells (PBMCs) and T- and B-lymphocytes from healthy individuals, as well as from five leukemia-derived cell lines and blasts derived from patients with leukemia. To analyze the effect of WNT4 on cell proliferation, PBMCs and cell lines were exposed to a commercially available WNT4 recombinant human protein. Furthermore, WNT4 expression was restored in BJAB cells using an inducible lentiviral expression system. Cell viability and proliferation were measured by the addition of WST-1 to cell cultures and counting cells; in addition, the progression of the cell cycle and the amount of apoptosis were analyzed in the absence or presence of WNT4. Finally, the expression of WNT-pathway target genes was measured by qRT-PCR. Results WNT4 expression was severely reduced in leukemia-derived cell lines and blasts derived from patients with leukemia. The exposure of cell lines to WNT4 recombinant protein significantly inhibited cell proliferation; inducing WNT4 expression in BJAB

  5. Stable SET knockdown in breast cell carcinoma inhibits cell migration and invasion

    SciTech Connect

    Li, Jie; Yang, Xi-fei; Ren, Xiao-hu; Meng, Xiao-jing; Huang, Hai-yan; Zhao, Qiong-hui; Yuan, Jian-hui; Hong, Wen-xu; Xia, Bo; Huang, Xin-feng; Zhou, Li; Liu, Jian-jun; Zou, Fei

    2014-10-10

    Highlights: • We employed RNA interference to knockdown SET expression in breast cancer cells. • Knockdown of SET expression inhibits cell proliferation, migration and invasion. • Knockdown of SET expression increases the activity and expression of PP2A. • Knockdown of SET expression decreases the expression of MMP-9. - Abstract: Breast cancer is the most malignant tumor for women, however, the mechanisms underlying this devastating disease remain unclear. SET is an endogenous inhibitor of protein phosphatase 2A (PP2A) and involved in many physiological and pathological processes. SET could promote the occurrence of tumor through inhibiting PP2A. In this study, we explore the role of SET in the migration and invasion of breast cancer cells MDA-MB-231 and ZR-75-30. The stable suppression of SET expression through lentivirus-mediated RNA interference (RNAi) was shown to inhibit the growth, migration and invasion of breast cancer cells. Knockdown of SET increases the activity and expression of PP2Ac and decrease the expression of matrix metalloproteinase 9 (MMP-9). These data demonstrate that SET may be involved in the pathogenic processes of breast cancer, indicating that SET can serve as a potential therapeutic target for the treatment of breast cancer.

  6. Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death

    PubMed Central

    Scott, Ryan C.; Juhász, Gábor; Neufeld, Thomas P.

    2007-01-01

    Background To survive starvation and other forms of stress, eukaryotic cells undergo a lysosomal process of cytoplasmic degradation known as autophagy. Autophagy has been implicated in a number of cellular and developmental processes, including cell growth control and programmed cell death. However, direct evidence of a causal role for autophagy in these processes is lacking, due in part to the pleiotropic effects of signaling molecules such as TOR that regulate autophagy. Here, we circumvent this difficulty by directly manipulating autophagy rates in Drosophila through the autophagy-specific protein kinase Atg1. Results We find that overexpression of Atg1 is sufficient to induce high levels of autophagy, the first such demonstration among wild type Atg proteins. In contrast to findings in yeast, induction of autophagy by Atg1 is dependent on its kinase activity. We find that cells with high levels of Atg1-induced autophagy are rapidly eliminated, demonstrating that autophagy is capable of inducing cell death. However, this cell death is caspase dependent and displays DNA fragmentation, suggesting that autophagy represents an alternative induction of apoptosis, rather than a distinct form of cell death. In addition, we demonstrate that Atg1-induced autophagy strongly inhibits cell growth, and that Atg1 mutant cells have a relative growth advantage under conditions of reduced TOR signaling. Finally, we show that Atg1 expression results in negative feedback on the activity of TOR itself. Conclusions Our results reveal a central role for Atg1 in mounting a coordinated autophagic response, and demonstrate that autophagy has the capacity to induce cell death. Furthermore, this work identifies autophagy as a critical mechanism by which inhibition of TOR signaling leads to reduced cell growth. PMID:17208179

  7. Shielding of the Geomagnetic Field Alters Actin Assembly and Inhibits Cell Motility in Human Neuroblastoma Cells

    PubMed Central

    Mo, Wei-Chuan; Zhang, Zi-Jian; Wang, Dong-Liang; Liu, Ying; Bartlett, Perry F.; He, Rong-Qiao

    2016-01-01

    Accumulating evidence has shown that absence of the geomagnetic field (GMF), the so-called hypomagnetic field (HMF) environment, alters the biological functions in seemingly non-magnetosensitive cells and organisms, which indicates that the GMF could be sensed by non-iron-rich and non-photo-sensing cells. The underlying mechanisms of the HMF effects on those cells are closely related to their GMF sensation but remain poorly understood so far. Previously, we found that the HMF represses expressions of genes associated with cell migration and cytoskeleton assembly in human neuroblastoma cells (SH-SY5Y cell line). Here, we measured the HMF-induced changes on cell morphology, adhesion, motility and actin cytoskeleton in SH-SY5Y cells. The HMF inhibited cell adhesion and migration accompanied with a reduction in cellular F-actin amount. Moreover, following exposure to the HMF, the number of cell processes was reduced and cells were smaller in size and more round in shape. Furthermore, disordered kinetics of actin assembly in vitro were observed during exposure to the HMF, as evidenced by the presence of granule and meshed products. These results indicate that elimination of the GMF affects assembly of the motility-related actin cytoskeleton, and suggest that F-actin is a target of HMF exposure and probably a mediator of GMF sensation. PMID:27029216

  8. Carboxyamidotriazole inhibits oxidative phosphorylation in cancer cells and exerts synergistic anti-cancer effect with glycolysis inhibition.

    PubMed

    Ju, Rui; Guo, Lei; Li, Juan; Zhu, Lei; Yu, Xiaoli; Chen, Chen; Chen, Wei; Ye, Caiying; Zhang, Dechang

    2016-01-28

    Targeting cancer cell metabolism is a promising strategy against cancer. Here, we confirmed that the anti-cancer drug carboxyamidotriazole (CAI) inhibited mitochondrial respiration in cancer cells for the first time and found a way to enhance its anti-cancer activity by further disturbing the energy metabolism. CAI promoted glucose uptake and lactate production when incubated with cancer cells. The oxidative phosphorylation (OXPHOS) in cancer cells was inhibited by CAI, and the decrease in the activity of the respiratory chain complex I could be one explanation. The anti-cancer effect of CAI was greatly potentiated when being combined with 2-deoxyglucose (2-DG). The cancer cells treated with the combination of CAI and 2-DG were arrested in G2/M phase. The apoptosis and necrosis rates were also increased. In a mouse xenograft model, this combination was well tolerated and retarded the tumor growth. The impairment of cancer cell survival was associated with significant cellular ATP decrease, suggesting that the combination of CAI and 2-DG could be one of the strategies to cause dual inhibition of energy pathways, which might be an effective therapeutic approach for a broad spectrum of tumors.

  9. Infantile hemangioma-derived stem cells and endothelial cells are inhibited by class 3 semaphorins

    SciTech Connect

    Nakayama, Hironao; Huang, Lan; Kelly, Ryan P.; Oudenaarden, Clara R.L.; Dagher, Adelle; Hofmann, Nicole A.; Moses, Marsha A.; Bischoff, Joyce; Klagsbrun, Michael

    2015-08-14

    Class 3 semaphorins were discovered as a family of axon guidance molecules, but are now known to be involved in diverse biologic processes. In this study, we investigated the anti-angiogenic potential of SEMA3E and SEMA3F (SEMA3E&F) in infantile hemangioma (IH). IH is a common vascular tumor that involves both vasculogenesis and angiogenesis. Our lab has identified and isolated hemangioma stem cells (HemSC), glucose transporter 1 positive (GLUT1{sup +}) endothelial cells (designated as GLUT1{sup sel} cells) based on anti-GLUT1 magnetic beads selection and GLUT1-negative endothelial cells (named HemEC). We have shown that these types of cells play important roles in hemangiogenesis. We report here that SEMA3E inhibited HemEC migration and proliferation while SEMA3F was able to suppress the migration and proliferation in all three types of cells. Confocal microscopy showed that stress fibers in HemEC were reduced by SEMA3E&F and that stress fibers in HemSC were decreased by SEMA3F, which led to cytoskeletal collapse and loss of cell motility in both cell types. Additionally, SEMA3E&F were able to inhibit vascular endothelial growth factor (VEGF)-induced sprouts in all three types of cells. Further, SEMA3E&F reduced the level of p-VEGFR2 and its downstream p-ERK in HemEC. These results demonstrate that SEMA3E&F inhibit IH cell proliferation and suppress the angiogenic activities of migration and sprout formation. SEMA3E&F may have therapeutic potential to treat or prevent growth of highly proliferative IH. - Highlights: • SEMA3E&F reduce actin stress fibers and induce cytoskeletal collapse in HemEC. • SEMA3E&F inhibit angiogenic activities of HemEC. • SEMA3E&F can interrupt the VEGF-A-VEGFR2-ERK signaling pathway in HemEC. • Plexin D1 and NRP2 are induced during HemSC/GLUT1{sup sel}-to-EC differentiation.

  10. Compounds in a particular production lot of tryptic soy broth inhibit Staphylococcus aureus cell growth.

    PubMed

    Ishii, Masaki; Matsumoto, Yasuhiko; Sekimizu, Kazuhisa

    2015-06-01

    Staphylococcus aureus Newman strain and several methicillin-resistant S. aureus (MRSA) clinical isolates were grown on agar plates prepared with conventional lots of tryptic soy broth (TSB). Cell growth of these strains was inhibited on agar plates containing TSB of a particular product lot (lot A), whereas the cell growth of S. aureus RN4220 strain and several other MRSA clinical isolates was not inhibited. The cell growth of a strain of S. epidermidis was also inhibited on agar plates containing TSB of lot A, whereas the cell growth of Bacillus subtilis, Lactococcus lactis, Klebsiella pneumonia, Salmonella enterica, Serratia marcescens, Pseudomonas aeruginosa, and Escherichia coli was not inhibited. Although cell growth of the Newman strain was inhibited on agar plates containing TSB of lot A that was autoclaved in stainless steel or glass containers, cell growth inhibition was not observed when the medium was autoclaved in polypropylene containers. Compounds that inhibited the cell growth of the Newman strain were extracted from a polypropylene tube that was preincubated with liquid medium prepared from TSB of lot A. These findings suggest that polypropylene-binding compounds in TSB of lot A inhibited the cell growth of S. aureus Newman strain, some MRSA clinical isolates, and S. epidermidis.

  11. HIV Infection of Monocytes-Derived Dendritic Cells Inhibits Vγ9Vδ2 T Cells Functions

    PubMed Central

    Sacchi, Alessandra; Rinaldi, Alessandra; Tumino, Nicola; Casetti, Rita; Agrati, Chiara; Turchi, Federica; Bordoni, Veronica; Cimini, Eleonora; Martini, Federico

    2014-01-01

    DCs act as sentinel cells against incoming pathogens and represent the most potent antigen presenting cells, having the unique capability to prime naïve T cells. In addition to their role in induction of adaptive immune responses, DC are also able to activate innate cells as γδ T cells; in particular, a reciprocal crosstalk between DC and γδ T cells was demonstrated. However, whether HIV infection may alter DC-Vγ9Vδ2 T cells cross-talk was not yet described. To clarify this issue, we cultured activated Vγ9Vδ2 T cells with HIV infected monocyte derived DC (MoDC). After 5 days we evaluated MoDC phenotype, and Vγ9Vδ2 T cells activation and proliferation. In our model, Vγ9Vδ2 T cells were not able to proliferate in response to HIV-infected MoDC, although an up-regulation of CD69 was observed. Upon phosphoantigens stimulation, Vγ9Vδ2 T cells proliferation and cytokine production were inhibited when cultured with HIV-infected MoDC in a cell-contact dependent way. Moreover, HIV-infected MoDC are not able to up-regulate CD86 molecules when cultured with activated Vγ9Vδ2 T cells, compared with uninfected MoDC. Further, activated Vγ9Vδ2 T cells are not able to induce HLA DR up-regulation and CCR5 down-regulation on HIV-infected MoDC. These data indicate that HIV-infected DC alter the capacity of Vγ9Vδ2 T cells to respond to their antigens, pointing out a new mechanisms of induction of Vγ9Vδ2 T cells anergy carried out by HIV, that could contribute to immune evasion. PMID:25340508

  12. Inhibition of glutamine metabolism counteracts pancreatic cancer stem cell features and sensitizes cells to radiotherapy

    PubMed Central

    Zhao, Xiaohui; Zhou, Yu; Zeng, Bing; Yu, Min; Zhou, Quanbo; Lin, Qing; Gao, Wenchao; Ye, Huilin; Zhou, Jiajia; Li, Zhihua; Liu, Yimin; Chen, Rufu

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) cells utilize a novel non-canonical pathway of glutamine metabolism that is essential for tumor growth and redox balance. Inhibition of this metabolic pathway in PDAC can potentially synergize with therapies that increase intracellular reactive oxygen species (ROS) such as radiation. Here, we evaluated the dependence of pancreatic cancer stem cells (PCSCs) on this non-canonical glutamine metabolism pathway and researched whether inhibiting this pathway can enhance radiosensitivity of PCSCs. We showed that glutamine deprivation significantly inhibited self-renewal, decreased expression of stemness-related genes, increased intracellular ROS, and induced apoptosis in PCSCs. These effects were countered by oxaloacetate, but not α-ketoglutarate. Knockdown of glutamic-oxaloacetic transaminase dramatically impaired PCSCs properties, while glutamate dehydrogenase knockdown had a limited effect, suggesting a dependence of PCSCs on non-canonical glutamine metabolism. Additionally, glutamine deprivation significantly increased radiation-induced ROS and sensitized PCSCs to fractionated radiation. Moreover, transaminase inhibitors effectively enhanced ROS generation, promoted radiation sensitivity, and attenuated tumor growth in nude mice following radiation exposure. Our findings reveal that inhibiting the non-canonical pathway of glutamine metabolism enhances the PCSC radiosensitivity and may be an effective adjunct in cancer radiotherapy. PMID:26439804

  13. Inhibition of cell proliferation and cell cycle progression by specific inhibition of basal JNK activity: evidence that mitotic Bcl-2 phosphorylation is JNK-independent.

    PubMed

    Du, Lihua; Lyle, Christopher S; Obey, Toria B; Gaarde, William A; Muir, Jeffrey A; Bennett, Brydon L; Chambers, Timothy C

    2004-03-19

    The c-Jun NH(2)-terminal kinase (JNK) subgroup of mitogen-activated protein kinases has been implicated largely in stress responses, but an increasing body of evidence has suggested that JNK also plays a role in cell proliferation and survival. We examined the effect of JNK inhibition, using either SP600125 or specific antisense oligonucleotides, on cell proliferation and cell cycle progression. SP600125 was selective for JNK in vitro and in vivo versus other kinases tested including ERK, p38, cyclin-dependent protein kinase 1 (CDK1), and CDK2. SP600125 inhibited JNK activity and KB-3 cell proliferation with the same dose dependence, suggesting that inhibition of proliferation was a direct consequence of JNK inhibition. Inhibition of proliferation by SP600125 was associated with an increase in the G(2)-M and apoptotic fractions of cells but was not associated with p53 or p21 induction. Antisense oligonucleotides to JNK2 but not JNK1 caused highly significant inhibition of cell proliferation. Wild-type mouse fibroblasts responded similarly with proliferation inhibition and apoptosis induction, whereas c-jun(-/-) fibroblasts were refractory to the effects of SP600125, suggesting that JNK signaling to c-Jun is required for cell proliferation. Studies in synchronized KB-3 cells indicated that SP600125 delayed transit time through S and G(2)-M phases. Correspondingly, JNK activity increased in late S phase and peaked in late G(2) phase. During synchronous mitotic progression, cyclin B levels increased concomitant with phosphorylation of c-Jun, H1 histone, and Bcl-2. In the presence of SP600125, mitotic progression was prolonged, and c-Jun phosphorylation was inhibited, but neither H1 nor Bcl-2 phosphorylation was inhibited. However, the CDK inhibitor roscovitine inhibited mitotic Bcl-2 phosphorylation. These results indicate that JNK, and more specifically the JNK2 isoform, plays a key role in cell proliferation and cell cycle progression. In addition, conclusive

  14. Small interfering RNA silencing of interleukin-6 in mesenchymal stromal cells inhibits multiple myeloma cell growth.

    PubMed

    Teoh, Hoon Koon; Chong, Pei Pei; Abdullah, Maha; Sekawi, Zamberi; Tan, Geok Chin; Leong, Chooi Fun; Cheong, Soon Keng

    2016-01-01

    Studies demonstrated that mesenchymal stromal cells (MSC) from bone marrow stroma produced high concentration of interleukin-6 (IL-6) that promoted multiple myeloma cell growth. In view of the failure of IL-6 monoclonal antibody therapy to demonstrate substantial clinical responses in early clinical trials, more effective methods are needed in order to disrupt the favourable microenvironment provided by the bone marrow stroma. In this study, we evaluated the short interfering RNA (siRNA)-mediated silencing of IL-6 in MSC and the efficacy of these genetically modified MSC, with IL-6 suppression, on inhibition of U266 multiple myeloma cell growth. IL-6 mRNA and protein were significantly suppressed by 72h post IL-6 siRNA transfection without affecting the biological properties of MSC. Here we show significant inhibition of cell growth and IL-6 production in U266 cells co-cultured with MSC transfected with IL-6 siRNA when compared to U266 cells co-cultured with control MSC. We also show that the tumour volume and mitotic index of tumours in nude mice co-injected with U266 and MSC transfected with IL-6 siRNA were significantly reduced compared to tumours of mice co-injected with control MSC. Our results suggest potential use of RNA interference mediated therapy for multiple myeloma.

  15. Semicarbazone EGA Inhibits Uptake of Diphtheria Toxin into Human Cells and Protects Cells from Intoxication

    PubMed Central

    Schnell, Leonie; Mittler, Ann-Katrin; Mattarei, Andrea; Tehran, Domenico Azarnia; Montecucco, Cesare; Barth, Holger

    2016-01-01

    Diphtheria toxin is a single-chain protein toxin that invades human cells by receptor-mediated endocytosis. In acidic endosomes, its translocation domain inserts into endosomal membranes and facilitates the transport of the catalytic domain (DTA) from endosomal lumen into the host cell cytosol. Here, DTA ADP-ribosylates elongation factor 2 inhibits protein synthesis and leads to cell death. The compound 4-bromobenzaldehyde N-(2,6-dimethylphenyl)semicarbazone (EGA) has been previously shown to protect cells from various bacterial protein toxins which deliver their enzymatic subunits from acidic endosomes to the cytosol, including Bacillus anthracis lethal toxin and the binary clostridial actin ADP-ribosylating toxins C2, iota and Clostridium difficile binary toxin (CDT). Here, we demonstrate that EGA also protects human cells from diphtheria toxin by inhibiting the pH-dependent translocation of DTA across cell membranes. The results suggest that EGA might serve for treatment and/or prevention of the severe disease diphtheria. PMID:27428999

  16. Semicarbazone EGA Inhibits Uptake of Diphtheria Toxin into Human Cells and Protects Cells Articlefrom Intoxication.

    PubMed

    Schnell, Leonie; Mittler, Ann-Katrin; Mattarei, Andrea; Tehran, Domenico Azarnia; Montecucco, Cesare; Barth, Holger

    2016-01-01

    Diphtheria toxin is a single-chain protein toxin that invades human cells by receptor-mediated endocytosis. In acidic endosomes, its translocation domain inserts into endosomal membranes and facilitates the transport of the catalytic domain (DTA) from endosomal lumen into the host cell cytosol. Here, DTA ADP-ribosylates elongation factor 2 inhibits protein synthesis and leads to cell death. The compound 4-bromobenzaldehyde N-(2,6-dimethylphenyl)semicarbazone (EGA) has been previously shown to protect cells from various bacterial protein toxins which deliver their enzymatic subunits from acidic endosomes to the cytosol, including Bacillus anthracis lethal toxin and the binary clostridial actin ADP-ribosylating toxins C2, iota and Clostridium difficile binary toxin (CDT). Here, we demonstrate that EGA also protects human cells from diphtheria toxin by inhibiting the pH-dependent translocation of DTA across cell membranes. The results suggest that EGA might serve for treatment and/or prevention of the severe disease diphtheria. PMID:27428999

  17. Precision of Inhibition: Dendritic Inhibition by Individual GABAergic Synapses on Hippocampal Pyramidal Cells Is Confined in Space and Time.

    PubMed

    Müllner, Fiona E; Wierenga, Corette J; Bonhoeffer, Tobias

    2015-08-01

    Inhibition plays a fundamental role in controlling neuronal activity in the brain. While perisomatic inhibition has been studied in detail, the majority of inhibitory synapses are found on dendritic shafts and are less well characterized. Here, we combine paired patch-clamp recordings and two-photon Ca(2+) imaging to quantify inhibition exerted by individual GABAergic contacts on hippocampal pyramidal cell dendrites. We observed that Ca(2+) transients from back-propagating action potentials were significantly reduced during simultaneous activation of individual nearby inhibitory contacts. The inhibition of Ca(2+) transients depended on the precise spike-timing (time constant < 5 ms) and declined steeply in the proximal and distal direction (length constants 23-28 μm). Notably, Ca(2+) amplitudes in spines were inhibited to the same degree as in the shaft. Given the known anatomical distribution of inhibitory synapses, our data suggest that the collective inhibitory input to a pyramidal cell is sufficient to control Ca(2+) levels across the entire dendritic arbor with micrometer and millisecond precision.

  18. NAC, Tiron and Trolox Impair Survival of Cell Cultures Containing Glioblastoma Tumorigenic Initiating Cells by Inhibition of Cell Cycle Progression

    PubMed Central

    Stigliani, Sara; Carra, Elisa; Monteghirfo, Stefano; Longo, Luca; Daga, Antonio; Dono, Mariella; Zupo, Simona; Giaretti, Walter; Castagnola, Patrizio

    2014-01-01

    Reactive oxygen species (ROS) are metabolism by-products that may act as signaling molecules to sustain tumor growth. Antioxidants have been used to impair cancer cell survival. Our goal was to determine the mechanisms involved in the response to antioxidants of a human cell culture (PT4) containing glioblastoma (GBM) tumorigenic initiating cells (TICs). ROS production in the absence or presence of N-acetyl-L-cysteine (NAC), tiron, and trolox was evaluated by flow cytometry (FCM). The effects of these antioxidants on cell survival and apoptosis were evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT) and FCM. The biological processes modulated by these drugs were determined by oligonucleotide microarray gene expression profiling. Our results showed that NAC, tiron and trolox impaired PT4 cell survival, had minor effects on ROS levels and caused wide deregulation of cell cycle genes. Furthermore, tiron and trolox caused inhibition of cell survival in two additional cell cultures containing TICs, FO-1 and MM1, established from a melanoma and a mesothelioma patient, respectively. NAC, instead, impaired survival of the MM1 cells but not of the FO-1 cells. However, when used in combination, NAC enhanced the inhibitory effect of PLX4032 (BRAF V600E inhibitor) and Gefitinib (EGFR inhibitor), on FO-1 and PT4 cell survival. Collectively, NAC, tiron and trolox modulated gene expression and impaired the growth of cultures containing TICs primarily by inhibiting cell cycle progression. PMID:24587218

  19. Inhibition of de novo Palmitate Synthesis by Fatty Acid Synthase Induces Apoptosis in Tumor Cells by Remodeling Cell Membranes, Inhibiting Signaling Pathways, and Reprogramming Gene Expression

    PubMed Central

    Ventura, Richard; Mordec, Kasia; Waszczuk, Joanna; Wang, Zhaoti; Lai, Julie; Fridlib, Marina; Buckley, Douglas; Kemble, George; Heuer, Timothy S.

    2015-01-01

    Inhibition of de novo palmitate synthesis via fatty acid synthase (FASN) inhibition provides an unproven approach to cancer therapy with a strong biological rationale. FASN expression increases with tumor progression and associates with chemoresistance, tumor metastasis, and diminished patient survival in numerous tumor types. TVB-3166, an orally-available, reversible, potent, and selective FASN inhibitor induces apoptosis, inhibits anchorage-independent cell growth under lipid-rich conditions, and inhibits in-vivo xenograft tumor growth. Dose-dependent effects are observed between 20–200 nM TVB-3166, which agrees with the IC50 in biochemical FASN and cellular palmitate synthesis assays. Mechanistic studies show that FASN inhibition disrupts lipid raft architecture, inhibits biological pathways such as lipid biosynthesis, PI3K–AKT–mTOR and β-catenin signal transduction, and inhibits expression of oncogenic effectors such as c-Myc; effects that are tumor-cell specific. Our results demonstrate that FASN inhibition has anti-tumor activities in biologically diverse preclinical tumor models and provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers, including those expressing mutant K-Ras, ErbB2, c-Met, and PTEN. The reported findings inform ongoing studies to link mechanisms of action with defined tumor types and advance the discovery of biomarkers supporting development of FASN inhibitors as cancer therapeutics. Research in context Fatty acid synthase (FASN) is a vital enzyme in tumor cell biology; the over-expression of FASN is associated with diminished patient prognosis and resistance to many cancer therapies. Our data demonstrate that selective and potent FASN inhibition with TVB-3166 leads to selective death of tumor cells, without significant effect on normal cells, and inhibits in vivo xenograft tumor growth at well-tolerated doses. Candidate biomarkers for

  20. Teroxirone inhibited growth of human non-small cell lung cancer cells by activating p53

    SciTech Connect

    Wang, Jing-Ping; Lin, Kai-Han; Liu, Chun-Yen; Yu, Ya-Chu; Wu, Pei-Tsun; Chiu, Chien-Chih; Su, Chun-Li; Chen, Kwun-Min; Fang, Kang

    2013-11-15

    In this work, we demonstrated that the growth of human non-small-cell-lung-cancer cells H460 and A549 cells can be inhibited by low concentrations of an epoxide derivative, teroxirone, in both in vitro and in vivo models. The cytotoxicity was mediated by apoptotic cell death through DNA damage. The onset of ultimate apoptosis is dependent on the status of p53. Teroxirone caused transient elevation of p53 that activates downstream p21 and procaspase-3 cleavage. The presence of caspase-3 inhibitor reverted apoptotic phenotype. Furthermore, we showed the cytotoxicity of teroxirone in H1299 cells with stable ectopic expression of p53, but not those of mutant p53. A siRNA-mediated knockdown of p53 expression attenuated drug sensitivity. The in vivo experiments demonstrated that teroxirone suppressed growth of xenograft tumors in nude mice. Being a potential therapeutic agent by restraining cell growth through apoptotic death at low concentrations, teroxirone provides a feasible perspective in reversing tumorigenic phenotype of human lung cancer cells. - Highlights: • Teroxirone repressed tumor cell growth in nude mice of human lung cancer cells. • The apoptotic cell death reverted by caspase-3 inhibitor is related to p53 status. • Teroxirone provides a good candidate for lung cancer treatment.

  1. Apoptotic Cells Activate AMP-activated Protein Kinase (AMPK) and Inhibit Epithelial Cell Growth without Change in Intracellular Energy Stores*

    PubMed Central

    Patel, Vimal A.; Massenburg, Donald; Vujicic, Snezana; Feng, Lanfei; Tang, Meiyi; Litbarg, Natalia; Antoni, Angelika; Rauch, Joyce; Lieberthal, Wilfred; Levine, Jerrold S.

    2015-01-01

    Apoptosis plays an indispensable role in the maintenance and development of tissues. We have shown that receptor-mediated recognition of apoptotic target cells by viable kidney proximal tubular epithelial cells (PTECs) inhibits the proliferation and survival of PTECs. Here, we examined the effect of apoptotic targets on PTEC cell growth (cell size during G1 phase of the cell cycle). Using a cell culture model, we show that apoptotic cells potently activate AMP-activated protein kinase (AMPK), a highly sensitive sensor of intracellular energy stores. AMPK activation leads to decreased activity of its downstream target, ribosomal protein p70 S6 kinase (p70S6K), and concomitant inhibition of cell growth. Importantly, these events occur without detectable change in intracellular levels of AMP, ADP, or ATP. Inhibition of AMPK, either pharmacologically by compound C or molecularly by shRNA, diminishes the effects of apoptotic targets and largely restores p70S6K activity and cell size to normal levels. Apoptotic targets also inhibit Akt, a second signaling pathway regulating cell growth. Expression of a constitutively active Akt construct partially relieved cell growth inhibition but was less effective than inhibition of AMPK. Inhibition of cell growth by apoptotic targets is dependent on physical interaction between apoptotic targets and PTECs but independent of phagocytosis. We conclude that receptor-mediated recognition of apoptotic targets mimics the effects of intracellular energy depletion, activating AMPK and inhibiting cell growth. By acting as sentinels of environmental change, apoptotic death may enable nearby viable cells, especially nonmigratory epithelial cells, to monitor and adapt to local stresses. PMID:26183782

  2. Inhibition of HIV replication by pokeweed antiviral protein targeted to CD4+ cells by monoclonal antibodies

    NASA Astrophysics Data System (ADS)

    Zarling, Joyce M.; Moran, Patricia A.; Haffar, Omar; Sias, Joan; Richman, Douglas D.; Spina, Celsa A.; Myers, Dorothea E.; Kuebelbeck, Virginia; Ledbetter, Jeffrey A.; Uckun, Fatih M.

    1990-09-01

    FUNCTIONAL impairment and selective depletion of CD4+ T cells, the hallmark of AIDS, are at least partly caused by human immunodeficiency virus (HIV-1) type 1 binding to the CD4 molecule and infecting CD4+ cells1,2. It may, therefore, be of therapeutic value to target an antiviral agent to CD4+ cells to prevent infection and to inhibit HIV-1 production in patients' CD4+ cells which contain proviral DNA3,4. We report here that HIV-1 replication in normal primary CD4+ T cells can be inhibited by pokeweed antiviral protein, a plant protein of relative molecular mass 30,000 (ref. 5), which inhibits replication of certain plant RNA viruses6-8, and of herpes simplex virus, poliovirus and influenza virus9-11. Targeting pokeweed antiviral protein to CD4+ T cells by conjugating it to monoclonal antibodies reactive with CDS, CD7 or CD4 expressed on CD4+ cells, increased its anti-HIV potency up to 1,000-fold. HIV-1 replication is inhibited at picomolar concentrations of conjugates of pokeweed antiviral protein and monoclonal antibodies, which do not inhibit proliferation of normal CD4+ T cells or CD4-dependent responses. These conjugates inhibit HIV-1 protein synthesis and also strongly inhibit HIV-1 production in activated CD4+ T cells from infected patients.

  3. Distinct apolipoprotein E isoform preference for inhibition of smooth muscle cell migration and proliferation.

    PubMed

    Zeleny, Michelle; Swertfeger, Debi K; Weisgraber, Karl H; Hui, David Y

    2002-10-01

    The current study compared the effectiveness of the various human apolipoprotein E (apoE) isoforms in inhibiting platelet-derived growth factor- (PDGF-) stimulated smooth muscle cell proliferation and migration. The incubation of primary mouse aortic smooth muscle cells with apoE3 resulted in dose-dependent inhibition of smooth muscle cells stimulated by 10 ng/mL PDGF. Greater than 50% inhibition of smooth muscle cell proliferation was observed at 15 microg/mL of human apoE3. Human apoE2 was less effective, requiring a higher concentration to achieve inhibition comparable to that of apoE3. Human apoE4 was the least effective of the apoE isoforms with no significant inhibition of cell proliferation observed at concentrations up to 15 microg/mL. Interestingly, apoE inhibition of PDGF-directed smooth muscle cell migration did not show preference for any apoE isoforms. Human apoE2, apoE3, and apoE4 were equally effective in inhibiting smooth muscle cell migration toward PDGF. These results are consistent with previous data showing that apoE inhibition of smooth muscle cell proliferation is mediated through its binding to heparan sulfate proteoglycans, whereas its inhibition of cell migration is mediated via binding to the low-density lipoprotein receptor related protein. The low efficiency of apoE4 to inhibit smooth muscle cell proliferation also suggested another mechanism to explain the association between the apolipoprotein epsilon4 allele with increased risk of coronary artery disease. PMID:12269825

  4. RPS27a promotes proliferation, regulates cell cycle progression and inhibits apoptosis of leukemia cells

    SciTech Connect

    Wang, Houcai; Yu, Jing; Zhang, Lixia; Xiong, Yuanyuan; Chen, Shuying; Xing, Haiyan; Tian, Zheng; Tang, Kejing; Wei, Hui; Rao, Qing; Wang, Min; Wang, Jianxiang

    2014-04-18

    Highlights: • RPS27a expression was up-regulated in advanced-phase CML and AL patients. • RPS27a knockdown changed biological property of K562 and K562/G01 cells. • RPS27a knockdown affected Raf/MEK/ERK, P21 and BCL-2 signaling pathways. • RPS27a knockdown may be applicable for new combination therapy in CML patients. - Abstract: Ribosomal protein S27a (RPS27a) could perform extra-ribosomal functions besides imparting a role in ribosome biogenesis and post-translational modifications of proteins. The high expression level of RPS27a was reported in solid tumors, and we found that the expression level of RPS27a was up-regulated in advanced-phase chronic myeloid leukemia (CML) and acute leukemia (AL) patients. In this study, we explored the function of RPS27a in leukemia cells by using CML cell line K562 cells and its imatinib resistant cell line K562/G01 cells. It was observed that the expression level of RPS27a was high in K562 cells and even higher in K562/G01 cells. Further analysis revealed that RPS27a knockdown by shRNA in both K562 and K562G01 cells inhibited the cell viability, induced cell cycle arrest at S and G2/M phases and increased cell apoptosis induced by imatinib. Combination of shRNA with imatinib treatment could lead to more cleaved PARP and cleaved caspase-3 expression in RPS27a knockdown cells. Further, it was found that phospho-ERK(p-ERK) and BCL-2 were down-regulated and P21 up-regulated in RPS27a knockdown cells. In conclusion, RPS27a promotes proliferation, regulates cell cycle progression and inhibits apoptosis of leukemia cells. It appears that drugs targeting RPS27a combining with tyrosine kinase inhibitor (TKI) might represent a novel therapy strategy in TKI resistant CML patients.

  5. Digitoxin and a synthetic monosaccharide analog inhibit cell viability in lung cancer cells

    SciTech Connect

    Elbaz, Hosam A.; Stueckle, Todd A.; Wang, Hua-Yu Leo; O'Doherty, George A.; Lowry, David T.; Sargent, Linda M.; Wang, Liying; Dinu, Cerasela Zoica; Rojanasakul, Yon

    2012-01-01

    Mechanisms of digitoxin-inhibited cell growth and induced apoptosis in human non-small cell lung cancer (NCI-H460) cells remain unclear. Understanding how digitoxin or derivate analogs induce their cytotoxic effect below therapeutically relevant concentrations will help in designing and developing novel, safer and more effective anti-cancer drugs. In this study, NCI-H460 cells were treated with digitoxin and a synthetic analog D6-MA to determine their anti-cancer activity. Different concentrations of digitoxin and D6-MA were used and the subsequent changes in cell morphology, viability, cell cycle, and protein expressions were determined. Digitoxin and D6-MA induced dose-dependent apoptotic morphologic changes in NCI-H460 cells via caspase-9 cleavage, with D6-MA possessing 5-fold greater potency than digitoxin. In comparison, non-tumorigenic immortalized bronchial and small airway epithelial cells displayed significantly less apoptotic sensitivity compared to NCI-H460 cells suggesting that both digitoxin and D6-MA were selective for NSCLC. Furthermore, NCI-H460 cells arrested in G(2)/M phase following digitoxin and D6-MA treatment. Post-treatment evaluation of key G2/M checkpoint regulatory proteins identified down-regulation of cyclin B1/cdc2 complex and survivin. Additionally, Chk1/2 and p53 related proteins experienced down-regulation suggesting a p53-independent cell cycle arrest mechanism. In summary, digitoxin and D6-MA exert anti-cancer effects on NCI-H460 cells through apoptosis or cell cycle arrest, with D6-MA showing at least 5-fold greater potency relative to digitoxin. -- Highlights: ► Digitoxin and synthetic analog D6-MA induced apoptotic morphologic changes in NCI-H460 cells in a dose-dependent manner. ► Apoptotic cell death induced by analog was 5-fold more potent when compared to digitoxin. ► NCI-H460 cells arrested in G(2)/M phase following digitoxin (≥ 5 nM) and analog (≥ 1 nM) treatment. ► Digitoxin inhibited the expression of cyclin

  6. Nitric oxide inhibits calpain-mediated proteolysis of talin in skeletal muscle cells

    NASA Technical Reports Server (NTRS)

    Koh, T. J.; Tidball, J. G.

    2000-01-01

    We tested the hypothesis that nitric oxide can inhibit cytoskeletal breakdown in skeletal muscle cells by inhibiting calpain cleavage of talin. The nitric oxide donor sodium nitroprusside prevented many of the effects of calcium ionophore on C(2)C(12) muscle cells, including preventing talin proteolysis and release into the cytosol and reducing loss of vinculin, cell detachment, and loss of cellular protein. These results indicate that nitric oxide inhibition of calpain protected the cells from ionophore-induced proteolysis. Calpain inhibitor I and a cell-permeable calpastatin peptide also protected the cells from proteolysis, confirming that ionophore-induced proteolysis was primarily calpain mediated. The activity of m-calpain in a casein zymogram was inhibited by sodium nitroprusside, and this inhibition was reversed by dithiothreitol. Previous incubation with the active site-targeted calpain inhibitor I prevented most of the sodium nitroprusside-induced inhibition of m-calpain activity. These data suggest that nitric oxide inhibited m-calpain activity via S-nitrosylation of the active site cysteine. The results of this study indicate that nitric oxide produced endogenously by skeletal muscle and other cell types has the potential to inhibit m-calpain activity and cytoskeletal proteolysis.

  7. Rapid Feedforward Inhibition and Asynchronous Excitation Regulate Granule Cell Activity in the Mammalian Main Olfactory Bulb

    PubMed Central

    Burton, Shawn D.

    2015-01-01

    Granule cell-mediated inhibition is critical to patterning principal neuron activity in the olfactory bulb, and perturbation of synaptic input to granule cells significantly alters olfactory-guided behavior. Despite the critical role of granule cells in olfaction, little is known about how sensory input recruits granule cells. Here, we combined whole-cell patch-clamp electrophysiology in acute mouse olfactory bulb slices with biophysical multicompartmental modeling to investigate the synaptic basis of granule cell recruitment. Physiological activation of sensory afferents within single glomeruli evoked diverse modes of granule cell activity, including subthreshold depolarization, spikelets, and suprathreshold responses with widely distributed spike latencies. The generation of these diverse activity modes depended, in part, on the asynchronous time course of synaptic excitation onto granule cells, which lasted several hundred milliseconds. In addition to asynchronous excitation, each granule cell also received synchronous feedforward inhibition. This inhibition targeted both proximal somatodendritic and distal apical dendritic domains of granule cells, was reliably recruited across sniff rhythms, and scaled in strength with excitation as more glomeruli were activated. Feedforward inhibition onto granule cells originated from deep short-axon cells, which responded to glomerular activation with highly reliable, short-latency firing consistent with tufted cell-mediated excitation. Simulations showed that feedforward inhibition interacts with asynchronous excitation to broaden granule cell spike latency distributions and significantly attenuates granule cell depolarization within local subcellular compartments. Collectively, our results thus identify feedforward inhibition onto granule cells as a core feature of olfactory bulb circuitry and establish asynchronous excitation and feedforward inhibition as critical regulators of granule cell activity. SIGNIFICANCE

  8. Membrane Vesicles Released by Intestinal Epithelial Cells Infected with Rotavirus Inhibit T-Cell Function

    PubMed Central

    Barreto, Alfonso; Rodríguez, Luz-Stella; Rojas, Olga Lucía; Wolf, Marie; Greenberg, Harry B.; Franco, Manuel A.

    2010-01-01

    Abstract Rotavirus (RV) predominantly replicates in intestinal epithelial cells (IEC), and “danger signals” released by these cells may modulate viral immunity. We have recently shown that human model IEC (Caco-2 cells) infected with rhesus-RV release a non-inflammatory group of immunomodulators that includes heat shock proteins (HSPs) and TGF-β1. Here we show that both proteins are released in part in association with membrane vesicles (MV) obtained from filtrated Caco-2 supernatants concentrated by ultracentrifugation. These MV express markers of exosomes (CD63 and others), but not of the endoplasmic reticulum (ER) or nuclei. Larger quantities of proteins associated with MV were released by RV-infected cells than by non-infected cells. VP6 co-immunoprecipitated with CD63 present in these MV, and VP6 co-localized with CD63 in RV-infected cells, suggesting that this viral protein is associated with the MV, and that this association occurs intracellularly. CD63 present in MV preparations from stool samples from 36 children with gastroenteritis due or not due to RV were analyzed. VP6 co-immunoprecipitated with CD63 in 3/8 stool samples from RV-infected children, suggesting that these MV are released by RV-infected cells in vivo. Moreover, fractions that contained MV from RV-infected cells induced death and inhibited proliferation of CD4+ T cells to a greater extent than fractions from non-infected cells. These effects were in part due to TGF-β, because they were reversed by treatment of the T cells with the TGF-β-receptor inhibitor ALK5i. MV from RV-infected and non-infected cells were heterogeneous, with morphologies and typical flotation densities described for exosomes (between 1.10 and 1.18 g/mL), and denser vesicles (>1.24 g/mL). Both types of MV from RV-infected cells were more efficient at inhibiting T-cell function than were those from non-infected cells. We propose that RV infection of IEC releases MV that modulate viral immunity. PMID:21142445

  9. CH5137291, an androgen receptor nuclear translocation-inhibiting compound, inhibits the growth of castration-resistant prostate cancer cells.

    PubMed

    Ishikura, Nobuyuki; Kawata, Hiromitsu; Nishimoto, Ayako; Nakamura, Ryo; Tsunenari, Toshiaki; Watanabe, Miho; Tachibana, Kazutaka; Shiraishi, Takuya; Yoshino, Hitoshi; Honma, Akie; Emura, Takashi; Ohta, Masateru; Nakagawa, Toshito; Houjo, Takao; Corey, Eva; Vessella, Robert L; Aoki, Yuko; Sato, Haruhiko

    2015-04-01

    Resistance of prostate cancer to castration is currently an unavoidable problem. The major mechanisms underlying such resistance are androgen receptor (AR) overexpression, androgen-independent activation of AR, and AR mutation. To address this problem, we developed an AR pure antagonist, CH5137291, with AR nuclear translocation-inhibiting activity, and compared its activity and characteristics with that of bicalutamide. Cell lines corresponding to the mechanisms of castration resistance were used: LNCaP-BC2 having AR overexpression and LNCaP-CS10 having androgen-independent AR activation. VCaP and LNCaP were used as hormone-sensitive prostate cancer cells. In vitro functional assay clearly showed that CH5137291 inhibited the nuclear translocation of wild-type ARs as well as W741C- and T877A-mutant ARs. In addition, it acted as a pure antagonist on the transcriptional activity of these types of ARs. In contrast, bicalutamide did not inhibit the nuclear translocation of these ARs, and showed a partial/full agonistic effect on the transcriptional activity. CH5137291 inhibited cell growth more strongly than bicalutamide in VCaP and LNCaP cells as well as in LNCaP-BC2 and LNCaP-CS10 cells in vitro. In xenograft models, CH5137291 strongly inhibited the tumor growth of LNCaP, LNCaP-BC2, and LNCaP-CS10, whereas bicalutamide showed a weaker effect in LNCaP and almost no effect in LNCaP-BC2 and LNCaP-CS10 xenografts. Levels of prostate-specific antigen (PSA) in plasma correlated well with the antitumor effect of both agents. CH5137291 inhibited the growth of LNCaP tumors that had become resistant to bicalutamide treatment. A docking model suggested that CH5137291 intensively collided with the M895 residue of helix 12, and therefore strongly inhibited the folding of helix 12, a cause of AR agonist activity, in wild-type and W741C-mutant ARs. In cynomolgus monkeys, the serum concentration of CH5137291 increased dose-dependently and PSA level decreased 80% at 100 mg/kg. CH

  10. MicroRNA-126 inhibits invasion in non-small cell lung carcinoma cell lines

    SciTech Connect

    Crawford, M.; Brawner, E.; Batte, K.; Yu, L.; Hunter, M.G.; Otterson, G.A.; Nuovo, G.; Marsh, C.B.; Nana-Sinkam, S.P.

    2008-09-05

    Crk is a member of a family of adaptor proteins that are involved in intracellular signal pathways altering cell adhesion, proliferation, and migration. Increased expression of Crk has been described in lung cancer and associated with increased tumor invasiveness. MicroRNAs (miRNAs) are a family of small non-coding RNAs (approximately 21-25 nt long) that are capable of targeting genes for either degradation of mRNA or inhibition of translation. Crk is a predicted putative target gene for miR-126. Over-expression of miR126 in a lung cancer cell line resulted in a decrease in Crk protein without any alteration in the associated mRNA. These lung cancer cells exhibit a decrease in adhesion, migration, and invasion. Decreased cancer cell invasion was also evident following targeted knockdown of Crk. MiR-126 alters lung cancer cell phenotype by inhibiting adhesion, migration, and invasion and the effects on invasion may be partially mediated through Crk regulation.

  11. Curcumin regulates cell fate and metabolism by inhibiting hedgehog signaling in hepatic stellate cells.

    PubMed

    Lian, Naqi; Jiang, Yuanyuan; Zhang, Feng; Jin, Huanhuan; Lu, Chunfeng; Wu, Xiafei; Lu, Yin; Zheng, Shizhong

    2015-07-01

    Accumulating evidence indicates that Hedgehog (Hh) signaling becomes activated in chronic liver injury and plays a role in the pathogenesis of hepatic fibrosis. Hepatic stellate cells (HSCs) are Hh-responsive cells and activation of the Hh pathway promotes transdifferentiation of HSCs into myofibroblasts. Targeting Hh signaling may be a novel therapeutic strategy for treatment of liver fibrosis. We previously reported that curcumin has potent antifibrotic effects in vivo and in vitro, but the underlying mechanisms are not fully elucidated. This study shows that curcumin downregulated Patched and Smoothened, two key elements in Hh signaling, but restored Hhip expression in rat liver with carbon tetrachloride-induced fibrosis and in cultured HSCs. Curcumin also halted the nuclear translocation, DNA binding, and transcription activity of Gli1. Moreover, the Hh signaling inhibitor cyclopamine, like curcumin, arrested the cell cycle, induced mitochondrial apoptosis, reduced fibrotic gene expression, restored lipid accumulation, and inhibited invasion and migration in HSCs. However, curcumin's effects on cell fate and fibrogenic properties of HSCs were abolished by the Hh pathway agonist SAG. Furthermore, curcumin and cyclopamine decreased intracellular levels of adenosine triphosphate and lactate, and inhibited the expression and/or function of several key molecules controlling glycolysis. However, SAG abrogated the curcumin effects on these parameters of glycolysis. Animal data also showed that curcumin downregulated glycolysis-regulatory proteins in rat fibrotic liver. These aggregated data therefore indicate that curcumin modulated cell fate and metabolism by disrupting the Hh pathway in HSCs, providing novel molecular insights into curcumin reduction of HSC activation.

  12. Gallic acid induces mitotic catastrophe and inhibits centrosomal clustering in HeLa cells.

    PubMed

    Tan, Si; Guan, Xin; Grün, Christoph; Zhou, Zhiqin; Schepers, Ute; Nick, Peter

    2015-12-25

    Cancer cells divide rapidly, providing medical targets for anticancer agents. The polyphenolic gallic acid (GA) is known to be toxic for certain cancer cells. However, the cellular mode of action has not been elucidated. Therefore, the current study addressed a potential effect of GA on the mitosis of cancer cells. GA inhibited viability of HeLa cells in a dose-dependent and time-dependent manner. We could show, using fluorescence-activated cell sorting (FACS), that this inhibition was accompanied by elevated frequency of cells arrested at the G2/M transition. This cell-cycle arrest was accompanied by mitotic catastrophe, and formation of cells with multiple nuclei. These aberrations were preceded by impaired centrosomal clustering. We arrive at a model of action, where GA inhibits the progression of the cell cycle at the G2/M phase by impairing centrosomal clustering which will stimulate mitotic catastrophe. Thus, GA has potential as compound against cervical cancer.

  13. Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells.

    PubMed

    Mou, Hongmei; Vinarsky, Vladimir; Tata, Purushothama Rao; Brazauskas, Karissa; Choi, Soon H; Crooke, Adrianne K; Zhang, Bing; Solomon, George M; Turner, Brett; Bihler, Hermann; Harrington, Jan; Lapey, Allen; Channick, Colleen; Keyes, Colleen; Freund, Adam; Artandi, Steven; Mense, Martin; Rowe, Steven; Engelhardt, John F; Hsu, Ya-Chieh; Rajagopal, Jayaraj

    2016-08-01

    Functional modeling of many adult epithelia is limited by the difficulty in maintaining relevant stem cell populations in culture. Here, we show that dual inhibition of SMAD signaling pathways enables robust expansion of primary epithelial basal cell populations. We find that TGFβ/BMP/SMAD pathway signaling is strongly activated in luminal and suprabasal cells of several epithelia, but suppressed in p63+ basal cells. In airway epithelium, SMAD signaling promotes differentiation, and its inhibition leads to stem cell hyperplasia. Using dual SMAD signaling inhibition in a feeder-free culture system, we have been able to expand airway basal stem cells from multiple species. Expanded cells can produce functional airway epithelium physiologically responsive to clinically relevant drugs, such as CFTR modulators. This approach is effective for the clonal expansion of single human cells and for basal cell populations from epithelial tissues from all three germ layers and therefore may be broadly applicable for modeling of epithelia. PMID:27320041

  14. Thymoquinone suppresses metastasis of melanoma cells by inhibition of NLRP3 inflammasome

    SciTech Connect

    Ahmad, Israr; Muneer, Kashiff M.; Tamimi, Iman A.; Chang, Michelle E.; Ata, Muhammad O.; Yusuf, Nabiha

    2013-07-01

    The inflammasome is a multi-protein complex which when activated regulates caspase-1 activation and IL-1β and IL-18 secretion. The NLRP3 (NACHT, LRR, and pyrin domain-containing protein 3) inflammasome is constitutively assembled and activated in human melanoma cells. We have examined the inhibitory effect of thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone), a major ingredient of black seed obtained from the plant Nigella sativa on metastatic human (A375) and mouse (B16F10) melanoma cell lines. We have assessed whether thymoquinone inhibits metastasis of melanoma cells by targeting NLRP3 subunit of inflammasomes. Using an in vitro cell migration assay, we found that thymoquinone inhibited the migration of both human and mouse melanoma cells. The inhibitory effect of thymoquinone on metastasis was also observed in vivo in B16F10 mouse melanoma model. The inhibition of migration of melanoma cells by thymoquinone was accompanied by a decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1. Inactivation of caspase-1 by thymoquinone resulted in inhibition of IL-1β and IL-18. Treatment of mouse melanoma cells with thymoquinone also inhibited NF-κB activity. Furthermore, inhibition of reactive oxygen species (ROS) by thymoquinone resulted in partial inactivation of NLRP3 inflammasome. Thus, thymoquinone exerts its inhibitory effect on migration of human and mouse melanoma cells by inhibition of NLRP3 inflammasome. Thus, our results indicate that thymoquinone can be a potential immunotherapeutic agent not only as an adjuvant therapy for melanoma, but also, in the control and prevention of metastatic melanoma. - Highlights: • Thymoquinone causes inhibition of migration of melanoma cells. • Thymoquinone causes inhibition of metastasis in vivo. • Thymoquinone causes inhibition of migration by activation of NLRP3 inflammasome.

  15. Halofuginone inhibits NF-kappaB and p38 MAPK in activated T cells.

    PubMed

    Leiba, M; Cahalon, L; Shimoni, A; Lider, O; Zanin-Zhorov, A; Hecht, I; Sela, U; Vlodavsky, I; Nagler, A

    2006-08-01

    Halofuginone, a low molecular weight plant alkaloid, inhibits collagen alpha1 (I) gene expression in several animal models and in patients with fibrotic disease, including scleroderma and graft-versus-host disease. In addition, halofuginone has been shown to inhibit angiogenesis and tumor progression. It was demonstrated recently that halofuginone inhibits transforming growth factor-beta (TGF-beta), an important immunomodulator. The present study was undertaken to explore the effects of halofuginone on activated T cells. Peripheral blood T cells were activated by anti-CD3 monoclonal antibodies in the absence and presence of halofuginone and assessed for nuclear factor (NF)-kappaB activity, production of tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma), T cell apoptosis, chemotaxis, and phosphorylation of p38 mitogen-activated protein kinase (MAPK). A delayed-type hypersensitivity (DTH) model was applied to investigate the effect of halofuginone on T cells in vivo. Preincubation of activated peripheral blood T cells with 10-40 ng/ml halofuginone resulted in a significant dose-dependent decrease in NF-kappaB activity (80% inhibition following incubation with 40 ng halofuginone, P = 0.002). In addition, 40 ng/ml halofuginone inhibited secretion of TNF-alpha, IFN-gamma, interleukin (IL)-4, IL-13, and TGF-beta (P < 0.005). Similarly, halofuginone inhibited the phosphorylation of p38 MAPK and apoptosis in activated T cells (P = 0.0001 and 0.005, respectively). In contrast, T cell chemotaxis was not affected. Halofuginone inhibited DTH response in mice, indicating suppression of T cell-mediated inflammation in vivo. Halofuginone inhibits activated peripheral blood T cell functions and proinflammatory cytokine production through inhibition of NF-kappaB activation and p38 MAPK phosphorylation. It also inhibited DTH response in vivo, making it an attractive immunomodulator and anti-inflammatory agent. PMID:16769768

  16. Cochlear supporting cell transdifferentiation and integration into hair cell layers by inhibition of ephrin-B2 signalling.

    PubMed

    Defourny, Jean; Mateo Sánchez, Susana; Schoonaert, Lies; Robberecht, Wim; Davy, Alice; Nguyen, Laurent; Malgrange, Brigitte

    2015-04-29

    In mammals, cochlear sensory hair cells that are responsible for hearing are postmitotic and are not replaced after loss. One of the most promising strategies to regenerate hair cells is to identify and inhibit the factors preventing the conversion of adjacent non-sensory supporting cells into hair cells. Here we demonstrate that mammalian hair cells can be directly generated from supporting cells by inhibition of ephrin-B2 signalling. Using either ephrin-B2 conditional knockout mice, shRNA-mediated gene silencing or soluble inhibitors, we found that downregulation of ephrin-B2 signalling at embryonic stages results in supporting cell translocation into hair cell layers and subsequent switch in cell identity from supporting cell to hair cell fate. As transdifferentiation is here a result of displacement across boundary, this original finding presents the interest that newly generated hair cells directly integrate either hair cell layer, then would be likely more rapidly able to fit into functional circuitry.

  17. Phycocyanin Inhibits Tumorigenic Potential of Pancreatic Cancer Cells: Role of Apoptosis and Autophagy

    PubMed Central

    Liao, Gaoyong; Gao, Bing; Gao, Yingnv; Yang, Xuegan; Cheng, Xiaodong; Ou, Yu

    2016-01-01

    Pancreatic adenocarcinoma (PDA) is one of the most lethal human malignancies, and unresponsive to current chemotherapies. Here we investigate the therapeutic potential of phycocyanin as an anti-PDA agent in vivo and in vitro. Phycocyanin, a natural product purified from Spirulina, effectively inhibits the pancreatic cancer cell proliferation in vitro and xenograft tumor growth in vivo. Phycocyanin induces G2/M cell cycle arrest, apoptotic and autophagic cell death in PANC-1 cells. Inhibition of autophagy by targeting Beclin 1 using siRNA significantly suppresses cell growth inhibition and death induced by phycocyanin, whereas inhibition of both autophagy and apoptosis rescues phycocyanin-mediated cell death. Mechanistically, cell death induced by phycocyanin is the result of cross-talk among the MAPK, Akt/mTOR/p70S6K and NF-κB pathways. Phycocyanin is able to induce apoptosis of PANC-1 cell by activating p38 and JNK signaling pathways while inhibiting Erk pathway. On the other hand, phycocyanin promotes autophagic cell death by inhibiting PI3/Akt/mTOR signaling pathways. Furthermore, phycocyanin promotes the activation and nuclear translocation of NF-κB, which plays an important role in balancing phycocyanin-mediated apoptosis and autosis. In conclusion, our studies demonstrate that phycocyanin exerts anti-pancreatic cancer activity by inducing apoptotic and autophagic cell death, thereby identifying phycocyanin as a promising anti-pancreatic cancer agent. PMID:27694919

  18. Holothurian glycosaminoglycan inhibits metastasis via inhibition of P-selectin in B16F10 melanoma cells.

    PubMed

    Yue, Zhiqiang; Wang, Aiyun; Zhu, Zhijie; Tao, Li; Li, Yao; Zhou, Liang; Chen, Wenxing; Lu, Yin

    2015-12-01

    P-selectin-mediated tumor cell adhesion to platelets is a well-established stage in the process of tumor metastasis. Through computerized structural analysis, we found a marine-derived polysaccharide, holothurian glycosaminoglycan (hGAG), behaved as a ligand-competitive inhibitor of P-selectin, indicating its potential to disrupt the binding of P-selectin to cell surface receptor and activation of downstream regulators of tumor cell migration. Our experimental data demonstrated that hGAG significantly inhibited P-selectin-mediated adhesion of tumor cells to platelets and tumor cell migration in vitro and reduced subsequent pulmonary metastasis in vivo. Furthermore, abrogation of the P-selectin-mediated adhesion of tumor cells led to down-regulation of protein levels of integrins, FAK and MMP-2/9 in B16F10 cells, which is a crucial molecular mechanism of hGAG to inhibit tumor metastasis. In conclusion, hGAG has emerged as a novel anti-cancer agent via blocking P-selectin-mediated malignant events of tumor metastasis.

  19. Carcinoid Heart Disease: From Pathophysiology to Treatment--'Something in the Way It Moves'.

    PubMed

    Grozinsky-Glasberg, Simona; Grossman, Ashley B; Gross, David J

    2015-01-01

    Carcinoid heart disease (CHD) is a rare cardiac manifestation occurring in patients with advanced neuroendocrine tumours and the carcinoid syndrome, usually involving the right-sided heart valves and eventually leading to right heart failure. The pathophysiology of CHD is still obscure and believed to be multifactorial, as a variety of vasoactive substances secreted by the tumour appear to be involved. The management of patients with CHD is complex, as both the systemic malignant disease and the heart involvement have to be addressed. Timely diagnosis and early surgical treatment in appropriately selected patients are of outmost importance, as CHD is associated with increased morbidity and mortality. Valve replacement surgery alleviates right heart failure and may also contribute to improved survival. In the present study we have comprehensively reviewed the existing literature to date, mainly focusing on the pathophysiology of CHD. Other aspects of CHD (such as the clinical presentation, diagnostic tools and therapeutic approach) are addressed in brief.

  20. Sporadic gastric carcinoid tumor successfully treated by two-stage laparoscopic surgery: A case report

    PubMed Central

    Kinoshita, Takahiro; Oshiro, Takashi; Urita, Tasuku; Yoshida, Yutaka; Ooshiro, Mitsuru; Okazumi, Shinichi; Katoh, Ryoji; Sasai, Daisuke; Hiruta, Nobuyuki

    2010-01-01

    We report a case of sporadic gastric carcinoid tumor successfully treated by two-stage laparoscopic surgery. A 38-year old asymptomatic woman was referred to our hospital for evaluation of a submucosal tumor of the stomach. Endoscopic examination showed a solitary submucosal tumor without ulceration or central depression on the posterior wall of the antrum and biopsy specimens were not sufficient to determine the diagnosis. Endoscopic ultrasound revealed a tumor nearly 2 cm in diameter arising from the muscle layer and a computed tomography scan showed the tumor enhanced in the arterial phase. Laparoscopic wedge resection was performed for definitive diagnosis. Pathologically, the tumor was shown to be gastric carcinoid infiltrating the muscle layer which indicated the probability of lymph node metastasis. Serum gastrin levels were normal. As a radical treatment, laparoscopy-assisted distal gastrectomy with regional lymphadenectomy was performed 3 wk after the initial surgery. Finally, pathological examination revealed no lymph node metastasis. PMID:21160902

  1. Acute appendicitis with a neuroendocrine tumor G1 (carcinoid): pitfalls of conservative treatment.

    PubMed

    Watanabe, Hiroyuki A; Fujimoto, Taketoshi; Kato, Yo; Sasaki, Mayumi; Ikusue, Toshikazu

    2016-08-01

    A man in his early thirties presented to our clinic with right lower abdominal pain. Computed tomography (CT) and ultrasonography (US) revealed a swollen appendix and an appendicolith. Abscess formation was not observed but ongoing appendiceal rupture was not ruled out. Three months after successful conservative therapy, the lumen of the apical portion was kept dilated and laparoscopic interval appendectomy was performed. No tumorous findings were observed macroscopically. However, histology revealed many tiny nests infiltrating the submucosa, muscular layer, and subserosa at the root of the appendix. An appendiceal neuroendocrine tumor G1 (NET G1; carcinoid) was diagnosed immunohistologically. Neither CT nor US visualized the tumor because of its non-tumor-forming but infiltrative growth. In conclusion, after successful conservative treatment, interval appendectomy should be considered to uncover a possible appendiceal NET G1 (carcinoid), particularly when dilatation of the distal lumen is kept under observation. PMID:27311320

  2. Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration

    PubMed Central

    2014-01-01

    Background Ewing’s sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15% at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis. Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties. Methods Invasion assays were performed in vitro in Boyden’s chambers covered with Matrigel. Matrix Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic injection of 106 human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 μg/kg, 3x/week) was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed by histology. Results ZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2 and −9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung metastases from a primary ES tumor but had no effect on the growth of established lung metastases. Conclusion These results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor growth but also to prevent the early metastatic events to the lungs. PMID:24612486

  3. Dasatinib inhibits both osteoclast activation and prostate cancer PC-3 cell-induced osteoclast formation

    PubMed Central

    Araujo, John C.; Poblenz, Ann; Corn, Paul G.; Parikh, Nila U.; Starbuck, Michael W.; Thompson, Jerry T.; Lee, Francis; Logothetis, Christopher J.; Darnay, Bryant G.

    2013-01-01

    Purpose Therapies to target prostate cancer bone metastases have only limited effects. New treatments are focused on the interaction between cancer cells, bone marrow cells and the bone matrix. Osteoclasts play an important role in the development of bone tumors caused by prostate cancer. Since Src kinase has been shown to be necessary for osteoclast function, we hypothesized that dasatinib, a Src family kinase inhibitor, would reduce osteoclast activity and prostate cancer (PC-3) cell-induced osteoclast formation. Results Dasatinib inhibited RANKL-induced osteoclast differentiation of bone marrow-derived monocytes with an EC50 of 7.5 nM. PC-3 cells, a human prostate cancer cell line, were able to differentiate RAW 264.7 cells, a murine monocytic cell line, into osteoclasts and dasatinib inhibited this differentiation. In addition, conditioned medium from PC-3 cell cultures was able to differentiate RAW 264.7 cells into osteoclasts and this too, was inhibited by dasatinib. Even the lowest concentration of dasatinib, 1.25 nmol, inhibited osteoclast differentiation by 29%. Moreover, dasatinib inhibited osteoclast activity by 58% as measured by collagen 1 release. Experimental design We performed in vitro experiments utilizing the Src family kinase inhibitor dasatinib to target osteoclast activation as a means of inhibiting prostate cancer bone metastases. Conclusion Dasatinib inhibits osteoclast differentiation of mouse primary bone marrow-derived monocytes and PC-3 cell-induced osteoclast differentiation. Dasatinib also inhibits osteoclast degradation activity. Inhibiting osteoclast differentiation and activity may be an effective targeted therapy in patients with prostate cancer bone metastases. PMID:19855158

  4. Myeloid Cell Arg1 Inhibits Control of Arthritogenic Alphavirus Infection by Suppressing Antiviral T Cells

    PubMed Central

    Burrack, Kristina S.; Tan, Jeslin J. L.; McCarthy, Mary K.; Her, Zhisheng; Berger, Jennifer N.; Ng, Lisa F. P.; Morrison, Thomas E.

    2015-01-01

    Arthritogenic alphaviruses, including Ross River virus (RRV) and chikungunya virus (CHIKV), are responsible for explosive epidemics involving millions of cases. These mosquito-transmitted viruses cause inflammation and injury in skeletal muscle and joint tissues that results in debilitating pain. We previously showed that arginase 1 (Arg1) was highly expressed in myeloid cells in the infected and inflamed musculoskeletal tissues of RRV- and CHIKV-infected mice, and specific deletion of Arg1 from myeloid cells resulted in enhanced viral control. Here, we show that Arg1, along with other genes associated with suppressive myeloid cells, is induced in PBMCs isolated from CHIKV-infected patients during the acute phase as well as the chronic phase, and that high Arg1 expression levels were associated with high viral loads and disease severity. Depletion of both CD4 and CD8 T cells from RRV-infected Arg1-deficient mice restored viral loads to levels detected in T cell-depleted wild-type mice. Moreover, Arg1-expressing myeloid cells inhibited virus-specific T cells in the inflamed and infected musculoskeletal tissues, but not lymphoid tissues, following RRV infection in mice, including suppression of interferon-γ and CD69 expression. Collectively, these data enhance our understanding of the immune response following arthritogenic alphavirus infection and suggest that immunosuppressive myeloid cells may contribute to the duration or severity of these debilitating infections. PMID:26436766

  5. Coniferyl Aldehyde Attenuates Radiation Enteropathy by Inhibiting Cell Death and Promoting Endothelial Cell Function

    PubMed Central

    Son, Yeonghoon; Jang, Jun-Ho; Lee, Yoon-Jin; Kim, Sung-Ho; Ko, Young-Gyo; Lee, Yun-Sil; Lee, Hae-June

    2015-01-01

    Radiation enteropathy is a common complication in cancer patients. The aim of this study was to investigate whether radiation-induced intestinal injury could be alleviated by coniferyl aldehyde (CA), an HSF1-inducing agent that increases cellular HSP70 expression. We systemically administered CA to mice with radiation enteropathy following abdominal irradiation (IR) to demonstrate the protective effects of CA against radiation-induced gastrointestinal injury. CA clearly alleviated acute radiation-induced intestinal damage, as reflected by the histopathological data and it also attenuated sub-acute enteritis. CA prevented intestinal crypt cell death and protected the microvasculature in the lamina propria during the acute and sub-acute phases of damage. CA induced HSF1 and HSP70 expression in both intestinal epithelial cells and endothelial cells in vitro. Additionally, CA protected against not only the apoptotic cell death of both endothelial and epithelial cells but also the loss of endothelial cell function following IR, indicating that CA has beneficial effects on the intestine. Our results provide novel insight into the effects of CA and suggest its role as a therapeutic candidate for radiation-induced enteropathy due to its ability to promote rapid re-proliferation of the intestinal epithelium by the synergic effects of the inhibition of cell death and the promotion of endothelial cell function. PMID:26029925

  6. Myeloid Cell Arg1 Inhibits Control of Arthritogenic Alphavirus Infection by Suppressing Antiviral T Cells.

    PubMed

    Burrack, Kristina S; Tan, Jeslin J L; McCarthy, Mary K; Her, Zhisheng; Berger, Jennifer N; Ng, Lisa F P; Morrison, Thomas E

    2015-10-01

    Arthritogenic alphaviruses, including Ross River virus (RRV) and chikungunya virus (CHIKV), are responsible for explosive epidemics involving millions of cases. These mosquito-transmitted viruses cause inflammation and injury in skeletal muscle and joint tissues that results in debilitating pain. We previously showed that arginase 1 (Arg1) was highly expressed in myeloid cells in the infected and inflamed musculoskeletal tissues of RRV- and CHIKV-infected mice, and specific deletion of Arg1 from myeloid cells resulted in enhanced viral control. Here, we show that Arg1, along with other genes associated with suppressive myeloid cells, is induced in PBMCs isolated from CHIKV-infected patients during the acute phase as well as the chronic phase, and that high Arg1 expression levels were associated with high viral loads and disease severity. Depletion of both CD4 and CD8 T cells from RRV-infected Arg1-deficient mice restored viral loads to levels detected in T cell-depleted wild-type mice. Moreover, Arg1-expressing myeloid cells inhibited virus-specific T cells in the inflamed and infected musculoskeletal tissues, but not lymphoid tissues, following RRV infection in mice, including suppression of interferon-γ and CD69 expression. Collectively, these data enhance our understanding of the immune response following arthritogenic alphavirus infection and suggest that immunosuppressive myeloid cells may contribute to the duration or severity of these debilitating infections. PMID:26436766

  7. Functional regulatory T cells produced by inhibiting cyclic nucleotide phosphodiesterase type 3 prevent allograft rejection

    PubMed Central

    Feng, Gang; Nadig, Satish N.; Bäckdahl, Liselotte; Beck, Stephan; Francis, Ross S.; Schiopu, Alexandru; Whatcott, Andrew; Wood, Kathryn J.; Bushell, Andrew

    2012-01-01

    Regulatory T cells (Tregs) manipulated ex vivo have potential as cellular therapeutics in autoimmunity and transplantation. Although it is possible to expand naturally occurring Tregs, an attractive alternative possibility, particularly suited to solid organ and bone marrow transplantation, is the stimulation of total T cell populations with defined allogeneic antigen presenting cells under conditions that lead to the generation or expansion of donor-reactive, adaptive Tregs. Here we demonstrate that stimulation of mouse CD4+ T cells by immature allogeneic dendritic cells (DCs) combined with pharmacological inhibition of phosphodiesterase 3 (PDEi) results in a functional enrichment of Foxp3+ T cells. Without further manipulation or selection, the resultant population delayed skin allograft rejection mediated by polyclonal CD4+ effectors or donor-reactive CD8+ TCR transgenic T cells and inhibited both effector cell proliferation and T cell priming for IFN-γ production. Notably, PDE inhibition also enhanced the enrichment of human Foxp3+ CD4+ T cells driven by allogeneic APC. These cells inhibited T cell proliferation in a standard in vitro mixed lymphocyte assay and importantly, attenuated the development of vasculopathy mediated by autologous PBMC in a functionally relevant humanized mouse transplant model. These data establish a method for the ex vivo generation of graft-reactive, functional mouse and human Tregs that uses a clinically approved agent, making pharmacological PDE inhibition a potential strategy for Treg-based therapies PMID:21593400

  8. Capsaicin Inhibits Preferentially the NADH Oxidase and Growth of Transformed Cells in Culture

    NASA Astrophysics Data System (ADS)

    Morre, D. James; Chueh, Pin-Ju; Morre, Dorothy M.

    1995-03-01

    A hormone- and growth factor-stimulated NADH oxidase of the mammalian plasma membrane, constitutively activated in transformed cells, was inhibited preferentially in HeLa, ovarian carcinoma, mammary adenocarcinoma, and HL-60 cells, all of human origin, by the naturally occurring quinone analog capsaicin (8-methyl-N-vanillyl-6-noneamide), compared with plasma membranes from human mammary epithelial, rat liver, normal rat kidney cells, or HL-60 cells induced to differentiate with dimethyl sulfoxide. With cells in culture, capsaicin preferentially inhibited growth of HeLa, ovarian carcinoma, mammary adenocarcinoma, and HL-60 cells but was largely without effect on the mammary epithelial cells, rat kidney cells, or HL-60 cells induced to differentiate with dimethyl sulfoxide. Inhibited cells became smaller and cell death was accompanied by a condensed and fragmented appearance of the nuclear DNA, as revealed by fluorescence microscopy with 4',6-diamidino-2-phenylindole, suggestive of apoptosis. The findings correlate capsaicin inhibition of cell surface NADH oxidase activity and inhibition of growth that correlate with capsaicin-induced apoptosis.

  9. In vitro growth inhibition of human cancer cells by novel honokiol analogs.

    PubMed

    Lin, Jyh Ming; Prakasha Gowda, A S; Sharma, Arun K; Amin, Shantu

    2012-05-15

    Honokiol possesses many pharmacological activities including anti-cancer properties. Here in, we designed and synthesized honokiol analogs that block major honokiol metabolic pathway which may enhance their effectiveness. We studied their cytotoxicity in human cancer cells and evaluated possible mechanism of cell cycle arrest. Two analogs, namely 2 and 4, showed much higher growth inhibitory activity in A549 human lung cancer cells and significant increase of cell population in the G0-G1 phase. Further elucidation of the inhibition mechanism on cell cycle showed that analogs 2 and 4 inhibit both CDK1 and cyclin B1 protien levels in A549 cells. PMID:22533983

  10. In vitro growth inhibition of human cancer cells by novel honokiol analogs.

    PubMed

    Lin, Jyh Ming; Prakasha Gowda, A S; Sharma, Arun K; Amin, Shantu

    2012-05-15

    Honokiol possesses many pharmacological activities including anti-cancer properties. Here in, we designed and synthesized honokiol analogs that block major honokiol metabolic pathway which may enhance their effectiveness. We studied their cytotoxicity in human cancer cells and evaluated possible mechanism of cell cycle arrest. Two analogs, namely 2 and 4, showed much higher growth inhibitory activity in A549 human lung cancer cells and significant increase of cell population in the G0-G1 phase. Further elucidation of the inhibition mechanism on cell cycle showed that analogs 2 and 4 inhibit both CDK1 and cyclin B1 protien levels in A549 cells.

  11. Functional inhibition in direction-selective retinal ganglion cells: spatiotemporal extent and intralaminar interactions.

    PubMed

    Stasheff, Steven F; Masland, Richard H

    2002-08-01

    We recorded from ON-OFF direction-selective ganglion cells (DS cells) in the rabbit retina to investigate in detail the inhibition that contributes to direction selectivity in these cells. Using paired stimuli moving sequentially across the cells' receptive fields in the preferred direction, we directly confirmed the prediction of that a wave of inhibition accompanies any moving excitatory stimulus on its null side, at a fixed spatial offset. Varying the interstimulus distance, stimulus size, luminance, and speed yielded a spatiotemporal map of the strength of inhibition within this region. This "null" inhibition was maximal at an intermediate distance behind a moving stimulus: 1/2 to 11/2 times the width of the receptive field. The strength of inhibition depended more on the distance behind the stimulus than on stimulus speed, and the inhibition often lasted 1-2 s. These spatial and temporal parameters appear to account for the known spatial frequency and velocity tuning of ON-OFF DS cells to drifting contrast gratings. Stimuli that elicit distinct ON and OFF responses to leading and trailing edges revealed that an excitatory response of either polarity could inhibit a subsequent response of either polarity. For example, an OFF response inhibited either an ON or OFF response of a subsequent stimulus. This inhibition apparently is conferred by a neural element or network spanning the ON and OFF sublayers of the inner plexiform layer, such as a multistratified amacrine cell. Trials using a stationary flashing spot as a probe demonstrated that the total amount of inhibition conferred on the DS cell was equivalent for stimuli moving in either the null or preferred direction. Apparently the cell does not act as a classic "integrate and fire" neuron, summing all inputs at the soma. Rather, computation of stimulus direction likely involves interactions between excitatory and inhibitory inputs in local regions of the dendrites. PMID:12163551

  12. Selected Phytochemicals and Culinary Plant Extracts Inhibit Fructose Uptake in Caco-2 Cells.

    PubMed

    Lee, Yurim; Lim, Yeni; Kwon, Oran

    2015-09-18

    This study compared the ability of nine culinary plant extracts containing a wide array of phytochemicals to inhibit fructose uptake and then explored the involvement of intestinal fructose transporters and phytochemicals for selected samples. The chemical signature was characterized by high performance liquid chromatography with mass spectrometry. Inhibition of [(14)C]-fructose uptake was tested by using human intestinal Caco-2 cells. Then, the relative contribution of the two apical-facing intestinal fructose transporters, GLUT2 and GLUT5, and the signature components for fructose uptake inhibition was confirmed in naive, phloretin-treated and forskolin-treated Caco-2 cells. HPLC/MS analysis of the chemical signature revealed that guava leaf contained quercetin and catechin, and turmeric contained curcumin, bisdemethoxycurcumin and dimethoxycurcumin. Similar inhibition of fructose uptake (by ~50%) was observed with guava leaf and turmeric in Caco-2 cells, but with a higher contribution of GLUT2 for turmeric and that of GLUT5 for guava leaf. The data suggested that, in turmeric, demethoxycurcumin specifically contributed to GLUT2-mediated fructose uptake inhibition, and curcumin did the same to GLUT5-mediated fructose uptake inhibition, but GLUT2 inhibition was more potent. By contrast, in guava leaf, catechin specifically contributed to GLUT5-mediated fructose uptake inhibition, and quercetin affected both GLUT5- and GLUT2-mediated fructose uptake inhibition, resulting in the higher contribution of GLUT5. These results suggest that demethoxycurcumin is an important contributor to GLUT2-mediated fructose uptake inhibition for turmeric extract, and catechin is the same to GLUT5-mediated fructose uptake inhibition for guava leaf extract. Quercetin, curcumin and bisdemethoxycurcumin contributed to both GLUT5- and GLUT2-mediated fructose uptake inhibition, but the contribution to GLUT5 inhibition was higher than the contribution to GLUT2 inhibition.

  13. Selected Phytochemicals and Culinary Plant Extracts Inhibit Fructose Uptake in Caco-2 Cells.

    PubMed

    Lee, Yurim; Lim, Yeni; Kwon, Oran

    2015-01-01

    This study compared the ability of nine culinary plant extracts containing a wide array of phytochemicals to inhibit fructose uptake and then explored the involvement of intestinal fructose transporters and phytochemicals for selected samples. The chemical signature was characterized by high performance liquid chromatography with mass spectrometry. Inhibition of [(14)C]-fructose uptake was tested by using human intestinal Caco-2 cells. Then, the relative contribution of the two apical-facing intestinal fructose transporters, GLUT2 and GLUT5, and the signature components for fructose uptake inhibition was confirmed in naive, phloretin-treated and forskolin-treated Caco-2 cells. HPLC/MS analysis of the chemical signature revealed that guava leaf contained quercetin and catechin, and turmeric contained curcumin, bisdemethoxycurcumin and dimethoxycurcumin. Similar inhibition of fructose uptake (by ~50%) was observed with guava leaf and turmeric in Caco-2 cells, but with a higher contribution of GLUT2 for turmeric and that of GLUT5 for guava leaf. The data suggested that, in turmeric, demethoxycurcumin specifically contributed to GLUT2-mediated fructose uptake inhibition, and curcumin did the same to GLUT5-mediated fructose uptake inhibition, but GLUT2 inhibition was more potent. By contrast, in guava leaf, catechin specifically contributed to GLUT5-mediated fructose uptake inhibition, and quercetin affected both GLUT5- and GLUT2-mediated fructose uptake inhibition, resulting in the higher contribution of GLUT5. These results suggest that demethoxycurcumin is an important contributor to GLUT2-mediated fructose uptake inhibition for turmeric extract, and catechin is the same to GLUT5-mediated fructose uptake inhibition for guava leaf extract. Quercetin, curcumin and bisdemethoxycurcumin contributed to both GLUT5- and GLUT2-mediated fructose uptake inhibition, but the contribution to GLUT5 inhibition was higher than the contribution to GLUT2 inhibition. PMID:26393568

  14. Crude Garlic Extract Inhibits Cell Proliferation and Induces Cell Cycle Arrest and Apoptosis of Cancer Cells In Vitro.

    PubMed

    Bagul, Mukta; Kakumanu, Srikanth; Wilson, Thomas A

    2015-07-01

    Garlic and its lipid-based extracts have played an important medicinal role in humans for centuries that includes antimicrobial, hypoglycemic, and lipid-lowering properties. The present study was to investigate the effects of crude garlic extract (CGE) on the proliferation of human breast, prostate, hepatic, and colon cancer cell lines and mouse macrophageal cells, not previously studied. The human cancer cell lines, such as hepatic (Hep-G2), colon (Caco-2), prostate (PC-3), and breast (MCF-7), were propagated at 37°C; air/CO2 (95:5 v/v) using the ATCC-formulated RPMI-1640 Medium and 10% fetal bovine serum (FBS), while the mouse macrophage cell line (TIB-71) was propagated at 37°C; air/CO2 (95:5 v/v) using the ATCC-formulated DMEM and 10% FBS. All cells were plated at a density of ∼5000 cells/well. After overnight incubation, the cells were treated with 0.125, 0.25, 0.5, or 1 μg/mL of CGE an additional 72 h. Inhibition of cell proliferation of 80-90% was observed for Hep-G2, MCF-7, TIB-71, and PC-3 cells, but only 40-55% for the Caco-2 cells when treated with 0.25, 0.5, or 1 μg/mL. In a coculture study of Caco-2 and TIB-71 cells, inhibition of cell proliferation of 90% was observed for Caco-2 cells compared to the 40-55% when cultured separately. CGE also induced cell cycle arrest and had a fourfold increase in caspase activity (apoptosis) in PC-3 cells when treated at a dose of 0.5 or 1 μg/mL. This investigation of CGE clearly highlights the fact that the lipid bioactive compounds in CGE have the potential as promising anticancer agents.

  15. Sparstolonin B Inhibits Pro-Angiogenic Functions and Blocks Cell Cycle Progression in Endothelial Cells

    PubMed Central

    Bateman, Henry R.; Liang, Qiaoli; Fan, Daping; Rodriguez, Vanessa; Lessner, Susan M.

    2013-01-01

    Sparstolonin B (SsnB) is a novel bioactive compound isolated from Sparganium stoloniferum, an herb historically used in Traditional Chinese Medicine as an anti-tumor agent. Angiogenesis, the process of new capillary formation from existing blood vessels, is dysregulated in many pathological disorders, including diabetic retinopathy, tumor growth, and atherosclerosis. In functional assays, SsnB inhibited endothelial cell tube formation (Matrigel method) and cell migration (Transwell method) in a dose-dependent manner. Microarray experiments with human umbilical vein endothelial cells (HUVECs) and human coronary artery endothelial cells (HCAECs) demonstrated differential expression of several hundred genes in response to SsnB exposure (916 and 356 genes, respectively, with fold change ≥2, p<0.05, unpaired t-test). Microarray data from both cell types showed significant overlap, including genes associated with cell proliferation and cell cycle. Flow cytometric cell cycle analysis of HUVECs treated with SsnB showed an increase of cells in the G1 phase and a decrease of cells in the S phase. Cyclin E2 (CCNE2) and Cell division cycle 6 (CDC6) are regulatory proteins that control cell cycle progression through the G1/S checkpoint. Both CCNE2 and CDC6 were downregulated in the microarray data. Real Time quantitative PCR confirmed that gene expression of CCNE2 and CDC6 in HUVECs was downregulated after SsnB exposure, to 64% and 35% of controls, respectively. The data suggest that SsnB may exert its anti-angiogenic properties in part by downregulating CCNE2 and CDC6, halting progression through the G1/S checkpoint. In the chick chorioallantoic membrane (CAM) assay, SsnB caused significant reduction in capillary length and branching number relative to the vehicle control group. Overall, SsnB caused a significant reduction in angiogenesis (ANOVA, p<0.05), demonstrating its ex vivo efficacy. PMID:23940584

  16. A case of diffused malignant pleural mesothelioma forming small multiple disseminations with intraoperatively suspicious carcinoid tumors.

    PubMed

    Suemitsu, Ryuichi; Takeo, Sadanori; Hamatake, Motoharu; Furuya, Kiyomi; Uesugi, Noriko

    2011-01-01

    A 65-year-old male, having symptoms suggestive of pulmonary malignant tumor, underwent video-assisted thoracic surgery (VATS). Surgery revealed a solid tumor originating from the thoracic wall, with many small solid tumors in the thoracic wall and diaphragm near the tumor. The intraoperative observation of a frozen section typed the tumor as carcinoid; however, hematoxylin-eosin staining and immunohistological findings provided the definitive diagnosis of diffused, malignant pleural mesothelioma (MPM).

  17. A case of bronchial carcinoid: diagnosis and follow-up with 111In-DTPA-octreotide.

    PubMed

    Orsolon, P; Bagni, B; Basadonna, P; Geatti, O; Talmassons, G; Guerra, U P

    1995-12-01

    Scintigraphy with radiolabelled analogue of somatostatin is highly sensitive in detecting carcinoid tumors especially if performed with Single Photon Computed Tomography (SPECT). In this report we describe our experience with 111In-DTPA-Octreotide in a female patient affected by a small asymptomatic intrabronchial carcinoid demonstrated by CT scan and bronchial endoscopy performed after recurrent left pneumonias. Planar views and SPECT images, using 111In-DTPA-Octreotide, were collected before and four hours after the first endoscopic laser resection. All groups of SPECT images were positive in the left parahilar region but at a different degree. Scans performed after resection showed a low degree of uptake which was considered to be probably secondary to local swelling; CT scan was negative. Follow up endoscopic biopsy repeated at six months, showed a relapse always in the same site; CT scan of the thorax was again negative. 111In-DTPA-Octreotide images obtained at twelve months were positive always in the left parahilar region, CT scan was negative but another biopsy was not possible. Therefore it was suspected a relapse of the carcinoid which was probably growing only through the bronchial wall without spreading towards the bronchial lumen and/or the lung parenchima. In this occasion, it was also thought that images collected four hours after resection could be positive not only for swelling but for a relapse as well. In every scintigraphic session, SPECT images presented higher quality than planar. This case suggests that 111In-DTPA-Octreotide SPECT is a non-invasive diagnostic technique which could be applied as a follow-up tool especially to patients with no-secreting carcinoid neoplasm and/or with negative or doubtful endoscopic and radiological investigations.

  18. Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent

    PubMed Central

    Alkasalias, Twana; Flaberg, Emilie; Kashuba, Vladimir; Alexeyenko, Andrey; Pavlova, Tatiana; Savchenko, Andrii; Szekely, Laszlo; Klein, George; Guven, Hayrettin

    2014-01-01

    Normal human and murine fibroblasts can inhibit proliferation of tumor cells when cocultured in vitro. The inhibitory capacity varies depending on the donor and the site of origin of the fibroblast. We showed previously that effective inhibition requires formation of a morphologically intact fibroblast monolayer before seeding of the tumor cells. Here we show that inhibition is extended to motility of tumor cells and we dissect the factors responsible for these inhibitory functions. We find that inhibition is due to two different sets of molecules: (i) the extracellular matrix (ECM) and other surface proteins of the fibroblasts, which are responsible for contact-dependent inhibition of tumor cell proliferation; and (ii) soluble factors secreted by fibroblasts when confronted with tumor cells (confronted conditioned media, CCM) contribute to inhibition of tumor cell proliferation and motility. However, conditioned media (CM) obtained from fibroblasts alone (nonconfronted conditioned media, NCM) did not inhibit tumor cell proliferation and motility. In addition, quantitative PCR (Q-PCR) data show up-regulation of proinflammatory genes. Moreover, comparison of CCM and NCM with an antibody array for 507 different soluble human proteins revealed differential expression of growth differentiation factor 15, dickkopf-related protein 1, endothelial-monocyte-activating polypeptide II, ectodysplasin A2, Galectin-3, chemokine (C-X-C motif) ligand 2, Nidogen1, urokinase, and matrix metalloproteinase 3. PMID:25404301

  19. Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis

    SciTech Connect

    Di Paolo, Julie A.; Huang, Tao; Balazs, Mercedesz; Barbosa, James; Barck, Kai H.; Bravo, Brandon J.; Carano, Richard A.D.; Darrow, James; Davies, Douglas R.; DeForge, Laura E.; Diehl, Lauri; Ferrando, Ronald; Gallion, Steven L.; Giannetti, Anthony M.; Gribling, Peter; Hurez, Vincent; Hymowitz, Sarah G.; Jones, Randall; Kropf, Jeffrey E.; Lee, Wyne P.; Maciejewski, Patricia M.; Mitchell, Scott A.; Rong, Hong; Staker, Bart L.; Whitney, J. Andrew; Yeh, Sherry; Young, Wendy B.; Yu, Christine; Zhang, Juan; Reif, Karin; Currie, Kevin S.

    2011-09-20

    Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which Btk mediates inflammation are poorly understood. Here we describe the discovery of CGI1746, a small-molecule Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor-dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btk inhibition abolishes Fc{gamma}RIII-induced TNF{alpha}, IL-1{beta} and IL-6 production. Accordingly, in myeloid- and Fc{gamma}R-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell- or myeloid cell-driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.

  20. Overexpression of Ref-1 Inhibits Lead-induced Endothelial Cell Death via the Upregulation of Catalase.

    PubMed

    Lee, Kwon Ho; Lee, Sang Ki; Kim, Hyo Shin; Cho, Eun Jung; Joo, Hee Kyoung; Lee, Eun Ji; Lee, Ji Young; Park, Myoung Soo; Chang, Seok Jong; Cho, Chung-Hyun; Park, Jin Bong; Jeon, Byeong Hwa

    2009-12-01

    The role of apurinic/apyrimidinic endonuclease1/redox factor-1 (Ref-1) on the lead (Pb)-induced cellular response was investigated in the cultured endothelial cells. Pb caused progressive cellular death in endothelial cells, which occurred in a concentration- and time-dependent manner. However, Ref-1 overexpression with AdRef-1 significantly inhibited Pb-induced cell death in the endothelial cells. Also the overexpression of Ref-1 significantly suppressed Pb-induced superoxide and hydrogen peroxide elevation in the endothelial cells. Pb exposure induced the downregulation of catalase, it was inhibited by the Ref-1 overexpression in the endothelial cells. Taken together, our data suggests that the overexpression of Ref-1 inhibited Pb-induced cell death via the upregulation of catalase in the cultured endothelial cells.

  1. Apoptosis and inhibition of proliferation of cancer cells induced by cordycepin

    PubMed Central

    TIAN, XUEWEN; LI, YUJIAN; SHEN, YINYU; LI, QIAOQIAO; WANG, QINGLU; FENG, LIANSHI

    2015-01-01

    Cordycepin, a 3-deoxyadenosine, is the predominant functional component of the fungus Cordyceps militaris, a traditional Chinese medicine. Previous studies investigating the inhibition of cancer cells by cordycepin identified that it not only promotes cell apoptosis, but also controls cell proliferation. Furthermore, studies have elucidated the molecular mechanisms of inhibiting cell proliferation by cordycepin binding the A3 adenosine receptor, activating G protein, inhibiting cAMP formation, decreasing glycogen synthase kinase-3β/β-catenin activation and suppressing cyclin D1 and c-myc expression. The most significant signaling pathway in which cell apoptosis is induced by cordycepin is the caspase pathway. Cordycepin induces cell apoptosis via binding the DR3 receptor and consequently activating caspase-8/-3. Taken together, these studies demonstrate that cordycepin may be used as a natural medicine, as it can not only control tumor cell proliferation, but also induce cancer cell apoptosis. PMID:26622539

  2. Overexpression of Ref-1 Inhibits Lead-induced Endothelial Cell Death via the Upregulation of Catalase

    PubMed Central

    Lee, Kwon Ho; Lee, Sang Ki; Kim, Hyo Shin; Cho, Eun Jung; Joo, Hee Kyoung; Lee, Eun Ji; Lee, Ji Young; Park, Myoung Soo; Chang, Seok Jong; Cho, Chung-Hyun; Park, Jin Bong

    2009-01-01

    The role of apurinic/apyrimidinic endonuclease1/redox factor-1 (Ref-1) on the lead (Pb)-induced cellular response was investigated in the cultured endothelial cells. Pb caused progressive cellular death in endothelial cells, which occurred in a concentration- and time-dependent manner. However, Ref-1 overexpression with AdRef-1 significantly inhibited Pb-induced cell death in the endothelial cells. Also the overexpression of Ref-1 significantly suppressed Pb-induced superoxide and hydrogen peroxide elevation in the endothelial cells. Pb exposure induced the downregulation of catalase, it was inhibited by the Ref-1 overexpression in the endothelial cells. Taken together, our data suggests that the overexpression of Ref-1 inhibited Pb-induced cell death via the upregulation of catalase in the cultured endothelial cells. PMID:20054488

  3. L-Asparaginase II Produced by Salmonella Typhimurium Inhibits T Cell Responses and Mediates Virulence

    PubMed Central

    Kullas, Amy L.; McClelland, Michael; Yang, Hee-Jeong; Tam, Jason W.; Torres, AnnMarie; Porwollik, Steffen; Mena, Patricio; McPhee, Joseph B.; Bogomolnaya, Lydia; Andrews-Polymenis, Helene; van der Velden, Adrianus W.M.

    2013-01-01

    SUMMARY Salmonella enterica serovar Typhimurium avoids clearance by the host immune system by suppressing T cell responses; however, the mechanisms that mediate this immunosuppression remain unknown. We show that S. Typhimurium inhibit T cell responses by producing L-Asparaginase II, which catalyzes the hydrolysis of L-asparagine to aspartic acid and ammonia. L-Asparaginase II is necessary and sufficient to suppress T cell blastogenesis, cytokine production, and proliferation and to downmodulate expression of the T cell receptor. Furthermore, S. Typhimurium-induced inhibition of T cells in vitro is prevented upon addition of L-asparagine. S. Typhimurium lacking the L-Asparaginase II gene (STM3106) are unable to inhibit T cell responses and exhibit attenuated virulence in vivo. L-Asparaginases are used to treat acute lymphoblastic leukemia through mechanisms that likely involve amino acid starvation of leukemic cells, and these findings indicate that pathogens similarly use L-asparagine deprivation to limit T cell responses. PMID:23245323

  4. Inhibition of Breast Cancer Cell Proliferation and In Vitro Tumorigenesis by a New Red Apple Cultivar

    PubMed Central

    Schiavano, Giuditta Fiorella; De Santi, Mauro; Brandi, Giorgio; Fanelli, Mirco; Bucchini, Anahi; Giamperi, Laura; Giomaro, Giovanna

    2015-01-01

    Purpose The aim of this study was to evaluate the antiproliferative activity in breast cancer cells and the inhibition of tumorigenesis in pre-neoplastic cells of a new apple cultivar with reddish pulp, called the Pelingo apple. Methods The antiproliferative activity was evaluated in MCF-7 and MDA-MB-231 human breast cancer cells. The inhibition of tumorigenesis was performed in JB6 promotion-sensitive (P+) cells. Results Results showed that Pelingo apple juice is characterized by a very high polyphenol content and strongly inhibited breast cancer cell proliferation. Its antiproliferative activity was found to be higher than the other five apple juices tested. Pelingo juice induced cell accumulation in the G2/M phase of the cell cycle and autophagy through overexpression of p21, inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) activity and an increase in lipidated microtubule-associated protein-1 light chain-3 beta (LC3B). Remarkably, Pelingo juice inhibited the 12-o-tetra-decanoyl-phorbol-13-acetate (TPA)-induced tumorigenesis of JB6 P+ cells, suppressing colony formation in semi-solid medium and TPA-induced ERK1/2 phosphorylation. Conclusions Our data indicate that the Pelingo apple is rich in food components that can markedly inhibit in vitro tumorigenesis and growth of human breast cancer cells and could provide natural bioactive non-nutrient compounds, with potential chemopreventive activity. PMID:26284516

  5. Inhibition of the cell cycle and induction of apoptosis by Noclosan and Loxat in cell lines irrespective of their origin.

    PubMed

    Schutte, B; Harmsa, M; Costongs, G; Henfling, M; Ummelen, M; Dignef, W; Ramaekers, F

    2004-06-01

    The effects of Noclosan and Loxat, extracts from the potato tuber, on cancer cell lines and human endothelial cells in culture were examined with respect to cell cycle inhibition and apoptosis induction. Both components effect the cell cycle of the cancer cell lines, most likely by inhibition of the M to G1-phase transition. Furthermore, both compounds very effectively induced apoptosis in a dose-dependent manner. Strikingly, combination of both compounds revealed a synergistic effect, that can be explained by the observation that induction of apoptosis occurs through both the mitochondrial and the non-mitochondrial route. Preliminary studies suggest that the components affect the SAPK/JNK cell signaling pathway.

  6. Ajoene inhibits the activation of human endothelial cells induced by porcine cells: implications for xenotransplantation.

    PubMed

    Benatuil, Lorenzo; Apitz-Castro, Rafael; Romano, Egidio

    2003-07-01

    Ajoene, is an organosulfur compound derived from garlic that strongly inhibit platelet aggregation, proliferation of human lymphocytes induced by phytohemagglutinin, and in general, blocks membrane-mediated signaling of cell activation. As a thrombotic microangiopathy frequently complicates procedures designed to induce pig-to-baboon chimerism by infusion of large amounts of pig progenitor cells in baboons, it was thought that ajoene might be useful to prevent such complication. For such purpose, we studied the effects of ajoene on the activation of human umbilical vein endothelial cells (HUVEC) induced by pig peripheral blood mononuclear cells (p-PBMC). Co-cultures of p-PBMC with HUVEC results in activation of the HUVEC as shown by over-expression of E-selectin and vascular cells adhesion molecule-1 (VCAM-1). Ajoene (25 microm) strongly inhibits HUVEC activation induced by tumor necrosis factor-alpha (TNF-alpha) or p-PBMC as shown by a down regulation of VCAM-1 and of E-selectin expression. After 5 or 8 h of pre-treatment with Ajoene, HUVEC incubated with TNF and p-PBMC showed an E-selectin or VCAM-1 expression, respectively, at levels similar to the positive control indicating that the inhibitory effect is transient. Ajoene at concentration of 25 microm or lower did not affect HUVEC viability. Based on the finding that Ajoene has a strong, although transient, inhibitory effect on the activation of the endothelium induced by pig cells and its known anti-platelet activity, it is suggested that this garlic compound could be useful to prevent the development of microangiopathy and thrombotic disorders seen in primates infused with pig cells.

  7. Haemophilus ducreyi Inhibits Phagocytosis by U-937 Cells, a Human Macrophage-Like Cell Line

    PubMed Central

    Wood, Gwendolyn E.; Dutro, Susan M.; Totten, Patricia A.

    2001-01-01

    Haemophilus ducreyi is a gram-negative obligate human pathogen that causes the genital ulcer disease chancroid. Chancroid lesions are deep necrotic ulcers with an immune cell infiltrate that includes macrophages. Despite the presence of these phagocytic cells, chancroid ulcers can persist for months and live H. ducreyi can be isolated from these lesions. To analyze the interaction of H. ducreyi with macrophages, we investigated the ability of H. ducreyi strain 35000 to adhere to, invade, and survive within U-937 cells, a human macrophage-like cell line. We found that although H. ducreyi strain 35000 adhered efficiently to U-937 cells, few bacteria were internalized, suggesting that H. ducreyi avoids phagocytosis by human macrophages. The few bacteria that were phagocytosed in these experiments were rapidly killed. We also found that H. ducreyi inhibits the phagocytosis of a secondary target (opsonized sheep red blood cells). Antiphagocytic activity was found in logarithmic, stationary-phase, and plate-grown cultures and was associated with whole, live bacteria but not with heat-killed cultures, sonicates, or culture supernatants. Phagocytosis was significantly inhibited after a 15-min exposure to H. ducreyi, and a multiplicity of infection of approximately 1 CFU per macrophage was sufficient to cause a significant reduction in phagocytosis by U-937 cells. Finally, all of nine H. ducreyi strains tested were antiphagocytic, suggesting that this is a common virulence mechanism for this organism. This finding suggests a mechanism by which H. ducreyi avoids killing and clearance by macrophages in chancroid lesions and inguinal lymph nodes. PMID:11447144

  8. Positional isomerism markedly affects the growth inhibition of colon cancer cells by NOSH-aspirin: COX inhibition and modeling☆

    PubMed Central

    Vannini, Federica; Chattopadhyay, Mitali; Kodela, Ravinder; Rao, Praveen P.N.; Kashfi, Khosrow

    2015-01-01

    We recently reported the synthesis of NOSH-aspirin, a novel hybrid that releases both nitric oxide (NO) and hydrogen sulfide (H2S). In NOSH-aspirin, the two moieties that release NO and H2S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e. ortho-NOSH-aspirin (o-NOSH-aspirin). In the present study, we compared the effects of the positional isomers of NOSH-ASA (o-NOSH-aspirin, m-NOSH-aspirin and p-NOSH-aspirin) to that of aspirin on growth of HT-29 and HCT 15 colon cancer cells, belonging to the same histological subtype, but with different expression of cyclooxygenase (COX) enzymes; HT-29 express both COX-1 and COX-2, whereas HCT 15 is COX-null. We also analyzed the effect of these compounds on proliferation and apoptosis in HT-29 cells. Since the parent compound aspirin, inhibits both COX-1 and COX-2, we also evaluated the effects of these compounds on COX-1 and COX-2 enzyme activities and also performed modeling of the interactions between the positional isomers of NOSH-aspirin and COX-1 and COX-2 enzymes. We observed that the three positional isomers of NOSH aspirin inhibited the growth of both colon cancer cell lines with IC50s in the nano-molar range. In particular in HT-29 cells the IC50s for growth inhibition were: o-NOSH-ASA, 0.04±0.011 µM; m-NOSH-ASA, 0.24±0.11 µM; p-NOSH-ASA, 0.46±0.17 µM; and in HCT 15 cells the IC50s for o-NOSH-ASA, m-NOSH-ASA, and p-NOSH-ASA were 0.062 ±0.006 µM, 0.092±0.004 µM, and 0.37±0.04 µM, respectively. The IC50 for aspirin in both cell lines was >5 mM at 24 h. The reduction of cell growth appeared to be mediated through inhibition of proliferation, and induction of apoptosis. All 3 positional isomers of NOSH-aspirin preferentially inhibited COX-1 over COX-2. These results suggest that the three positional isomers of NOSH-aspirin have the same biological actions, but that o-NOSH-ASA displayed the strongest anti-neoplastic potential. PMID:26319435

  9. Positional isomerism markedly affects the growth inhibition of colon cancer cells by NOSH-aspirin: COX inhibition and modeling.

    PubMed

    Vannini, Federica; Chattopadhyay, Mitali; Kodela, Ravinder; Rao, Praveen P N; Kashfi, Khosrow

    2015-12-01

    We recently reported the synthesis of NOSH-aspirin, a novel hybrid that releases both nitric oxide (NO) and hydrogen sulfide (H2S). In NOSH-aspirin, the two moieties that release NO and H2S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e. ortho-NOSH-aspirin (o-NOSH-aspirin). In the present study, we compared the effects of the positional isomers of NOSH-ASA (o-NOSH-aspirin, m-NOSH-aspirin and p-NOSH-aspirin) to that of aspirin on growth of HT-29 and HCT 15 colon cancer cells, belonging to the same histological subtype, but with different expression of cyclooxygenase (COX) enzymes; HT-29 express both COX-1 and COX-2, whereas HCT 15 is COX-null. We also analyzed the effect of these compounds on proliferation and apoptosis in HT-29 cells. Since the parent compound aspirin, inhibits both COX-1 and COX-2, we also evaluated the effects of these compounds on COX-1 and COX-2 enzyme activities and also performed modeling of the interactions between the positional isomers of NOSH-aspirin and COX-1 and COX-2 enzymes. We observed that the three positional isomers of NOSH aspirin inhibited the growth of both colon cancer cell lines with IC50s in the nano-molar range. In particular in HT-29 cells the IC50s for growth inhibition were: o-NOSH-ASA, 0.04±0.011 µM; m-NOSH-ASA, 0.24±0.11 µM; p-NOSH-ASA, 0.46±0.17 µM; and in HCT 15 cells the IC50s for o-NOSH-ASA, m-NOSH-ASA, and p-NOSH-ASA were 0.062 ±0.006 µM, 0.092±0.004 µM, and 0.37±0.04 µM, respectively. The IC50 for aspirin in both cell lines was >5mM at 24h. The reduction of cell growth appeared to be mediated through inhibition of proliferation, and induction of apoptosis. All 3 positional isomers of NOSH-aspirin preferentially inhibited COX-1 over COX-2. These results suggest that the three positional isomers of NOSH-aspirin have the same biological actions, but that o-NOSH-ASA displayed the strongest anti-neoplastic potential.

  10. The novel herbicide oxaziclomefone inhibits cell expansion in maize cell cultures without affecting turgor pressure or wall acidification.

    PubMed

    O'Looney, Nichola; Fry, Stephen C

    2005-11-01

    Oxaziclomefone [OAC; IUPAC name 3-(1-(3,5-dichlorophenyl)-1-methylethyl)-3,4-dihydro-6-methyl-5-phenyl-2H-1,3-oxazin-4-one] is a new herbicide that inhibits cell expansion in grass roots. Its effects on cell cultures and mode of action were unknown. In principle, cell expansion could be inhibited by a decrease in either turgor pressure or wall extensibility. Cell expansion was estimated as settled cell volume; cell division was estimated by cell counting. Membrane permeability to water was measured by a novel method involving simultaneous assay of the efflux of (3)H(2)O and [(14)C]mannitol from a 'bed' of cultured cells. Osmotic potential was measured by depression of freezing point. OAC inhibited cell expansion in cultures of maize (Zea mays), spinach (Spinacia oleracea) and rose (Rosa sp.), with an ID(50) of 5, 30 and 250 nm, respectively. In maize cultures, OAC did not affect cell division for the first 40 h. It did not affect the osmotic potential of cell sap or culture medium, nor did it impede water transport across cell membranes. It did not affect cells' ability to acidify the apoplast (medium), which may be necessary for 'acid growth'. As OAC did not diminish turgor pressure, its ability to inhibit cell expansion must depend on changes in wall extensibility. It could be a valuable tool for studies on cell expansion.

  11. Inhibition of cholesterol metabolism underlies synergy between mTOR pathway inhibition and chloroquine in bladder cancer cells

    PubMed Central

    King, M A; Ganley, I G; Flemington, V

    2016-01-01

    Mutations to fibroblast growth factor receptor 3 (FGFR3) and phosphatase and tensin homologue (PTEN) signalling pathway components (for example, PTEN loss, PIK3CA, AKT1, TSC1/2) are common in bladder cancer, yet small-molecule inhibitors of these nodes (FGFR/PTENi) show only modest activity in preclinical models. As activation of autophagy is proposed to promote survival under FGFR/PTENi, we have investigated this relationship in a panel of 18 genetically diverse bladder cell lines. We found that autophagy inhibition does not sensitise bladder cell lines to FGFR/PTENi, but newly identify an autophagy-independent cell death synergy in FGFR3-mutant cell lines between mTOR (mammalian target of rapamycin) pathway inhibitors and chloroquine (CQ)—an anti-malarial drug used as a cancer therapy adjuvant in over 30 clinical trials. The mechanism of synergy is consistent with lysosomal cell death (LCD), including cathepsin-driven caspase activation, and correlates with suppression of cSREBP1 and cholesterol biosynthesis in sensitive cell lines. Remarkably, loss of viability can be rescued by saturating cellular membranes with cholesterol or recapitulated by statin-mediated inhibition, or small interfering RNA knockdown, of enzymes regulating cholesterol metabolism. Modulation of CQ-induced cell death by atorvastatin and cholesterol is reproduced across numerous cell lines, confirming a novel and fundamental role for cholesterol biosynthesis in regulating LCD. Thus, we have catalogued the molecular events underlying cell death induced by CQ in combination with an anticancer therapeutic. Moreover, by revealing a hitherto unknown aspect of lysosomal biology under stress, we propose that suppression of cholesterol metabolism in cancer cells should elicit synergy with CQ and define a novel approach to future cancer treatments. PMID:26853465

  12. Inhibition of cholesterol metabolism underlies synergy between mTOR pathway inhibition and chloroquine in bladder cancer cells.

    PubMed

    King, M A; Ganley, I G; Flemington, V

    2016-08-25

    Mutations to fibroblast growth factor receptor 3 (FGFR3) and phosphatase and tensin homologue (PTEN) signalling pathway components (for example, PTEN loss, PIK3CA, AKT1, TSC1/2) are common in bladder cancer, yet small-molecule inhibitors of these nodes (FGFR/PTENi) show only modest activity in preclinical models. As activation of autophagy is proposed to promote survival under FGFR/PTENi, we have investigated this relationship in a panel of 18 genetically diverse bladder cell lines. We found that autophagy inhibition does not sensitise bladder cell lines to FGFR/PTENi, but newly identify an autophagy-independent cell death synergy in FGFR3-mutant cell lines between mTOR (mammalian target of rapamycin) pathway inhibitors and chloroquine (CQ)-an anti-malarial drug used as a cancer therapy adjuvant in over 30 clinical trials. The mechanism of synergy is consistent with lysosomal cell death (LCD), including cathepsin-driven caspase activation, and correlates with suppression of cSREBP1 and cholesterol biosynthesis in sensitive cell lines. Remarkably, loss of viability can be rescued by saturating cellular membranes with cholesterol or recapitulated by statin-mediated inhibition, or small interfering RNA knockdown, of enzymes regulating cholesterol metabolism. Modulation of CQ-induced cell death by atorvastatin and cholesterol is reproduced across numerous cell lines, confirming a novel and fundamental role for cholesterol biosynthesis in regulating LCD. Thus, we have catalogued the molecular events underlying cell death induced by CQ in combination with an anticancer therapeutic. Moreover, by revealing a hitherto unknown aspect of lysosomal biology under stress, we propose that suppression of cholesterol metabolism in cancer cells should elicit synergy with CQ and define a novel approach to future cancer treatments. PMID:26853465

  13. Inhibition of prolidase activity by nickel causes decreased growth of proline auxotrophic CHO cells.

    PubMed

    Miltyk, Wojciech; Surazynski, Arkadiusz; Kasprzak, Kazimierz S; Fivash, Matthew J; Buzard, Gregory S; Phang, James M

    2005-04-15

    Occupational exposure to nickel has been epidemiologically linked to increased cancer risk in the respiratory tract. Nickel-induced cell transformation is associated with both genotoxic and epigenetic mechanisms that are poorly understood. Prolidase [E.C.3.4.13.9] is a cytosolic Mn(II)-activated metalloproteinase that specifically hydrolyzes imidodipeptides with C-terminal proline or hydroxyproline and plays an important role in the recycling of proline for protein synthesis and cell growth. Prolidase also provides free proline as substrate for proline oxidase, whose gene is activated by p53 during apoptosis. The inhibition of prolidase activity by nickel has not yet been studied. We first showed that Ni(II) chloride specifically inhibited prolidase activity in CHO-K1 cells in situ. This interpretation was possible because CHO-K1 cells are proline auxotrophs requiring added free proline or proline released from added Gly-Pro by prolidase. In a dose-dependent fashion, Ni(II) inhibited growth on Gly-Pro but did not inhibit growth on proline, thereby showing inhibition of prolidase in situ in the absence of nonspecific toxicity. Studies using cell-free extracts showed that Ni(II) inhibited prolidase activity when present during prolidase activation with Mn(II) or during incubation with Gly-Pro. In kinetic studies, we found that Ni(II) inhibition of prolidase varied with respect to Mn(II) concentration. Analysis of these data suggested that increasing concentrations of Mn(II) stabilized the enzyme protein against Ni(II) inhibition. Because prolidase is an important enzyme in collagen metabolism, inhibition of the enzyme activity by nickel could alter the metabolism of collagen and other matrix proteins, and thereby alter cell-matrix and cell-cell interactions involved in gene expression, genomic stability, cellular differentiation, and cell proliferation. PMID:15696600

  14. Roentgenologic diagnosis of primary corticotropin-producing carcinoid tumors of the mediastinum

    SciTech Connect

    Brown, L.R.; Aughenbaugh, G.L.; Wick, M.R.; Baker, B.A.; Salassa, R.M.

    1982-01-01

    A study was undertaken of five patients with Cushing syndrome due to adrenocorticotropin (ACTH) production by thymic carcinoid tumor (primary mediastinal Apudomas), including two recent patients examined by computed tomography (CT) of the chest. Plain roentgenography of the chest initially failed to detect tumor in four of the five patients, while CT of the chest yielded definitive diagnostic information in both patients in whom it was employed. For one of these patients, a mediastinal tumor could be seen retrospectively on plain roentgenograms of the chest, although it had been missed on the first examination. One of the tumors appeared to be partially calcified on CT scan, a finding not previously reported. Blastic osseous metastasis, which is common when malignant carcinoid tumors spread to bone, was seen in one patient. Our data suggest that in patients with suspected ectopic ACTH production, CT scanning of the mediastinum should be performed early in order to avoid delay in diagnosis of an ACTH-secreting carcinoid tumor of the mediastinum.

  15. Mature Ovarian Teratoma with Carcinoid Tumor in a 28-Year-Old Patient

    PubMed Central

    Petousis, Stamatios; Kalogiannidis, Ioannis; Margioula-Siarkou, Chrysoula; Traianos, Alexandros; Miliaras, Dimosthenis; Kamparoudis, Apostolos; Mamopoulos, Apostolos; Rousso, David

    2013-01-01

    Introduction. Coexistence of carcinoid tumor inside a mature cystic teratoma is an extremely rare phenomenon, especially in young women. We present the case of a 28-year-old woman diagnosed with a right ovarian carcinoid and treated uneventfully with conservative surgical approach. Case Report. A 28-year-old woman, gravid 0, parity 0, presented to our department for her annual gynecological examination and Pap smear test. During her examination, a mobile cystic mass was detected in the right lower abdomen. Ultrasound indicated a right ovarian mass 10.5 × 6.3 cm, confirmed by CT scan. Further investigation revealed AFP levels (1539 ng/mL). The ovarian mass was excised by laparoscopy, leaving intact the remaining right ovary. Frozen sections showed a mature cystic teratoma. However, paraffin sections revealed the presence of a small carcinoid within the teratoma's gastric-type mucosa. The patient was set to a close followup. Nine months postoperatively, ultrasound pelvis imaging and CT scan of the abdomen as well as serum tumor markers have shown no evidence of recurrence disease. Conclusion. Despite the weak evidence, fertility spare surgical approach for women wanting to preserve their genital tract might be a reasonable option. PMID:23984130

  16. An extract of Uncaria tomentosa inhibiting cell division and NF-kappa B activity without inducing cell death.

    PubMed

    Akesson, Christina; Lindgren, Hanna; Pero, Ronald W; Leanderson, Tomas; Ivars, Fredrik

    2003-12-01

    Previous reports have demonstrated that extracts of the plant Uncaria tomentosa inhibit tumor cell proliferation and inflammatory responses. We have confirmed that C-Med 100, a hot water extract of this plant, inhibits tumor cell proliferation albeit with variable efficiency. We extend these findings by showing that this extract also inhibits proliferation of normal mouse T and B lymphocytes and that the inhibition is not caused by toxicity or by induction of apoptosis. Further, the extract did not interfere with IL-2 production nor IL-2 receptor signaling. Since there was no discrete cell cycle block in C-Med 100-treated cells, we propose that retarded cell cycle progression caused the inhibition of proliferation. Collectively, these data suggested interference with a common pathway controlling cell growth and cell cycle progression. Indeed, we provide direct evidence that C-Med 100 inhibits nuclear factor kappa B (NF-kappa B) activity and propose that this at least partially causes the inhibition of proliferation.

  17. Pulmonary surfactant and its components inhibit secretion of phosphatidylcholine from cultured rat alveolar type II cells

    SciTech Connect

    Dobbs, L.G.; Wright, J.R.; Hawgood, S.; Gonzalez, R.; Venstrom, K.; Nellenbogen, J.

    1987-02-01

    Pulmonary surfactant is synthesized and secreted by alveolar type II cells. Radioactive phosphatidylcholine has been used as a marker for surfactant secretion. The authors report findings that suggest that surfactant inhibits secretion of /sup 3/H-labeled phosphatidylcholine by cultured rat type II cells. The lipid components and the surfactant protein group of M/sub r/ 26,000-36,000 (SP 26-36) inhibit secretion to different extents. Surfactant lipids do not completely inhibit release; in concentrations of 100 ..mu..g/ml, lipids inhibit stimulated secretion by 40%. SP 26-36 inhibits release with an EC/sub 50/ of 0.1 ..mu..g/ml. At concentrations of 1.0 ..mu..g/ml, SP 26-36 inhibits basal secretion and reduces to basal levels secretion stimulated by terbutaline, phorbol 12-myristate 13-acetate, and the ionophore A23187. The inhibitory effect of SP 26-36 can be blocked by washing type II cells after adding SP 26-36, by heating the proteins to 100/sup 0/C for 10 min, by adding antiserum specific to SP 26-36, or by incubating cells in the presence of 0.2 mM EGTA. SP 26-36 isolated from canine and human sources also inhibits phosphatidylcholine release from rat type II cells. Neither type I collagen nor serum apolipoprotein A-1 inhibits secretion. These findings are compatible with the hypothesis that surfactant secretion is under feedback regulatory control.

  18. Slit2 inhibits glioma cell invasion in the brain by suppression of Cdc42 activity.

    PubMed

    Yiin, Jia-Jean; Hu, Bo; Jarzynka, Michael J; Feng, Haizhong; Liu, Kui-Wei; Wu, Jane Y; Ma, Hsin-I; Cheng, Shi-Yuan

    2009-12-01

    Acquisition of insidious invasiveness by malignant glioma cells involves multiple genetic alterations in signaling pathways. Slit2, a chemorepulsive factor, controls cell migration of neuronal and glial cells during development and inhibits chemotaxic migration of various types of cells in vitro. However, the role of Slit2 in vitro remains controversial, and the biological significance of Slit2 expression in cancer cell invasion in vivo has not yet been determined. In the present study, we characterized the effects of Slit2 expression on the migration and invasion of invasive glioma cells in vitro and in vivo. By reverse transcriptase polymerase chain reaction (PCR) analyses, Slit2 was found to be expressed at lower levels in primary glioma specimens and invasive glioma cells compared with normal human brain cells and astrocytes. Ectopic expression of Slit2 or treatment with recombinant Slit2 on glioma cells attenuates cell migration and invasion through inhibition of Cdc42 activity in vitro. Cellular depletion of Robo1, a cognate receptor for Slit2, prevented Slit2 inhibition of Cdc42 activity and glioma cell migration. In vivo, expression of Slit2 by invasive SNB19 glioma cells markedly inhibited glioma cell infiltration into the brain of mice. Moreover, impediment of glioma cell invasion by Slit2 did not affect the expression of N-cadherin and beta-catenin in glioma cells. These results provide the first evidence demonstrating that Slit2-Robo1 inhibits glioma invasion through attenuating Cdc42 activity in vitro and in the brain. Understanding the mechanisms of Slit2-Robo1 inhibition of glioma cell invasion will foster new treatments for malignant gliomas.

  19. Oxidative stress-mediated inhibition of intestinal epithelial cell proliferation by silver nanoparticles.

    PubMed

    McCracken, Christie; Zane, Andrew; Knight, Deborah A; Hommel, Elizabeth; Dutta, Prabir K; Waldman, W James

    2015-10-01

    Given the increasing use of silver nanoparticles (Ag NP) by the food and food packaging industries, this study investigated potential consequences of Ag NP ingestion in intestinal epithelial C2BBe1 cells. Treatment of proliferating cells (<10,000 cells/cm(2)) with 0.25 μg/cm(2) (1.25 μg/mL) of 23 nm Ag NP for 24 h induced 15% necrotic cell death and an 80% reduction in metabolic activity and decreased the GSH/GSSG ratio, indicating oxidative stress. G2/M phase cell cycle arrest and complete inhibition of cell proliferation was also induced by Ag NP treatment. Simulated in vitro digestion of Ag NP prior to cell exposure required the use of slightly higher doses to induce the same toxicity, likely due to slower Ag dissolution. Treatment of cells with silica, titania, and ZnO NP partially inhibited cell proliferation, but inhibition at low doses was unique to Ag NP. These data suggest that Ag NP induces oxidative stress, cell cycle arrest, and the inhibition of cell proliferation. However, toxicity and induction of oxidative stress were not observed in confluent cells (>100,000 cells/cm(2)) treated with 10 μg/cm(2) (40-50 μg/mL) Ag NP, indicating that these cells are less sensitive to Ag NP.

  20. Role of calcium in growth inhibition induced by a novel cell surface sialoglycopeptide

    NASA Technical Reports Server (NTRS)

    Betz, N. A.; Westhoff, B. A.; Johnson, T. C.; Spooner, B. S. (Principal Investigator)

    1995-01-01

    Our laboratory has purified an 18 kDa cell surface sialoglycopeptide growth inhibitor (CeReS-18) from intact bovine cerebral cortex cells. Evidence presented here demonstrates that sensitivity to CeReS-18-induced growth inhibition in BALB-c 3T3 cells is influenced by calcium, such that a decrease in the calcium concentration in the growth medium results in an increase in sensitivity to CeReS-18. Calcium did not alter CeReS-18 binding to its cell surface receptor and CeReS-18 does not bind calcium directly. Addition of calcium, but not magnesium, to CeReS-18-inhibited 3T3 cells results in reentry into the cell cycle. A greater than 3-hour exposure to increased calcium is required for escape from CeReS-18-induced growth inhibition. The calcium ionophore ionomycin could partially mimic the effect of increasing extracellular calcium, but thapsigargin was ineffective in inducing escape from growth inhibition. Increasing extracellular calcium 10-fold resulted in an approximately 7-fold increase in total cell-associated 45Ca+2, while free intracellular calcium only increased approximately 30%. However, addition of CeReS-18 did not affect total cell-associated calcium or the increase in total cell-associated calcium observed with an increase in extracellular calcium. Serum addition induced mobilization of intracellular calcium and influx across the plasma membrane in 3T3 cells, and pretreatment of 3T3 cells with CeReS-18 appeared to inhibit these calcium mobilization events. These results suggest that a calcium-sensitive step exists in the recovery from CeReS-18-induced growth inhibition. CeReS-18 may inhibit cell proliferation through a novel mechanism involving altering the intracellular calcium mobilization/regulation necessary for cell cycle progression.

  1. Houttuynia cordata Thunb extract inhibits cell growth and induces apoptosis in human primary colorectal cancer cells.

    PubMed

    Lai, Kuang-Chi; Chiu, Yu-Jen; Tang, Yih-Jing; Lin, Kuei-Li; Chiang, Jo-Hua; Jiang, Yi-Lin; Jen, Hsiu-Fang; Kuo, Yueh-Hsiung; Agamaya, Sakae; Chung, Jing-Gung; Yang, Jai-Sing

    2010-09-01

    It is reported that Houttuynia cordata Thunb. (HCT), a traditional Chinese herbal medicine, has many biological properties such as antiviral, antibacterial and antileukemic activities. However, the molecular mechanisms of cytotoxicity and apoptosis in human primary colorectal cancer cells are not clear. In this study, whether HCT induced cytotoxicity in primary colorectal cancer cells obtained from three patients was investigated. The results indicated that HCT inhibited growth of cancer cells in a dose-dependent manner. After treatment with HCT (250 μg/ml) for 24 h, cells exhibited chromatin condensation (an apoptotic characteristic). HCT increased reactive oxygen species (ROS) production and decreased the mitochondrial membrane potential (ΔΨ(m)) in examined cells. Mitochondria-dependent apoptotic signaling pathway was shown to be involved as determined by increase in the levels of cytochrome c, Apaf-1, and caspase-3 and -9. The decrease in the level of ΔΨ(m) was associated with an increase in the BAX/BCL-2 ratio which led to activation of caspase-9 and -3. Based on our results, HCT induced apoptotic cell death in human primary colorectal cancer cells through a mitochondria-dependent signaling pathway. PMID:20944136

  2. Cyclosporin A inhibits programmed cell death and cytochrome c release induced by fusicoccin in sycamore cells.

    PubMed

    Contran, N; Cerana, R; Crosti, P; Malerba, M

    2007-01-01

    Programmed cell death plays a vital role in normal plant development, response to environmental stresses, and defense against pathogen attack. Different types of programmed cell death occur in plants and the involvement of mitochondria is still under investigation. In sycamore (Acer pseudoplatanus L.) cultured cells, the phytotoxin fusicoccin induces cell death that shows apoptotic features, including chromatin condensation, DNA fragmentation, and release of cytochrome c from mitochondria. In this work, we show that cyclosporin A, an inhibitor of the permeability transition pore of animal mitochondria, inhibits the cell death, DNA fragmentation, and cytochrome c release induced by fusicoccin. In addition, we show that fusicoccin induces a change in the shape of mitochondria which is not prevented by cyclosporin A. These results suggest that the release of cytochrome c induced by fusicoccin occurs through a cyclosporin A-sensitive system that is similar to the permeability transition pore of animal mitochondria and they make it tempting to speculate that this release may be involved in the phytotoxin-induced programmed cell death of sycamore cells.

  3. Nitrogen-containing bisphosphonates inhibit cell cycle progression in human melanoma cells.

    PubMed

    Forsea, A-M; Müller, C; Riebeling, C; Orfanos, C E; Geilen, C C

    2004-08-16

    Cutaneous melanoma is one of the highly malignant human tumours, due to its tendency to generate early metastases and its resistance to classical chemotherapy. We recently demonstrated that pamidronate, a nitrogen-containing bisphosphonate, has an antiproliferative and proapoptotic effect on different melanoma cell lines. In the present study, we compared the in vitro effects of three different bisphosphonates on human melanoma cell lines and we demonstrated that the two nitrogen-containing bisphosphonates pamidronate and zoledronate inhibited the proliferation of melanoma cells and induced apoptosis in a dose- and time-dependent manner. Moreover, cell cycle progression was altered, the two compounds causing accumulation of the cells in the S phase of the cycle. In contrast, the nonaminobisphosphonate clodronate had no effect on melanoma cells. These findings suggest a direct antitumoural effect of bisphosphonates on melanoma cells in vitro and further support the hypothesis of different intracellular mechanisms of action for nitrogen-containing and nonaminobisphosphonates. Our data indicate that nitrogen-containing bisphosphonates may be a useful novel therapeutic class for treatment and/or prevention of melanoma metastases.

  4. ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion

    PubMed Central

    Chronopoulos, Antonios; Robinson, Benjamin; Sarper, Muge; Cortes, Ernesto; Auernheimer, Vera; Lachowski, Dariusz; Attwood, Simon; García, Rebeca; Ghassemi, Saba; Fabry, Ben; del Río Hernández, Armando

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal survival rate. Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homoeostasis of the tumour microenvironment to favour cancer cell invasion. Here we report that ATRA, an active metabolite of vitamin A, restores mechanical quiescence in PSCs via a mechanism involving a retinoic acid receptor beta (RAR-β)-dependent downregulation of actomyosin (MLC-2) contractility. We show that ATRA reduces the ability of PSCs to generate high traction forces and adapt to extracellular mechanical cues (mechanosensing), as well as suppresses force-mediated extracellular matrix remodelling to inhibit local cancer cell invasion in 3D organotypic models. Our findings implicate a RAR-β/MLC-2 pathway in peritumoural stromal remodelling and mechanosensory-driven activation of PSCs, and further suggest that mechanical reprogramming of PSCs with retinoic acid derivatives might be a viable alternative to stromal ablation strategies for the treatment of PDAC. PMID:27600527

  5. ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion.

    PubMed

    Chronopoulos, Antonios; Robinson, Benjamin; Sarper, Muge; Cortes, Ernesto; Auernheimer, Vera; Lachowski, Dariusz; Attwood, Simon; García, Rebeca; Ghassemi, Saba; Fabry, Ben; Del Río Hernández, Armando

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal survival rate. Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homoeostasis of the tumour microenvironment to favour cancer cell invasion. Here we report that ATRA, an active metabolite of vitamin A, restores mechanical quiescence in PSCs via a mechanism involving a retinoic acid receptor beta (RAR-β)-dependent downregulation of actomyosin (MLC-2) contractility. We show that ATRA reduces the ability of PSCs to generate high traction forces and adapt to extracellular mechanical cues (mechanosensing), as well as suppresses force-mediated extracellular matrix remodelling to inhibit local cancer cell invasion in 3D organotypic models. Our findings implicate a RAR-β/MLC-2 pathway in peritumoural stromal remodelling and mechanosensory-driven activation of PSCs, and further suggest that mechanical reprogramming of PSCs with retinoic acid derivatives might be a viable alternative to stromal ablation strategies for the treatment of PDAC. PMID:27600527

  6. Differentiation of trophoblast stem cells into giant cells is triggered by p57/Kip2 inhibition of CDK1 activity

    PubMed Central

    Ullah, Zakir; Kohn, Matthew J.; Yagi, Rieko; Vassilev, Lyubomir T.; DePamphilis, Melvin L.

    2008-01-01

    Genome endoreduplication during mammalian development is a rare event for which the mechanism is unknown. It first appears when fibroblast growth factor 4 (FGF4) deprivation induces differentiation of trophoblast stem (TS) cells into the nonproliferating trophoblast giant (TG) cells required for embryo implantation. Here we show that RO3306 inhibition of cyclin-dependent protein kinase 1 (CDK1), the enzyme required to enter mitosis, induced differentiation of TS cells into TG cells. In contrast, RO3306 induced abortive endoreduplication and apoptosis in embryonic stem cells, revealing that inactivation of CDK1 triggers endoreduplication only in cells programmed to differentiate into polyploid cells. Similarly, FGF4 deprivation resulted in CDK1 inhibition by overexpressing two CDK-specific inhibitors, p57/KIP2 and p21/CIP1. TS cell mutants revealed that p57 was required to trigger endoreduplication by inhibiting CDK1, while p21 suppressed expression of the checkpoint protein kinase CHK1, thereby preventing induction of apoptosis. Furthermore, Cdk2−/− TS cells revealed that CDK2 is required for endoreduplication when CDK1 is inhibited. Expression of p57 in TG cells was restricted to G-phase nuclei to allow CDK activation of S phase. Thus, endoreduplication in TS cells is triggered by p57 inhibition of CDK1 with concomitant suppression of the DNA damage response by p21. PMID:18981479

  7. Patched1 and Patched2 inhibit Smoothened non-cell autonomously.

    PubMed

    Roberts, Brock; Casillas, Catalina; Alfaro, Astrid C; Jägers, Carina; Roelink, Henk

    2016-01-01

    Smoothened (Smo) inhibition by Patched (Ptch) is central to Hedgehog (Hh) signaling. Ptch, a proton driven antiporter, is required for Smo inhibition via an unknown mechanism. Hh ligand binding to Ptch reverses this inhibition and activated Smo initiates the Hh response. To determine whether Ptch inhibits Smo strictly in the same cell or also mediates non-cell-autonomous Smo inhibition, we generated genetically mosaic neuralized embryoid bodies (nEBs) from mouse embryonic stem cells (mESCs). These experiments utilized novel mESC lines in which Ptch1, Ptch2, Smo, Shh and 7dhcr were inactivated via gene editing in multiple combinations, allowing us to measure non-cell autonomous interactions between cells with differing Ptch1/2 status. In several independent assays, the Hh response was repressed by Ptch1/2 in nearby cells. When 7dhcr was targeted, cells displayed elevated non-cell autonomous inhibition. These findings support a model in which Ptch1/2 mediate secretion of a Smo-inhibitory cholesterol precursor. PMID:27552050

  8. Patched1 and Patched2 inhibit Smoothened non-cell autonomously

    PubMed Central

    Roberts, Brock; Casillas, Catalina; Alfaro, Astrid C; Jägers, Carina; Roelink, Henk

    2016-01-01

    Smoothened (Smo) inhibition by Patched (Ptch) is central to Hedgehog (Hh) signaling. Ptch, a proton driven antiporter, is required for Smo inhibition via an unknown mechanism. Hh ligand binding to Ptch reverses this inhibition and activated Smo initiates the Hh response. To determine whether Ptch inhibits Smo strictly in the same cell or also mediates non-cell-autonomous Smo inhibition, we generated genetically mosaic neuralized embryoid bodies (nEBs) from mouse embryonic stem cells (mESCs). These experiments utilized novel mESC lines in which Ptch1, Ptch2, Smo, Shh and 7dhcr were inactivated via gene editing in multiple combinations, allowing us to measure non-cell autonomous interactions between cells with differing Ptch1/2 status. In several independent assays, the Hh response was repressed by Ptch1/2 in nearby cells. When 7dhcr was targeted, cells displayed elevated non-cell autonomous inhibition. These findings support a model in which Ptch1/2 mediate secretion of a Smo-inhibitory cholesterol precursor. DOI: http://dx.doi.org/10.7554/eLife.17634.001 PMID:27552050

  9. Sites of inhibition of mitochondrial electron transport in macrophage-injured neoplastic cells.

    PubMed

    Granger, D L; Lehninger, A L

    1982-11-01

    Previous work has shown that injury of neoplastic cells by cytotoxic macrophages (CM) in cell culture is accompanied by inhibition of mitochondrial respiration. We have investigated the nature of this inhibition by studying mitochondrial respiration in CM-injured leukemia L1210 cells permeabilized with digitonin. CM-induced injury affects the mitochondrial respiratory chain proper. Complex I (NADH-coenzyme Q reductase) and complex II (succinate-coenzyme Q reductase) are markedly inhibited. In addition a minor inhibition of cytochrome oxidase was found. Electron transport from alpha-glycerophosphate through the respiratory chain to oxygen is unaffected and permeabilized CM-injured L1210 cells oxidizing this substrate exhibit acceptor control. However, glycerophosphate shuttle activity was found not to occur within CM-injured or uninjured L1210 cells in culture hence, alpha-glycerophosphate is apparently unavailable for mitochondrial oxidation in the intact cell. It is concluded that the failure of respiration of intact neoplastic cells injured by CM is caused by the nearly complete inhibition of complexes I and II of the mitochondrial electron transport chain. The time courses of CM-induced electron transport inhibition and arrest of L1210 cell division are examined and the possible relationship between these phenomena is discussed.

  10. Inhibition of O-GlcNAc transferase activity reprograms prostate cancer cell metabolism

    PubMed Central

    Itkonen, Harri M.; Gorad, Saurabh S.; Duveau, Damien Y.; Martin, Sara E.S.; Barkovskaya, Anna; Bathen, Tone F.; Moestue, Siver A.; Mills, Ian G.

    2016-01-01

    Metabolic networks are highly connected and complex, but a single enzyme, O-GlcNAc transferase (OGT) can sense the availability of metabolites and also modify target proteins. We show that inhibition of OGT activity inhibits the proliferation of prostate cancer cells, leads to sustained loss of c-MYC and suppresses the expression of CDK1, elevated expression of which predicts prostate cancer recurrence (p=0.00179). Metabolic profiling revealed decreased glucose consumption and lactate production after OGT inhibition. This decreased glycolytic activity specifically sensitized prostate cancer cells, but not cells representing normal prostate epithelium, to inhibitors of oxidative phosphorylation (rotenone and metformin). Intra-cellular alanine was depleted upon OGT inhibitor treatment. OGT inhibitor increased the expression and activity of alanine aminotransferase (GPT2), an enzyme that can be targeted with a clinically approved drug, cycloserine. Simultaneous inhibition of OGT and GPT2 inhibited cell viability and growth rate, and additionally activated a cell death response. These combinatorial effects were predominantly seen in prostate cancer cells, but not in a cell-line derived from normal prostate epithelium. Combinatorial treatments were confirmed with two inhibitors against both OGT and GPT2. Taken together, here we report the reprogramming of energy metabolism upon inhibition of OGT activity, and identify synergistically lethal combinations that are prostate cancer cell specific. PMID:26824323

  11. Patient characteristics, treatment and survival in pulmonary carcinoid tumours: an analysis from the UK National Lung Cancer Audit

    PubMed Central

    Hobbins, Stephanie; West, Doug; Peake, Michael; Beckett, Paul; Woolhouse, Ian

    2016-01-01

    Objectives Pulmonary carcinoid (PC) is a rare tumour with good prognosis following surgical resection. However, little is known regarding patient characteristics and use of other treatments modalities. Our objective was to review patient characteristics, treatment and survival for patients with PC and contrast these results with other forms of non-small cell lung cancer (NSCLC). Setting Audit data from UK National Lung Cancer Audit (NLCA) 2008–2013. Participants 184 906 lung cancer cases were submitted to the NLCA. Outcome measures Primary outcome—survival rates between PC and NSCLC. Secondary outcome—differences in performance status, lung function and treatment modality between PC and NSCLC. Results PC histology was recorded in 1341 (0.73%) patients and non-carcinoid NSCLC histology in 162 959 (87.4%) cases. 91% of patients with PC had good performance status (Eastern Cooperative Oncology Group (ECOG) 0–1), compared with only 53% of NSCLC. 66% of PC had localised disease. Of all PC cases, 77% were treated with surgery, 6.2% received chemotherapy and 3.6% received radiotherapy, with the remainder treated with best supportive care. Overall 1-year and 3-year survival rates for PC were 92% and 84.7%, respectively. In contrast, 1-year and 3-year survival rates for NSCLC were 36.2% and 15.6%, However, 3-year survival for PC markedly decreased with worsening performance status and advanced disease to 23.8% for performance status ECOG 3–4 and 33.6% for stage IV disease. Conclusions In contrast to other forms of NSCLC, the majority of patients with PC present with good performance status, preserved lung function and early stage disease amenable to surgical resection. However, 1 in 5 patients with PC has metastatic disease which is associated with poor prognosis, as is poor performance status at presentation. We believe these data will help clinicians provide accurate prognostic predictions stratified according to patient characteristics at presentation, as

  12. Prolyl oligopeptidase inhibition-induced growth arrest of human gastric cancer cells

    SciTech Connect

    Suzuki, Kanayo; Sakaguchi, Minoru; Tanaka, Satoshi; Yoshimoto, Tadashi; Takaoka, Masanori

    2014-01-03

    Highlights: •We examined the effects of prolyl oligopeptidase (POP) inhibition on p53 null gastric cancer cell growth. •POP inhibition-induced cell growth suppression was associated with an increase in a quiescent G{sub 0} state. •POP might regulate the exit from and/or reentry into the cell cycle. -- Abstract: Prolyl oligopeptidase (POP) is a serine endopeptidase that hydrolyzes post-proline peptide bonds in peptides that are <30 amino acids in length. We recently reported that POP inhibition suppressed the growth of human neuroblastoma cells. The growth suppression was associated with pronounced G{sub 0}/G{sub 1} cell cycle arrest and increased levels of the CDK inhibitor p27{sup kip1} and the tumor suppressor p53. In this study, we investigated the mechanism of POP inhibition-induced cell growth arrest using a human gastric cancer cell line, KATO III cells, which had a p53 gene deletion. POP specific inhibitors, 3-((4-[2-(E)-styrylphenoxy]butanoyl)-L-4-hydroxyprolyl)-thiazolidine (SUAM-14746) and benzyloxycarbonyl-thioprolyl-thioprolinal, or RNAi-mediated POP knockdown inhibited the growth of KATO III cells irrespective of their p53 status. SUAM-14746-induced growth inhibition was associated with G{sub 0}/G{sub 1} cell cycle phase arrest and increased levels of p27{sup kip1} in the nuclei and the pRb2/p130 protein expression. Moreover, SUAM-14746-mediated cell cycle arrest of KATO III cells was associated with an increase in the quiescent G{sub 0} state, defined by low level staining for the proliferation marker, Ki-67. These results indicate that POP may be a positive regulator of cell cycle progression by regulating the exit from and/or reentry into the cell cycle by KATO III cells.

  13. Effect of thiourea on PCMBS inhibition of osmotic water transport in human red cells.

    PubMed

    Chasan, B; Lukacovic, M F; Toon, M R; Solomon, A K

    1984-11-21

    The organomercurial reagent p-chloromercuribenzene sulfonate (PCMBS) is an inhibitor of osmotic water permeability in the human red cell membrane. We have found that thiourea, when added along with PCMBS to a red cell suspension, interferes with this inhibition and at high enough concentrations prevents the inhibition from developing altogether. For a 2 mM PCMBS concentration Ki = 3 +/- 1 mM. When thiourea is added at a later time, the PCMBS inhibition, which normally takes about 20 min to develop fully, is halted and remains fixed at the value attained by that time. Thiourea also inhibits the reversal of PCMBS inhibition by a 10 mM concentration of cysteine, the half-time for reversal increasing by more than an order of magnitude when [thiourea] = 50 mM. Possible implications for the nature of the water and urea transport pathways across the red cell membrane are discussed. PMID:6093879

  14. Control of Mitral/Tufted Cell Output by Selective Inhibition among Olfactory Bulb Glomeruli.

    PubMed

    Economo, Michael N; Hansen, Kyle R; Wachowiak, Matt

    2016-07-20

    Inhibition is fundamental to information processing by neural circuits. In the olfactory bulb (OB), glomeruli are the functional units for odor information coding, but inhibition among glomeruli is poorly characterized. We used two-photon calcium imaging in anesthetized and awake mice to visualize both odorant-evoked excitation and suppression in OB output neurons (mitral and tufted, MT cells). MT cell response polarity mapped uniformly to discrete OB glomeruli, allowing us to analyze how inhibition shapes OB output relative to the glomerular map. Odorants elicited unique patterns of suppression in only a subset of glomeruli in which such suppression could be detected, and excited and suppressed glomeruli were spatially intermingled. Binary mixture experiments revealed that interglomerular inhibition could suppress excitatory mitral cell responses to odorants. These results reveal that inhibitory OB circuits nonlinearly transform odor representations and support a model of selective and nonrandom inhibition among glomerular ensembles. PMID:27346531

  15. Senescent stromal cells induce cancer cell migration via inhibition of RhoA/ROCK/myosin-based cell contractility.

    PubMed

    Aifuwa, Ivie; Giri, Anjil; Longe, Nick; Lee, Sang Hyuk; An, Steven S; Wirtz, Denis

    2015-10-13

    Cells induced into senescence exhibit a marked increase in the secretion of pro-inflammatory cytokines termed senescence-associated secretory phenotype (SASP). Here we report that SASP from senescent stromal fibroblasts promote spontaneous morphological changes accompanied by an aggressive migratory behavior in originally non-motile human breast cancer cells. This phenotypic switch is coordinated, in space and time, by a dramatic reorganization of the actin and microtubule filament networks, a discrete polarization of EB1 comets, and an unconventional front-to-back inversion of nucleus-MTOC polarity. SASP-induced morphological/migratory changes are critically dependent on microtubule integrity and dynamics, and are coordinated by the inhibition of RhoA and cell contractility. RhoA/ROCK inhibition reduces focal adhesions and traction forces, while promoting a novel gliding mode of migration. PMID:26483365

  16. The Neurorepellent Slit2 Inhibits Postadhesion Stabilization of Monocytes Tethered to Vascular Endothelial Cells.

    PubMed

    Mukovozov, Ilya; Huang, Yi-Wei; Zhang, Qiuwang; Liu, Guang Ying; Siu, Allan; Sokolskyy, Yaroslav; Patel, Sajedabanu; Hyduk, Sharon J; Kutryk, Michael J B; Cybulsky, Myron I; Robinson, Lisa A

    2015-10-01

    The secreted neurorepellent Slit2, acting through its transmembrane receptor, Roundabout (Robo)-1, inhibits chemotaxis of varied cell types, including leukocytes, endothelial cells, and vascular smooth muscle cells, toward diverse attractants. The role of Slit2 in regulating the steps involved in recruitment of monocytes in vascular inflammation is not well understood. In this study, we showed that Slit2 inhibited adhesion of monocytic cells to activated human endothelial cells, as well as to immobilized ICAM-1 and VCAM-1. Microfluidic live cell imaging showed that Slit2 inhibited the ability of monocytes tethered to endothelial cells to stabilize their actin-associated anchors and to resist detachment in response to increasing shear forces. Transfection of constitutively active plasmids revealed that Slit2 inhibited postadhesion stabilization of monocytes on endothelial cells by preventing activation of Rac1. We further found that Slit2 inhibited chemotaxis of monocytes toward CXCL12 and CCL2. To determine whether Slit2 and Robo-1 modulate pathologic monocyte recruitment associated with vascular inflammation and cardiovascular disease, we tested PBMC from patients with coronary artery disease. PBMC from these patients had reduced surface levels of Robo-1 compared with healthy age- and sex-matched subjects, and Slit2 failed to inhibit chemotaxis of PBMC of affected patients, but not healthy control subjects, toward CCL2. Furthermore, administration of Slit2 to atherosclerosis-prone LDL receptor-deficient mice inhibited monocyte recruitment to nascent atherosclerotic lesions. These results demonstrate that Slit2 inhibits chemotaxis of monocytes, as well as their ability to stabilize adhesions and resist detachment forces. Slit2 may represent a powerful new tool to inhibit pathologic monocyte recruitment in vascular inflammation and atherosclerosis.

  17. Anticancer agent xanthohumol inhibits IL-2 induced signaling pathways involved in T cell proliferation.

    PubMed

    Liu, Yongbo; Gao, Xiaohua; Deeb, Dorrah; Arbab, Ali S; Dulchavsky, Scott A; Gautam, Subhash C

    2012-01-01

    Xanthohumol (XN), a prenylated chalcone present in hops exhibits anti-inflammatory, antioxidant and anticancer activity. In the present study we show that XN inhibits the proliferation of mouse lymphoma cells and IL-2 induced proliferation and cell cycle progression in mouse splenic T cells. The suppression of T cell proliferation by XN was due to the inhibition of IL-2 induced Janus kinase/signal transducers and activators of transcription (Jak/STAT) and extracellular signal-regulated kinase 1 and 2 (Erk1/2) signaling pathways. XN also inhibited proliferation-related cellular proteins such as c-Myc, c-Fos and NF-kappaB and cyclin D1. Thus, understanding of IL-2 induced cell signaling pathways in normal T cells, which are constitutively turned on in T cell lymphomas may facilitate development of XN for the treatment of hematologic cancers. PMID:22946339

  18. Anticancer agent xanthohumol inhibits IL-2 induced signaling pathways involved in T cell proliferation

    PubMed Central

    Liu, Yongbo; Gao, Xiaohua; Deeb, Dorrah; Arbab, Ali S.; Dulchavsky, Scott A.; Gautam, Subhash C.

    2013-01-01

    Xanthohumol (XN), a prenylated chalcone present in hops exhibits anti-inflammatory, antioxidant and anticancer activity. In the present study we show that XN inhibits the proliferation of mouse lymphoma cells and IL-2 induced proliferation and cell cycle progression in mouse splenic T cells. The suppression of T cell proliferation by XN was due to the inhibition of IL-2 induced Janus kinase/signal transducers and activators of transcription (Jak/STAT) and extracellular signal-regulated kinase 1 and 2 (Erk1/2) signaling pathways. XN also inhibited proliferation-related cellular proteins such as c-Myc, c-Fos and NF-κB and cyclin D1. Thus, understanding of IL-2 induced cell signaling pathways in normal T cells, which are constitutively turned on in T cell lymphomas may facilitate development of XN for the treatment of hematologic cancers. PMID:22946339

  19. RhoE inhibits cell cycle progression and Ras-induced transformation.

    PubMed

    Villalonga, Priam; Guasch, Rosa M; Riento, Kirsi; Ridley, Anne J

    2004-09-01

    Rho GTPases are major regulators of cytoskeletal dynamics, but they also affect cell proliferation, transformation, and oncogenesis. RhoE, a member of the Rnd subfamily that does not detectably hydrolyze GTP, inhibits RhoA/ROCK signaling to promote actin stress fiber and focal adhesion disassembly. We have generated fibroblasts with inducible RhoE expression to investigate the role of RhoE in cell proliferation. RhoE expression induced a loss of stress fibers and cell rounding, but these effects were only transient. RhoE induction inhibited cell proliferation and serum-induced S-phase entry. Neither ROCK nor RhoA inhibition accounted for this response. Consistent with its inhibitory effect on cell cycle progression, RhoE expression was induced by cisplatin, a DNA damage-inducing agent. RhoE-expressing cells failed to accumulate cyclin D1 or p21(cip1) protein or to activate E2F-regulated genes in response to serum, although ERK, PI3-K/Akt, FAK, Rac, and cyclin D1 transcription was activated normally. The expression of proteins that bypass the retinoblastoma (pRb) family cell cycle checkpoint, including human papillomavirus E7, adenovirus E1A, and cyclin E, rescued cell cycle progression in RhoE-expressing cells. RhoE also inhibited Ras- and Raf-induced fibroblast transformation. These results indicate that RhoE inhibits cell cycle progression upstream of the pRb checkpoint.

  20. Slow and sustained nitric oxide releasing compounds inhibit multipotent vascular stem cell proliferation and differentiation without causing cell death

    SciTech Connect

    Curtis, Brandon M.; Leix, Kyle Alexander; Ji, Yajing; Glaves, Richard Samuel Elliot; Ash, David E.; Mohanty, Dillip K.

    2014-07-18

    Highlights: • Multipotent vascular stem cells (MVSCs) proliferate and differentiate. • Nitric oxide inhibits proliferation of MVSCs. • Nitric oxide inhibits MVSC differentiation to mesenchymal-like stem cells (MSCs). • Smooth muscle cells (SMCs) neither de-differentiate nor proliferate. - Abstract: Atherosclerosis is the leading cause of cerebral and myocardial infarction. It is believed that neointimal growth common in the later stages of atherosclerosis is a result of vascular smooth muscle cell (SMC) de-differentiation in response to endothelial injury. However, the claims of the SMC de-differentiation theory have not been substantiated by monitoring the fate of mature SMCs in response to such injuries. A recent study suggests that atherosclerosis is a consequence of multipotent vascular stem cell (MVSC) differentiation. Nitric oxide (NO) is a well-known mediator against atherosclerosis, in part because of its inhibitory effect on SMC proliferation. Using three different NO-donors, we have investigated the effects of NO on MVSC proliferation. Results indicate that NO inhibits MVSC proliferation in a concentration dependent manner. A slow and sustained delivery of NO proved to inhibit proliferation without causing cell death. On the other hand, larger, single-burst NO concentrations, inhibits proliferation, with concurrent significant cell death. Furthermore, our results indicate that endogenously produced NO inhibits MVSC differentiation to mesenchymal-like stem cells (MSCs) and subsequently to SMC as well.

  1. Magnobovatol inhibits smooth muscle cell migration by suppressing PDGF-Rβ phosphorylation and inhibiting matrix metalloproteinase-2 expression

    PubMed Central

    KANG, HYREEN; AHN, DONG HYEON; PAK, JHANG HO; SEO, KYEONG-HWA; BAEK, NAM-IN; JANG, SUNG-WUK

    2016-01-01

    The migration of vascular smooth muscle cells (VSMCs) may play a crucial role in the pathogenesis of vascular diseases, such as atherosclerosis and post-angioplasty restenosis. Platelet-derived growth factor (PDGF)-BB is a potent mitogen for VSMCs and plays an important role in the intimal accumulation of VSMCs. Magnobovatol, a new neolignan from the fruits of Magnolia obovata, has been shown to have anticancer properties. However, the effects of magnobovatol on VSMCs are unknown. In the present study, we examined the effects of magnobovatol on the PDGF-BB-induced migration of mouse and human VSMCs, as well as the underlying mechanisms. Magnobovatol significantly inhibited the PDGF-BB-induced migration of mouse and human VSMCs without inducing cell death (as shown by MTT assay and wound healing assay). Additionally, we demonstrated that magnobovatol significantly blocked the PDGF-BB-induced phosphorylation of the PDGF receptor (PDGF-R), Akt and extracellular signal-regulated kinase (ERK)1/2 by inhibiting the activation of the PDGF-BB signaling pathway. Moreover, in both mouse and human VSMCs, magnobovatol inhibited PDGF-induced matrix metalloproteinase (MMP)-2 expression at the mRNA and protein level, as well as the proteolytic activity of MMP-2 (as shown by western blot analysis, RT-PCR, gelatin zymography and ELISA). In addition, the sprout outgrowth formation of aortic rings induced by PDGF-BB was inhibited by magnobovatol (as shown by aortic ring assay). Taken together, our findings indicate that magnobovatol inhibits VSMC migration by decreasing MMP-2 expression through PDGF-R and the ERK1/2 and Akt pathways. Our data may improve the understanding of the anti-atherogenic effects of magnobovatol in VSMCs. PMID:27049716

  2. Mosla dianthera inhibits mast cell-mediated allergic reactions through the inhibition of histamine release and inflammatory cytokine production

    SciTech Connect

    Lee, Dong-Hee; Kim, Sang-Hyun . E-mail: shkim72@knu.ac.kr; Eun, Jae-Soon; Shin, Tae-Yong . E-mail: tyshin@woosuk.ac.kr

    2006-11-01

    In this study, we investigated the effect of the aqueous extract of Mosla dianthera (Maxim.) (AEMD) on the mast cell-mediated allergy model and studied the possible mechanism of action. Mast cell-mediated allergic disease is involved in many diseases such as asthma, sinusitis and rheumatoid arthritis. The discovery of drugs for the treatment of allergic disease is an important subject in human health. AEMD inhibited compound 48/80-induced systemic reactions in mice. AEMD decreased immunoglobulin E-mediated local allergic reactions, passive cutaneous anaphylaxis. AEMD attenuated intracellular calcium level and release of histamine from rat peritoneal mast cells activated by compound 48/80. Furthermore, AEMD attenuated the phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187-stimulated TNF-{alpha}, IL-8 and IL-6 secretion in human mast cells. The inhibitory effect of AEMD on the pro-inflammatory cytokines was nuclear factor-{kappa}B (NF-{kappa}B) dependent. AEMD decreased PMA and A23187-induced degradation of I{kappa}B{alpha} and nuclear translocation of NF-{kappa}B. Our findings provide evidence that AEMD inhibits mast cell-derived immediate-type allergic reactions and involvement of pro-inflammatory cytokines and NF-{kappa}B in these effects.

  3. Schisandrin B inhibits cell proliferation and induces apoptosis in human cholangiocarcinoma cells

    PubMed Central

    Yang, Xiaohui; Wang, Shuai; Mu, Yunchuan; Zheng, Yixiong

    2016-01-01

    Cholangiocarcinoma (CCA) is the second most common hepatic cancer with high resistance to current chemotherapies and extremely poor prognosis. The present study aimed to examine the effects of schisandrin B (Sch B) on CCA cells both in vitro and in vivo and to examine its underlying mechanism. We found that Sch B inhibited the viability and proliferation of CCA cells in a dose- and time-dependent manner as assessed by MTT and colony formation assays. The flow cytometric assay revealed G0/G1 phase arrest in the Sch B-treated HCCC-9810 and RBE cells. In addition, Sch B induced intrahepatic cholangiocarcinoma apoptosis as shown by the results of Annexin V/PI double staining. Rhodamine 123 staining revealed that Sch B decreased the mitochondrial membrane potential (ΔΨm) in a dose-dependent manner. Mechanistically, western blot analysis indicated that Sch B induced apoptosis by upregulating Bax, cleaved caspase-3, cleaved caspase-9 and cleaved PARP, and by downregulating cyclin D1, Bcl-2 and CDK-4. Moreover, Sch B significantly inhibited HCCC-9810 xenograft growth in athymic nude mice. In summary, these findings suggest that Sch B exhibited potent antitumor activities via the induction of CCA apoptosis and that Sch B may be a promising drug for the treatment of CCA. PMID:27499090

  4. Schisandrin B inhibits cell proliferation and induces apoptosis in human cholangiocarcinoma cells.

    PubMed

    Yang, Xiaohui; Wang, Shuai; Mu, Yunchuan; Zheng, Yixiong

    2016-10-01

    Cholangiocarcinoma (CCA) is the second most common hepatic cancer with high resistance to current chemotherapies and extremely poor prognosis. The present study aimed to examine the effects of schisandrin B (Sch B) on CCA cells both in vitro and in vivo and to examine its underlying mechanism. We found that Sch B inhibited the viability and proliferation of CCA cells in a dose- and time-dependent manner as assessed by MTT and colony formation assays. The flow cytometric assay revealed G0/G1 phase arrest in the Sch B-treated HCCC-9810 and RBE cells. In addition, Sch B induced intrahepatic cholangiocarcinoma apoptosis as shown by the results of Annexin V/PI double staining. Rhodamine 123 staining revealed that Sch B decreased the mitochondrial membrane potential (ΔΨm) in a dose-dependent manner. Mechanistically, western blot analysis indicated that Sch B induced apoptosis by upregulating Bax, cleaved caspase-3, cleaved caspase-9 and cleaved PARP, and by downregulating cyclin D1, Bcl-2 and CDK-4. Moreover, Sch B significantly inhibited HCCC-9810 xenograft growth in athymic nude mice. In summary, these findings suggest that Sch B exhibited potent antitumor activities via the induction of CCA apoptosis and that Sch B may be a promising drug for the treatment of CCA. PMID:27499090

  5. Morin, a Flavonoid from Moraceae, Inhibits Cancer Cell Adhesion to Endothelial Cells and EMT by Downregulating VCAM1 and Ncadherin.

    PubMed

    Lee, JeongHee; Jin, Hana; Lee, Won Sup; Nagappan, Arulkumar; Choi, Yung Hyun; Kim, Gon Sup; Jung, JinMyung; Ryu, Chung Ho; Shin, Sung Chul; Hong, Soon Chan; Kim, Hye Jung

    2016-01-01

    Morin, a flavonoid found in figs and other Moraceae species, displays a variety of biological actions, exerting antioxidant, antiinflammatory and anticarcinogenic effects. Here, we investigated the anticancer activity of morin focusing on antiadhesive influence. We performed experiments with MDAMB231 human breast cancer cells. Morin inhibited TNFinduced cancer cell adhesion to human umbilical vein endothelial cells (HUVECs) without showing any toxicity. It further inhibited the expression of VCAM1 on MDAMB231 cells as well as HUVECs. Morin also decreased the expression of Ncadherin on MDAMB231 cells. In addition, there was apparent antimetastatic activity in vivo. In conclusion, this study suggested that morin inhibits cancer cell adhesion to HUVECs by reducing VCAM1, and EMT by targeting Ncadherin, and that it features antimetastatic activity in vivo. Further investigation of possible antimetastatic activity of morin against human breast cancer cells is warranted.

  6. [Appendiceal carcinoid tumors. Evaluation of long-term outcomes in a tertiary level].

    PubMed

    Suárez-Grau, Juan Manuel; García-Ruiz, Salud; Rubio-Chaves, Carolina; Bustos-Jiménez, Manuel; Docobo-Durantez, Fernando; Padillo-Ruiz, Francisco Javier

    2014-01-01

    Antecedentes: los tumores apendiculares se encuentran en cerca de 1% de las apendicectomías y representan 0.5% de las neoplasias intestinales. El tipo de tumor más frecuente es el carcinoide apendicular, que casi siempre es un hallazgo durante la apendicectomía por otro motivo. Su pronóstico es excelente y la supervivencia es mayor de 95% a cinco años de la intervención. Objetivo: reportar una serie de casos y analizar la supervivencia media a cinco años posteriores a la identificación el tumor. Material y métodos: análisis retrospectivo (1990-2010) de pacientes con tumor carcinoide apendicular intervenidos en el servicio de Cirugía General y del Aparato Digestivo del Hospital Universitario Virgen del Rocío, Sevilla, España. Se analizaron: la supervivencia a cinco años, la necesidad de tratamiento complementario y las pruebas para seguimiento en la consulta. Resultados: se encontraron 42 pacientes intervenidos por tener un tumor carcinoide apendicular. En 38 pacientes la operación fue de urgencia, la mayoría por sospecha de apendicitis aguda, sin que en ninguno se hubiera establecido el diagnóstico de tumor carcinoide antes de la operación. El síntoma predominante al ingreso fue el dolor abdominal. El tratamiento quirúrgico fue: apendicectomía en 34 pacientes (12 por laparoscopia), en el intraoperatorio siete pacientes requirieron resecciones colónicas mayores debido a la afectación del colon; sólo uno requirió la reintervención para completar la hemicolectomía derecha. Al momento del diagnóstico dos pacientes tenían enfermedad diseminada (metástasis hepáticas). La supervivencia a cinco años fue superior a 95%, sin recidivas o tratamiento posterior de la enfermedad. Conclusiones: el tumor carcinoide apendicular difícilmente se diagnostica antes del procedimiento quirúrgico. La apendicectomía suele ser suficiente aunque en algunos pacientes las resecciones colónicas son necesarias por diseminación. La supervivencia a 5 años es

  7. MiR-503 inhibits hepatocellular carcinoma cell growth via inhibition of insulin-like growth factor 1 receptor

    PubMed Central

    Xiao, Yao; Tian, Qinggang; He, Jiantai; Huang, Ming; Yang, Chao; Gong, Liansheng

    2016-01-01

    MicroRNAs (miRs) have been demonstrated to play key roles in the development and progression of hepatocellular carcinoma (HCC). However, the regulatory mechanism of miR-503 in HCC has not been fully uncovered. In this study, we found that miR-503 was significantly downregulated in HCC tissues compared to nontumorous liver tissues. Moreover, lower miR-503 levels were associated with the malignant progression of HCC, and the expression of miR-503 was also decreased in several common HCC cell lines compared to normal human liver cell line THLE-3. Overexpression of miR-503 inhibited proliferation but induced apoptosis of LM3 and HepG2 cells. Bioinformatical analysis and luciferase reporter assay further identified insulin-like growth factor 1 receptor (IGF-1R) as a novel target of miR-503 in 293T cells. Moreover, overexpression of miR-503 led to a significant decrease in the protein levels of IGF-1R, while knockdown of miR-503 enhanced its protein levels in LM3 and HepG2 cells. Besides, overexpression of IGF-1R reversed the effects of miR-503-mediated HCC cell proliferation and apoptosis, indicating that IGF-1R acts as a downstream effector of miR-503 in HCC cells. Furthermore, IGF-1R was found to be significantly upregulated in HCC tissues compared to nontumorous liver tissues. In addition, the mRNA levels of IGF-1R were inversely correlated to the miR-503 levels in the HCC tissues. Thus, we demonstrate that miR-503 inhibits the proliferation and induces the apoptosis of HCC cells, partly at least, by directly targeting IGF-1R, and suggest that IGF-1R may serve as a promising target for the treatment of HCC. PMID:27366090

  8. Inhibition of cholesterol biosynthesis by Delta22-unsaturated phytosterols via competitive inhibition of sterol Delta24-reductase in mammalian cells.

    PubMed Central

    Fernández, Carlos; Suárez, Yajaira; Ferruelo, Antonio J; Gómez-Coronado, Diego; Lasunción, Miguel A

    2002-01-01

    Dietary phytosterols are cholesterol-lowering agents that interfere with the intestinal absorption of cholesterol. In the present study, we have studied their effects on cholesterol biosynthesis in human cells, particularly in the sterol-conversion pathway. For this, both Caco-2 (intestinal mucosa) and HL-60 (promyelocytic) human cell lines were incubated with [(14)C]acetate, and the incorporation of radioactivity into sterols was determined using HPLC and radioactivity detection online. Sterols containing a double bond at C-22 in the side chain (stigmasterol, brassicasterol and ergosterol) dramatically inhibited the activity of sterol Delta(24)-reductase, as indicated by the decrease in radioactivity incorporation into cholesterol and the accumulation of its precursors (mainly desmosterol). Phytosterols with the saturated side chain (beta-sitosterol and campesterol) were inactive in this regard. The inhibition of sterol (24)-reductase was confirmed in rat liver microsomes by using (14)C-labelled desmosterol as the substrate. The (22)-unsaturated phytosterols acted as competitive inhibitors of sterol (24)-reductase, with K(i) values (41.1, 42.7 and 36.8 microM for stigmasterol, brassicasterol and ergosterol respectively) similar to the estimated K(m) for desmosterol (26.3 microM). The sterol 5,22-cholestedien-3beta-ol, an unusual desmosterol isomer that lacks the alkyl groups characteristic of phytosterols, acted as a much stronger inhibitor of (24)-reductase (K(i)=3.34 microM). The usually low intracellular concentrations of the physiological substrates of (24)-reductase explains the strong inhibition of cholesterol biosynthesis that these compounds exert in cells. Given that inhibition of sterol (24)-reductase was achieved at physiologically relevant concentrations, it may represent an additional mechanism for the cholesterol-lowering action of phytosterols, and opens up the possibility of using certain (22)-unsaturated sterols as effective hypocholesterolaemic

  9. Close interactions between mesenchymal stem cells and neuroblastoma cell lines lead to tumor growth inhibition.

    PubMed

    Bianchi, Giovanna; Morandi, Fabio; Cilli, Michele; Daga, Antonio; Bocelli-Tyndall, Chiara; Gambini, Claudio; Pistoia, Vito; Raffaghello, Lizzia

    2012-01-01

    Mesenchymal stem cells (MSCs) have attracted much interest in oncology since they exhibit marked tropism for the tumor microenvironment and support or suppress malignant cell growth depending on the tumor model tested. The aim of this study was to investigate the role of MSCs in the control of the growth of neuroblastoma (NB), which is the second most common solid tumor in children. In vivo experiments showed that systemically administered MSCs, under our experimental conditions, did not home to tumor sites and did not affect tumor growth or survival. However, MSCs injected intratumorally in an established subcutaneous NB model reduced tumor growth through inhibition of proliferation and induction of apoptosis of NB cells and prolonged the survival of hMSC-treated mice. The need for contact between MSCs and NB cells was further supported by in vitro experiments. In particular, MSCs were found to be attracted by NB cells, and to affect NB cell proliferation with different results depending on the cell line tested. Moreover, NB cells, after pre-incubation with hMSCs, acquired a more invasive behavior towards CXCL12 and the bone marrow, i.e., the primary site of NB metastases. In conclusion, this study demonstrates that functional cross-talk between MSCs and NB cell lines used in our experiments can occur only within short range interaction. Thus, this report does not support the clinical use of MSCs as vehicles for selective delivery of antitumor drugs at the NB site unless chemotherapy and/or radiotherapy create suitable local conditions for MSCs recruitment.

  10. Close Interactions between Mesenchymal Stem Cells and Neuroblastoma Cell Lines Lead to Tumor Growth Inhibition

    PubMed Central

    Bianchi, Giovanna; Morandi, Fabio; Cilli, Michele; Daga, Antonio; Bocelli-Tyndall, Chiara; Gambini, Claudio

    2012-01-01

    Mesenchymal stem cells (MSCs) have attracted much interest in oncology since they exhibit marked tropism for the tumor microenvironment and support or suppress malignant cell growth depending on the tumor model tested. The aim of this study was to investigate the role of MSCs in the control of the growth of neuroblastoma (NB), which is the second most common solid tumor in children. In vivo experiments showed that systemically administered MSCs, under our experimental conditions, did not home to tumor sites and did not affect tumor growth or survival. However, MSCs injected intratumorally in an established subcutaneous NB model reduced tumor growth through inhibition of proliferation and induction of apoptosis of NB cells and prolonged the survival of hMSC-treated mice. The need for contact between MSCs and NB cells was further supported by in vitro experiments. In particular, MSCs were found to be attracted by NB cells, and to affect NB cell proliferation with different results depending on the cell line tested. Moreover, NB cells, after pre-incubation with hMSCs, acquired a more invasive behavior towards CXCL12 and the bone marrow, i.e., the primary site of NB metastases. In conclusion, this study demonstrates that functional cross-talk between MSCs and NB cell lines used in our experiments can occur only within short range interaction. Thus, this report does not support the clinical use of MSCs as vehicles for selective delivery of antitumor drugs at the NB site unless chemotherapy and/or radiotherapy create suitable local conditions for MSCs recruitment. PMID:23119082

  11. TAZ promotes cell growth and inhibits Celastrol-induced cell apoptosis

    PubMed Central

    Wang, Shuren; Ma, Kai; Chen, Lechuang; Zhu, Hongxia; Liang, Shufang; Liu, Mei; Xu, Ningzhi

    2016-01-01

    Hippo pathway is a highly conservative signalling pathway related to the development of organisms, which has been demonstrated to be strongly linked to the tumorigenesis and tumour progression. As the major downstream effector of Hippo pathway, yes-associated protein (YAP), is a transcriptional activator of target genes that are involved in cell proliferation and survival. As an oncogene, YAP can promote cell growth and inhibit cell apoptosis. Another major downstream effector of Hippo pathway, transcriptional co-activators with PDZ-binding motif (TAZ), is nearly 60% homologous with YAP. In the present study, we assume that TAZ probably has the similar function to YAP. To test this issue, we established an inducible and a stable expression system of TAZ in T-Rex-293 and HEK293 cells respectively. The results of cell growth curves, colony formation assay and tumour xenograft growth showed that overexpression of TAZ could promote cell growth in vitro and in vivo. Meanwhile, we found that up-regulated expression of TAZ could partially restore Celastrol-induced cell apoptosis. Induced overexpression of TAZ could up-regulate its target genes including ankyrin repeat domain-containing protein (ANKRD), cysteine-rich 61 (CYR61) and connective tissue growth factor (CTGF), increase the expression of B-cell lymphoma-2 (Bcl-2), decrease the expression of Bcl-2 associated X protein (Bax) and activate the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, which may be the mechanism underlying anti-apoptosis of TAZ. All these findings indicated that TAZ acts as an oncogene that could be a key regulator of cell proliferation and apoptosis. PMID:27515420

  12. Wnt Signaling Inhibits Adrenal Steroidogenesis by Cell-Autonomous and Non–Cell-Autonomous Mechanisms

    PubMed Central

    Walczak, Elisabeth M.; Kuick, Rork; Finco, Isabella; Bohin, Natacha; Hrycaj, Steven M.; Wellik, Deneen M.

    2014-01-01

    Wnt/β-catenin (βcat) signaling is critical for adrenal homeostasis. To elucidate how Wnt/βcat signaling elicits homeostatic maintenance of the adrenal cortex, we characterized the identity of the adrenocortical Wnt-responsive population. We find that Wnt-responsive cells consist of sonic hedgehog (Shh)-producing adrenocortical progenitors and differentiated, steroidogenic cells of the zona glomerulosa, but not the zona fasciculata and rarely cells that are actively proliferating. To determine potential direct inhibitory effects of βcat signaling on zona fasciculata-associated steroidogenesis, we used the mouse ATCL7 adrenocortical cell line that serves as a model system of glucocorticoid-producing fasciculata cells. Stimulation of βcat signaling caused decreased corticosterone release consistent with the observed reduced transcription of steroidogenic genes Cyp11a1, Cyp11b1, Star, and Mc2r. Decreased steroidogenic gene expression was correlated with diminished steroidogenic factor 1 (Sf1; Nr5a1) expression and occupancy on steroidogenic promoters. Additionally, βcat signaling suppressed the ability of Sf1 to transactivate steroidogenic promoters independent of changes in Sf1 expression level. To investigate Sf1-independent effects of βcat on steroidogenesis, we used Affymetrix gene expression profiling of Wnt-responsive cells in vivo and in vitro. One candidate gene identified, Ccdc80, encodes a secreted protein with unknown signaling mechanisms. We report that Ccdc80 is a novel βcat-regulated gene in adrenocortical cells. Treatment of adrenocortical cells with media containing secreted Ccdc80 partially phenocopies βcat-induced suppression of steroidogenesis, albeit through an Sf1-independent mechanism. This study reveals multiple mechanisms of βcat-mediated suppression of steroidogenesis and suggests that Wnt/βcat signaling may regulate adrenal homeostasis by inhibiting fasciculata differentiation and promoting the undifferentiated state of progenitor

  13. Ionene polymers for selectively inhibiting the vitro growth of malignant cells

    NASA Technical Reports Server (NTRS)

    Rembaum, Alan (Inventor)

    1977-01-01

    Ionene polymers of the structure ##STR1## WHERE X AND Y ARE INTEGERS FROM 3 TO 16, Z.sup.- is an anion such as a halogen and n is an integer from 50 to 150 are found to bind negatively charged mammalian cells such as malignant cells and can be utilized to selectively inhibit the growth of malignant cells in vitro.

  14. Inner retinal inhibition shapes the receptive field of retinal ganglion cells in primate

    PubMed Central

    Protti, D A; Di Marco, S; Huang, J Y; Vonhoff, C R; Nguyen, V; Solomon, S G

    2014-01-01

    Abstract The centre–surround organisation of receptive fields is a feature of most retinal ganglion cells (RGCs) and is critical for spatial discrimination and contrast detection. Although lateral inhibitory processes are known to be important in generating the receptive field surround, the contribution of each of the two synaptic layers in the primate retina remains unclear. Here we studied the spatial organisation of excitatory and inhibitory synaptic inputs onto ON and OFF ganglion cells in the primate retina. All RGCs showed an increase in excitation in response to stimulus of preferred polarity. Inhibition onto RGCs comprised two types of responses to preferred polarity: some RGCs showed an increase in inhibition whilst others showed removal of tonic inhibition. Excitatory inputs were strongly spatially tuned but inhibitory inputs showed more variable organisation: in some neurons they were as strongly tuned as excitation, and in others inhibitory inputs showed no spatial tuning. We targeted one source of inner retinal inhibition by functionally ablating spiking amacrine cells with bath application of tetrodotoxin (TTX). TTX significantly reduced the spatial tuning of excitatory inputs. In addition, TTX reduced inhibition onto those RGCs where a stimulus of preferred polarity increased inhibition. Reconstruction of the spatial tuning properties by somatic injection of excitatory and inhibitory synaptic conductances verified that TTX-mediated inhibition onto bipolar cells increases the strength of the surround in RGC spiking output. These results indicate that in the primate retina inhibitory mechanisms in the inner plexiform layer sharpen the spatial tuning of ganglion cells. PMID:24042496

  15. SAMHD1 is down regulated in lung cancer by methylation and inhibits tumor cell proliferation

    SciTech Connect

    Wang, Jia-lei; Lu, Fan-zhen; Shen, Xiao-Yong; Wu, Yun; Zhao, Li-ting

    2014-12-12

    Highlights: • SAMHD1 expression level is down regulated in lung adenocarcinoma. • The promoter of SAMHD1 is methylated in lung adenocarcinoma. • Over expression of SAMHD1 inhibits the proliferation of lung cancer cells. - Abstract: The function of dNTP hydrolase SAMHD1 as a viral restriction factor to inhibit the replication of several viruses in human immune cells was well established. However, its regulation and function in lung cancer have been elusive. Here, we report that SAMHD1 is down regulated both on protein and mRNA levels in lung adenocarcinoma compared to adjacent normal tissue. We also found that SAMHD1 promoter is highly methylated in lung adenocarcinoma, which may inhibit its gene expression. Furthermore, over expression of the SAMHD1 reduces dNTP level and inhibits the proliferation of lung tumor cells. These results reveal the regulation and function of SAMHD1 in lung cancer, which is important for the proliferation of lung tumor cells.

  16. Inhibition of proliferation of normal and transformed neural cells by blood group-related oligosaccharides

    PubMed Central

    1992-01-01

    A synthetic tetrasaccharide structurally related to blood groups and selectin ligands inhibited division of astrocytes, gliomas, and neuroblastomas at micromolar concentrations. The compound was cytostatic for primary astrocytes in culture, but cytotoxic for fast proliferating cell lines. PMID:1512552

  17. Dichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis

    PubMed Central

    Vogel, Robert M.; Erez, Amir; Altan-Bonnet, Grégoire

    2016-01-01

    Despite progress in drug development, a quantitative and physiological understanding of how small-molecule inhibitors act on cells is lacking. Here, we measure the signalling and proliferative response of individual primary T-lymphocytes to a combination of antigen, cytokine and drug. We uncover two distinct modes of signalling inhibition: digital inhibition (the activated fraction of cells diminishes upon drug treatment, but active cells appear unperturbed), versus analogue inhibition (the activated fraction is unperturbed whereas activation response is diminished). We introduce a computational model of the signalling cascade that accounts for such inhibition dichotomy, and test the model predictions for the phenotypic variability of cellular responses. Finally, we demonstrate that the digital/analogue dichotomy of cellular response as revealed on short (signal transduction) timescales, translates into similar dichotomy on longer (proliferation) timescales. Our single-cell analysis of drug action illustrates the strength of quantitative approaches to translate in vitro pharmacology into functionally relevant cellular settings. PMID:27687249

  18. N-Octanoyl dopamine transiently inhibits T cell proliferation via G1 cell-cycle arrest and inhibition of redox-dependent transcription factors.

    PubMed

    Wedel, Johannes; Hottenrott, Maximillia C; Stamellou, Eleni; Breedijk, Annette; Tsagogiorgas, Charalambos; Hillebrands, Jan-Luuk; Yard, Benito A

    2014-09-01

    Recently, we developed a nonhemodynamic dopamine derivative, NOD, which has profound anti-inflammatory effects in vitro. As NOD also protects rats from ischemic AKI, the present study tested whether NOD is able to modulate cellular immunity for potential use as a T cell-suppressive agent. To this end, T cells were stimulated by anti-CD3/CD28 or PMA/ionomycin in the presence or absence of different concentrations of NOD. T cell proliferation, activation markers, intracellular cytokine expression, and activation of transcription factors were assessed. Whereas T cell proliferation was inhibited significantly by NOD at Day 3, proliferation was restored at Day 7 or later depending on the NOD concentration used. Inhibition of proliferation was reflected by a diminished CD25 expression and switch from naive to memory T cells. Early TCR activation events were unaffected, yet NF-κB and AP-1 were strongly inhibited by NOD. The inhibitory effect of NOD seemed to be dependent on its redox activity, as NOT, a redox-inactive NOD derivate, did not influence proliferation. NOD displayed synergistic effects with CNIs on T cell proliferation. Our data demonstrate that NOD displays T cell-suppressive activity. In keeping with its anti-inflammatory action and its beneficial effect on ischemia-induced AKI, NOD may be an interesting drug candidate to prevent CNI-related side-effects.

  19. Carnosic Acid Inhibits the Epithelial-Mesenchymal Transition in B16F10 Melanoma Cells: A Possible Mechanism for the Inhibition of Cell Migration

    PubMed Central

    Park, So Young; Song, Hyerim; Sung, Mi-Kyung; Kang, Young-Hee; Lee, Ki Won; Park, Jung Han Yoon

    2014-01-01

    Carnosic acid is a natural benzenediol abietane diterpene found in rosemary and exhibits anti-inflammatory, antioxidant, and anti-carcinogenic activities. In this study, we evaluated the effects of carnosic acid on the metastatic characteristics of B16F10 melanoma cells. When B16F10 cells were cultured in an in vitro Transwell system, carnosic acid inhibited cell migration in a dose-dependent manner. Carnosic acid suppressed the adhesion of B16F10 cells, as well as the secretion of matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1, urokinase plasminogen activator (uPA), and vascular cell adhesion molecule (VCAM)-1. Interestingly, secretion of TIMP-2 increased significantly in B16F10 cells treated with 10 μmol/L carnosic acid. Additionally, carnosic acid suppressed the mesenchymal markers snail, slug, vimentin, and N-cadherin and induced epithelial marker E-cadherin. Furthermore, carnosic acid suppressed phosphorylation of Src, FAK, and AKT. These results indicate that inhibition of the epithelial-mesenchymal transition may be important for the carnosic acid-induced inhibition of B16F10 cell migration. PMID:25036034

  20. Romidepsin in Treating Patients With Locally Advanced or Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2013-06-03

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Pancreatic Polypeptide Tumor; Pulmonary Carcinoid Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Regional Gastrointestinal Carcinoid Tumor; Somatostatinoma

  1. Cinobufagin inhibits tumor growth by inducing intrinsic apoptosis through AKT signaling pathway in human nonsmall cell lung cancer cells

    PubMed Central

    Zhang, Guangxin; Wang, Chao; Sun, Mei; Li, Jindong; Wang, Bin; Jin, Chengyan; Hua, Peiyan; Song, Ge; Zhang, Yifan; Nguyen, Lisa L.H.; Cui, Ranji; Liu, Runhua; Wang, Lizhong; Zhang, Xingyi

    2016-01-01

    The cinobufagin (CB) has a broad spectrum of cytotoxicity to inhibit cell proliferation of various human cancer cell lines, but the molecular mechanisms still remain elusive. Here we observed that CB inhibited the cell proliferation and tumor growth, but induced cell cycle arrest and apoptosis in a dose-dependent manner in non-small cell lung cancer (NSCLC) cells. Treatment with CB significantly increased the reactive oxygen species but decreased the mitochondrial membrane potential in NSCLC cells. These effects were markedly blocked when the cells were pretreated with N-acetylcysteine, a specific reactive oxygen species inhibitor. Furthermore, treatment with CB induced the expression of BAX but reduced that of BCL-2, BCL-XL and MCL-1, leading to an activation of caspase-3, chromatin condensation and DNA degradation in order to induce programmed cell death in NSCLC cells. In addition, treatment with CB reduced the expressions of p-AKTT308 and p-AKTS473 and inhibited the AKT/mTOR signaling pathway in NSCLC cells in a time-dependent manner. Our results suggest that CB inhibits tumor growth by inducing intrinsic apoptosis through the AKT signaling pathway in NSCLC cells. PMID:26959116

  2. Time-lapse cinematography of the capillary tube cell migration inhibition test.

    PubMed

    Bray, M A

    1980-01-01

    The kinetics of human and guinea pig cell migration inhibition have been studied using time-lapse cinematography of cells migrating from capillary tubes. Guinea pig and human cells exhibit markedly different kinetics in the absence of inhibitors. Specific antigen causes a dose-related inhibition of migration for up to 60 h using guinea pig cells and a peak of inhibition after 18 h using the human leucocyte system. The timing of measurement of maximum activity more critical for the latter test. The kinetics of lymphokine generation have been examined and the migration inhibitory activity of the plant mitogen (PHA), a Kurloff cell product and a continuous cell line supernatant have been compared with the inhibitory profiles of lymphokine preparations and specific antigen. PMID:7350125

  3. Time-lapse cinematography of the capillary tube cell migration inhibition test.

    PubMed

    Bray, M A

    1980-01-01

    The kinetics of human and guinea pig cell migration inhibition have been studied using time-lapse cinematography of cells migrating from capillary tubes. Guinea pig and human cells exhibit markedly different kinetics in the absence of inhibitors. Specific antigen causes a dose-related inhibition of migration for up to 60 h using guinea pig cells and a peak of inhibition after 18 h using the human leucocyte system. The timing of measurement of maximum activity more critical for the latter test. The kinetics of lymphokine generation have been examined and the migration inhibitory activity of the plant mitogen (PHA), a Kurloff cell product and a continuous cell line supernatant have been compared with the inhibitory profiles of lymphokine preparations and specific antigen.

  4. Lumican Inhibits SNAIL-Induced Melanoma Cell Migration Specifically by Blocking MMP-14 Activity.

    PubMed

    Stasiak, Marta; Boncela, Joanna; Perreau, Corinne; Karamanou, Konstantina; Chatron-Colliet, Aurore; Proult, Isabelle; Przygodzka, Patrycja; Chakravarti, Shukti; Maquart, François-Xavier; Kowalska, M Anna; Wegrowski, Yanusz; Brézillon, Stéphane

    2016-01-01

    Lumican, a small leucine rich proteoglycan, inhibits MMP-14 activity and melanoma cell migration in vitro and in vivo. Snail triggers epithelial-mesenchymal transitions endowing epithelial cells with migratory and invasive properties during tumor progression. The aim of this work was to investigate lumican effects on MMP-14 activity and migration of Snail overexpressing B16F1 (Snail-B16F1) melanoma cells and HT-29 colon adenocarcinoma cells. Lumican inhibits the Snail induced MMP-14 activity in B16F1 but not in HT-29 cells. In Snail-B16F1 cells, lumican inhibits migration, growth, and melanoma primary tumor development. A lumican-based strategy targeting Snail-induced MMP-14 activity might be useful for melanoma treatment. PMID:26930497

  5. Lumican Inhibits SNAIL-Induced Melanoma Cell Migration Specifically by Blocking MMP-14 Activity

    PubMed Central

    Stasiak, Marta; Boncela, Joanna; Perreau, Corinne; Karamanou, Konstantina; Chatron-Colliet, Aurore; Proult, Isabelle; Przygodzka, Patrycja; Chakravarti, Shukti; Maquart, François-Xavier; Kowalska, M. Anna; Wegrowski, Yanusz; Brézillon, Stéphane

    2016-01-01

    Lumican, a small leucine rich proteoglycan, inhibits MMP-14 activity and melanoma cell migration in vitro and in vivo. Snail triggers epithelial-mesenchymal transitions endowing epithelial cells with migratory and invasive properties during tumor progression. The aim of this work was to investigate lumican effects on MMP-14 activity and migration of Snail overexpressing B16F1 (Snail-B16F1) melanoma cells and HT-29 colon adenocarcinoma cells. Lumican inhibits the Snail induced MMP-14 activity in B16F1 but not in HT-29 cells. In Snail-B16F1 cells, lumican inhibits migration, growth, and melanoma primary tumor development. A lumican-based strategy targeting Snail-induced MMP-14 activity might be useful for melanoma treatment. PMID:26930497

  6. Sulfatides inhibit binding of Helicobacter pylori to the gastric cancer Kato III cell line.

    PubMed

    Wadström, T; Hirmo, S; Novak, H; Guzman, A; Ringnér-Pantzar, M; Utt, M; Aleljung, P

    1997-05-01

    Helicobacter pylori adhere to Kato III and Hela S3 cells in monolayer cultures. To explore whether cell surface glycoconjugates on these two cell lines mediate binding of H. pylori, various carbohydrates, glycoproteins, and glycolipids were tested to inhibit H.pylori cell adhesion. The adhesion was measured (i) with a urease-based assay and (ii) by cells stained with fluorescein. Sodium periodate and sialidase treatment (but not alpha- or beta-galactosidase, heparitinase,lysozyme, or trypsin) inhibited H. pylori binding to both cell lines. Sulfatides and sulfated glycoconjugates (50 microg/ml) but not heparin or a number of simple carbohydrates inhibited binding (1 mg/ml). The two H.pylori strains studied (CCUG 17874 and strain 25) showed high binding of soluble 125I-labeled heparin and other sulfated carbohydrate compounds. PMID:9099625

  7. Mosla punctulata Inhibits Mast Cell-mediated Allergic Reactions Through the Inhibition of Histamine Release and Inflammatory Cytokine Production

    PubMed Central

    Je, I. G.; Shin, T. Y.; Kim, S. H.

    2013-01-01

    Allergic inflammatory diseases such as food allergy, asthma, sinusitis and atopic dermatitis are increasing worldwide. This study examined the effects of aqueous extract of Mosla punctulata on mast cell-mediated allergic inflammation and studied the possible mechanism of action. Aqueous extract of Mosla punctulata inhibited compound 48/80-induced systemic and immunoglobulin E-mediated local anaphylaxis and it also reduced intracellular calcium level and down-streamed histamine release from mast cells. In addition, aqueous extract of Mosla punctulata decreased gene expression and secretion of tumour necrosis factor alpha, an important proinflammatory cytokine, in mast cells. The inhibitory effect on tumour necrosis factor alpha expression was nuclear factor kappa B dependent. The results indicate that aqueous extract of Mosla punctulata inhibited mast cell-mediated allergic inflammatory reaction by suppressing histamine release and expression of tumour necrosis factor alpha, and involvement of calcium and nuclear factor kappa B in these effects. Hence it can be concluded that, the aqueous extract of Mosla punctulata might be a possible therapeutic candidate for allergic inflammatory disorders. PMID:24591741

  8. Resveratrol inhibits cancer cell metabolism by down regulating pyruvate kinase M2 via inhibition of mammalian target of rapamycin.

    PubMed

    Iqbal, Mohd Askandar; Bamezai, Rameshwar N K

    2012-01-01

    Metabolism of cancer cells with pyruvate kinase M2 (PKM2) at its centre stage has assumed a prime significance in cancer research in recent times. Cancer cell metabolism, characterized by enhanced glucose uptake, production of lactate and anabolism is considered an ideal target for therapeutic interventions. Expression of PKM2 switches metabolism in favor of cancer cells, therefore, the present study was designed to investigate the hitherto unknown effect of resveratrol, a phytoalexin, on PKM2 expression and resultant implications on cancer metabolism. We observed that resveratrol down-regulated PKM2 expression by inhibiting mTOR signaling and suppressed cancer metabolism, adjudged by decreased glucose uptake, lactate production (aerobic glycolysis) and reduced anabolism (macromolecule synthesis) in various cancer cell lines. A contingent decrease in intracellular levels of ribose-5-phosphate (R5P), a critical intermediate of pentose phosphate pathway, accounted for a reduced anabolism. Consequently, the state of suppressed cancer metabolism resulted in decreased cellular proliferation. Interestingly, shRNA-mediated silencing of PKM2 inhibited glucose uptake and lactate production, providing evidence for the critical role of PKM2 and its mediation in the observed effects of resveratrol on cancer metabolism. Further, an over-expression of PKM2 abolished the observed effects of resveratrol, signifying the role of PKM2 downregulation as a critical function of resveratrol. The study reports a novel PKM2-mediated effect of resveratrol on cancer metabolism and provides a new dimension to its therapeutic potential.

  9. Blockade of MUC1 expression by glycerol guaiacolate inhibits proliferation of human breast cancer cells.

    PubMed

    Smith, J S; Colon, J; Madero-Visbal, R; Isley, B; Konduri, S D; Baker, C H

    2010-10-01

    We sought to determine whether administration of glycerol guaiacolate at an optimal biological dose inhibits human breast cancer cell growth. Human breast cancer MCF-7 and ZR-75-1 cells were treated with glycerol guaiacolate and the therapeutic efficacy and biological activity of this drug was investigated on breast cancer cell growth. MCF-7 cells were injected into the mammary fat pad of overectamized female athymic nude mice. Ten days later, animals were treated with daily intraperitoneal injections of glycerol guaiacolate for six weeks. Tumor size and volume was monitored and immunohistochemistry analysis on MUC1, p21 and ki-67 was performed. Glycerol guaiacolate decreased breast cancer cell growth in a dose-dependent manner, decreased cell migration, and caused G1 cell cycle arrest. Our results demonstrate that glycerol guaiacolate inhibits MUC1 protein and mRNA expression levels and significantly increased p21 expression in human breast cancer cells as well as induced PARP cleavage. Similarly, glycerol guaiacolate inhibited breast tumor growth in vivo as well as enhanced p21 expression and decreased breast tumor cell proliferation (ki-67 expression). Collectively, our results demonstrate that glycerol guaiacolate decreased MUC1 expression and enhanced cell growth inhibition by inducing p21 expression in breast cancer cells. These findings suggest that glycerol guaiacolate may provide a novel and effective approach for the treatment of human breast cancer. PMID:21184665

  10. ERP44 inhibits human lung cancer cell migration mainly via IP3R2.

    PubMed

    Huang, Xue; Jin, Meng; Chen, Ying-Xiao; Wang, Jun; Zhai, Kui; Chang, Yan; Yuan, Qi; Yao, Kai-Tai; Ji, Guangju

    2016-06-01

    Cancer cell migration is involved in tumour metastasis. However, the relationship between calcium signalling and cancer migration is not well elucidated. In this study, we used the human lung adenocarcinoma A549 cell line to examine the role of endoplasmic reticulum protein 44 (ERP44), which has been reported to regulate calcium release inside of the endoplasmic reticulum (ER), in cell migration. We found that the inositol 1,4,5-trisphosphate receptors (IP3Rs/ITPRs) inhibitor 2-APB significantly inhibited A549 cell migration by inhibiting cell polarization and pseudopodium protrusion, which suggests that Ca2+ is necessary for A549 cell migration. Similarly, the overexpression of ERP44 reduced intracellular Ca2+ release via IP3Rs, altered cell morphology and significantly inhibited the migration of A549 cells. These phenomena were primarily dependent on IP3R2 because wound healing in A549 cells with IP3R2 rather than IP3R1 or IP3R3 siRNA was markedly inhibited. Moreover, the overexpression of ERP44 did not affect the migration of the human neuroblastoma cell line SH-SY5Y, which mainly expresses IP3R1. Based on the above observations, we conclude that ERP44 regulates A549 cell migration mainly via an IP3R2-dependent pathway.

  11. ERP44 inhibits human lung cancer cell migration mainly via IP3R2

    PubMed Central

    Zhai, Kui; Chang, Yan; Yuan, Qi; Yao, Kai-Tai; Ji, Guangju

    2016-01-01

    Cancer cell migration is involved in tumour metastasis. However, the relationship between calcium signalling and cancer migration is not well elucidated. In this study, we used the human lung adenocarcinoma A549 cell line to examine the role of endoplasmic reticulum protein 44 (ERP44), which has been reported to regulate calcium release inside of the endoplasmic reticulum (ER), in cell migration. We found that the inositol 1,4,5-trisphosphate receptors (IP3Rs/ITPRs) inhibitor 2-APB significantly inhibited A549 cell migration by inhibiting cell polarization and pseudopodium protrusion, which suggests that Ca2+ is necessary for A549 cell migration. Similarly, the overexpression of ERP44 reduced intracellular Ca2+ release via IP3Rs, altered cell morphology and significantly inhibited the migration of A549 cells. These phenomena were primarily dependent on IP3R2 because wound healing in A549 cells with IP3R2 rather than IP3R1 or IP3R3 siRNA was markedly inhibited. Moreover, the overexpression of ERP44 did not affect the migration of the human neuroblastoma cell line SH-SY5Y, which mainly expresses IP3R1. Based on the above observations, we conclude that ERP44 regulates A549 cell migration mainly via an IP3R2-dependent pathway. PMID:27347718

  12. Inhibition of Human Colon Cancer Growth by Antibody-Directed Human LAK Cells in SCID Mice

    NASA Astrophysics Data System (ADS)

    Takahashi, Hiroshi; Nakada, Tetsuya; Puisieux, Isabelle

    1993-03-01

    Advanced human colon cancer does not respond to lymphokine-activated killer (LAK) cells. In order to direct cytotoxic cells to the tumor, human LAK cells linked with antibodies to a tumor cell surface antigen were tested with established hepatic metastases in severe combined immunodeficient (SCID) mice. These cells had increased uptake into the tumor and suppression of tumor growth as compared with LAK cells alone, thereby improving the survival of tumor-bearing mice. Thus, tumor growth can be inhibited by targeted LAK cells, and SCID mice can be used to test the antitumor properties of human effector cells.

  13. Inhibition of HIF-1α Affects Autophagy Mediated Glycosylation in Oral Squamous Cell Carcinoma Cells

    PubMed Central

    Li, Yi-Ning; Hu, Ji-An; Wang, Hui-Ming

    2015-01-01

    Purpose. To validate the function of autophagy with the regulation of hypoxia inhibitor-induced glycosylation in oral squamous cell carcinoma cell. Methods. Human Tca8113 cell line was used to detect autophagy and glycosylation related protein expression by western blotting and immunofluorescence with HIF-1α inhibitor. Short interfering RNA (siRNA) transfection blocked human ATG12 and ATG1. Results. HIF-1α inhibitor PX-478 reduced the amount of LC3-II and LC3-I in Tca8113 cells. PX-478 decreased the expression of O-GlcNAc and OGT and increased OGA expression. The tendency of O-GlcNAc showed a similar pattern to OGT. PX-478 gradually decreased OGT expression in Tca8113 cells. Protein level of O-GlcNAc and OGT increased in ATG12 and ATG1 depletion. The expression of OGT decreased at first and then rose slowly with the treatment of Atg12 and Atg1 siRNA and PX-478 fluctuant. Autophagy affected the stability of OGT when HIF-1α signaling was blocked. Conclusions. Autophagy reduced by hypoxic stress inhibited. HIF-1α inhibitor decreased glycosylation. OGT became unstable in the absence of autophagy when HIF-1α signaling was blocked. PMID:26640316

  14. Silencing of stat4 gene inhibits cell proliferation and invasion of colorectal cancer cells.

    PubMed

    Cheng, J M; Yao, M R; Zhu, Q; Wu, X Y; Zhou, J; Tan, W L; Zhan, S H

    2015-01-01

    Signal transducers and activators of transcription (STAT) play critical roles in development, proliferation, and immune defense. However the consequences of STAT hyperactivity can predispose to diseases, including colorectal cancer. In the present study, we aimed to evaluate the function of STAT4 in human colorectal cancer (CRC). The expression of STAT4 was examined by immunohistochemical assay using a tissue microarray procedure. A loss-of-function experiment was carried out to investigate the effects of lentivirus-mediated STAT4 shRNA (Lv-shSTAT4) on cell proliferation and invasive potential indicated by MTT and Transwell assays in CRC cell lines (SW480 and Caco2). As a consequence, it was found that the expression of STAT4 protein was significantly increased in CRC tissues compared with that in adjacent non-cancerous tissues (ANCT) (71.1% vs 44.4%, P=0.015), and was related with the Duke’s staging and depth of invasion in CRC patients (P=0.022; P=0.001). Silencing of STAT4 gene suppressed cell proliferation and invasion of CRC cells. Taken together, these findings demonstrate that increased expression of STAT4 is positively correlated with the depth of invasion in CRC patients, and inhibition of STAT4 expression represses the growth and invasion of CRC cells, suggesting that STAT4 may be a promising therapeutic target for the treatment of CRC.

  15. TLR4 plays a crucial role in MSC-induced inhibition of NK cell function

    SciTech Connect

    Lu, Ying; Liu, Jin; Liu, Yang; Qin, Yaru; Luo, Qun; Wang, Quanli; Duan, Haifeng

    2015-08-21

    Mesenchymal stem cells (MSC) are a kind of stromal cell within the tumor microenvironment. In our research, MSC derived from acute myeloid leukemia patients' bone marrow (AML-MSC) and lung cancer tissues (LC-MSC) as well as normal bone marrow-derived MSC (BM-MSC) cultured in conditioned medium of HeLa cells were found to have higher expressions of Toll-like receptor (TLR4) mRNA compared with BM-MSC. The sorted TLR4-positive MSC (TLR4+ MSC) differed in cytokine (interleukin-6, interleukin-8, and monocyte chemoattractant protein-1) secretion from those of unsorted MSC. MSC was reported to inhibit natural killer (NK) cell proliferation and function. In this research, we confirmed that TLR4+ MSC aggravate this suppression. Furthermore, when TLR4 in the sorted cells were stimulated by LPS or following blocked by antibody, the suppression on NK cell proliferation and cytotoxicity were more intensive or recovered respectively. Compared to unsorted MSC, NKG2D receptor expression on NK cells were also inhibited by TLR4+ MSC. These findings suggest that activation of TLR4 pathway is important for TLR4+ MSC and MSC to obstruct anti-tumor immunity by inhibiting NK cell function, which may provide a potential stroma-targeted tumor therapy. - Highlights: • TLR4+ MSC inhibit NK cell proliferation in vivo and in vitro. • TLR4+ MSC inhibit NKG2D expression on NK cells and NK cell cytotoxicity. • The distinguished cytokine expression of TLR4+ MSC may contribute to the inhibition on NK cell function.

  16. Interleukin-6 inhibits adrenal androgen release from bovine adrenal zona reticularis cells by inhibiting the expression of steroidogenic proteins.

    PubMed

    McIlmoil, S; Call, G B; Barney, M; Strickland, J; Judd, A M

    2015-10-01

    Interleukin-6 (IL-6) is secreted by adrenocortical cells and modifies cortisol secretion. In this study, the effects of IL-6 on adrenal androgen release were investigated. The zona reticularis (ZR) was generally isolated from bovine adrenal glands by dissection. In select experiments, the intact adrenal cortex (ie, all 3 adrenocortical zones) was dissected from the adrenal glands. For androgen release experiments, ZR and intact adrenocortical cubes were dispersed into isolated cells, the cells cultured and exposed to IL-6 and/or adrenocorticotropic hormone (ACTH), and androgen release determined by radioimmunoassay. Basal and ACTH-stimulated androgen release from the ZR was inhibited by IL-6 in a concentration-dependent (10-1000 pg/mL) and time-dependent (4-24 h) manner (P < 0.01 by 1-way analysis of variance and the Bonferroni test). In contrast, IL-6 increased basal and ACTH-stimulated androgen release from mixed adrenocortical cells (P < 0.01). The mechanism of IL-6 inhibition of androgen release was investigated by exposing ZR strips to IL-6 and measuring the expression of the messenger RNA (mRNA) and protein of steroidogenic factors. Basal and ACTH-stimulated expression of the mRNA and protein for steroidogenic acute regulatory protein, cholesterol side chain cleavage enzyme, 3-β-hydroxysteroid dehydrogenase type 2, steroid 17-α-hydroxylase/17,20 lyase/17,20 desmolase, and the nuclear factor steroidogenic factor 1 (SF-1), that stimulates steroidogenesis, were decreased by IL-6 (P < 0.01). In contrast IL-6 increased the mRNA and protein for dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX-1), a nuclear factor that inhibits steroidogenesis (P < 0.01). In summary, IL-6 decreased androgen release and the expression of steroidogenic factors in the ZR, and this decrease may be mediated in part through increasing DAX-1 and decreasing SF-1. PMID:26218834

  17. Trifluoperazine inhibits 45Ca2+ uptake and catecholamine secretion and synthesis in adrenal medullary cells.

    PubMed

    Wada, A; Yanagihara, N; Izumi, F; Sakurai, S; Kobayashi, H

    1983-02-01

    In isolated adrenal medullary cells, carbamylcholine and high K+ cause the calcium-dependent secretion of catecholamines with a simultaneous increase in the synthesis of 14C-catecholamines from [14C]tyrosine. In these cells, trifluoperazine, a selective antagonist of calmodulin, inhibited both the secretion and synthesis of catecholamines. The stimulatory effect of carbamylcholine was inhibited to a greater extent than that of high K+. The inhibitory effect of trifluoperazine on carbamylcholine-evoked secretion of catecholamines was not overcome by an increase in either carbamylcholine or calcium concentration, showing that inhibition by trifluoperazine occurs by a mechanism distinct from competitive antagonism at the cholinergic receptor and from direct inactivation of calcium channels. Doses of trifluoperazine that inhibited catecholamine secretion and synthesis also inhibited the uptake of radioactive calcium by the cells. These results suggest that trifluoperazine inhibits the secretion and synthesis of catecholamines mainly due to its inhibition of calcium uptake. Trifluoperazine seems to inhibit calcium uptake by uncoupling the linkage between calcium uptake by uncoupling the linkage between cholinergic receptor stimulation and calcium channel activation.

  18. Inhibition of transferring binding and iron uptake of hematopoietic cell lines by phorbol esters.

    PubMed

    Pelicci, P G; Testa, U; Thomopoulos, P; Tabilio, A; Vainchenker, W; Titeux, M; Gourdin, M F; Rochant, H

    1984-01-01

    Phorbol esters inhibit cell growth and the binding of transferrin to receptors on K 562, HL 60 and U 937 human leukemic cell lines. Exposure of these cells to 12-0-tetradecanoyl phorbol-13-acetate (TPA) at 37 degrees C results in a 40% reduction of the specific binding of 125I-transferrin, which is apparent within 15 min. Half-maximal inhibition occurs at about 1 nM. Other tumor promoting phorbol esters also inhibit 125I-transferrin binding in a dose-dependent manner which parallels their known promoting activity in vivo. TPA reduces the number of transferrin receptors, and does not alter the degradation or the internalization of transferrin. In addition, TPA inhibits iron uptake by these cell lines. These effects are specific, since phorbol esters do not affect either cell growth or the binding of transferrin to Friend erythroleukemia cells and Raji cell line. On the basis of these findings it is suggested that the inhibition of transferrin binding may represent one of the mechanisms by which phorbol esters affect the growth and the differentiation of hematopoietic cell lines. PMID:6088899

  19. Pyridalyl inhibits cellular protein synthesis in insect, but not mammalian, cell lines.

    PubMed

    Moriya, Koko; Hirakura, Setsuko; Kobayashi, Jun; Ozoe, Yoshihisa; Saito, Shigeru; Utsumi, Toshihiko

    2008-09-01

    To gain insight into the mechanism of action and selectivity of the insecticidal activity of pyridalyl, the cytotoxicity of pyridalyl against various insect and mammalian cell lines was characterized by measuring the inhibition of cellular protein synthesis. When the effect of pyridalyl on the cellular protein synthesis in Sf9 cells was evaluated by measuring the incorporation of [(3)H]leucine, rapid and significant inhibition of protein synthesis was observed. However, pyridalyl did not inhibit protein synthesis in a cell-free protein synthesis system, indicating that pyridalyl does not directly inhibit protein synthesis. No obvious cytotoxicity was observed against any of the mammalian cell lines tested. In the case of insect cell lines, remarkable differences in the cytotoxicity of pyridalyl were observed: the highest cytotoxicity (IC50 mM) was found against Sf9 cells derived from Spodoptera frugiperda, whereas no obvious cytotoxicity was observed against BmN4 cells derived from Bombyx mori. Measurements of the insecticidal activity of pyridalyl against Spodoptera litura and B. mori revealed a correlation between the cytotoxicity against cultured cell lines and the insecticidal activity. From these observations, it was concluded that the selective inhibition of cellular protein synthesis by pyridalyl might contribute significantly to the insecticidal activity and the selectivity of this compound. PMID:18454491

  20. Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis

    SciTech Connect

    Di Paolo, Julie A; Huang, Tao; Balazs, Mercedesz; Barbosa, James; Barck, Kai H; Bravo, Brandon J; Carano, Richard A.D.; Darrow, James; Davies, Douglas R; DeForge, Laura E; Diehl, Lauri; Ferrando, Ronald; Gallion, Steven L; Giannetti, Anthony M; Gribling, Peter; Hurez, Vincent; Hymowitz, Sarah G; Jones, Randall; Kropf, Jeffrey E; Lee, Wyne P; Maciejewski, Patricia M; Mitchell, Scott A; Rong, Hong; Staker, Bart L; Whitney, J Andrew; Yeh, Sherry; Young, Wendy B; Yu, Christine; Zhang, Juan; Reif, Karin; Currie, Kevin S

    2011-08-29

    Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which Btk mediates inflammation are poorly understood. Here we describe the discovery of CGI1746, a small-molecule Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor–dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btk inhibition abolishes FcγRIII-induced TNFα, IL-1β and IL-6 production. Accordingly, in myeloid- and FcγR-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell– or myeloid cell–driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.

  1. Different effects of LDH-A inhibition by oxamate in non-small cell lung cancer cells

    PubMed Central

    Yang, Yang; Su, Dan; Zhao, Lin; Zhang, Dan; Xu, Jiaying; Wan, Jianmei; Fan, Saijun; Chen, Ming

    2014-01-01

    Higher rate of glycolysis has been long observed in cancer cells, as a vital enzyme in glycolysis, lactate dehydrogenase A (LDH-A) has been shown with great potential as an anti-cancer target. Accumulating evidence indicates that inhibition of LDH-A induces apoptosis mediated by oxidative stress in cancer cells. To date, it's still unclear that whether autophagy can be induced by LDH-A inhibition. Here, we investigated the effects of oxamate, one classic inhibitor of LDH-A in non-small cell lung cancer (NSCLC) cells as well as normal lung epithelial cells. The results showed that oxamate significantly suppressed the proliferation of NSCLC cells, while it exerted a much lower toxicity in normal cells. As previous studies reported, LDH-A inhibition resulted in ATP reduction and ROS (reactive oxygen species) burst in cancer cells, which lead to apoptosis and G2/M arrest in H1395 cells. However, when being exposed to oxamate, A549 cells underwent autophagy as a protective mechanism against apoptosis. Furthermore, we found evidence that LDH-A inhibition induced G0/G1 arrest dependent on the activation of GSK-3β in A549 cells. Taken together, our results provide useful clues for targeting LDH-A in NSCLC treatment and shed light on the discovery of molecular predictors for the sensitivity of LDH-A inhibitors. PMID:25361010

  2. IL-15 inhibits pre-B cell proliferation by selectively expanding Mac-1{sup +}B220{sup +} NK cells

    SciTech Connect

    Nakajima, Shinsuke; Hida, Shigeaki; Taki, Shinsuke

    2008-05-16

    Natural killer (NK) cells are the cells critical for inhibition of repopulation of allogenic bone marrow cells. However, it is not well known if NK cells affect autologous lymphopoiesis. Here, we observed that NK cells could inhibit pre-B cell proliferation in vitro driven by interleukin (IL)-7 in a manner dependent on IL-15. Interestingly, the great majority of expanding NK cells were Mac-1{sup +}B220{sup +}, a recently identified potent interferon (IFN)-{gamma} producer. Indeed, IFN-{gamma} was produced in those cultures, and pre-B cells lacking IFN-{gamma} receptors, but not those lacking type I IFN receptors, were resistant to such an inhibition. Furthermore, even NK cells from mice lacking {beta}2-microglobulin, which were known to be functionally dampened, inhibited pre-B cell proliferation as well. Thus, activated NK cells, which were expanded selectively by IL-15, could potentially regulate B lymphopoiesis through IFN-{gamma} beyond the selection imposed upon self-recognition.

  3. Inhibition of LINE-1 retrotransposon-encoded reverse transcriptase modulates the expression of cell differentiation genes in breast cancer cells.

    PubMed

    Patnala, Radhika; Lee, Sung-Hun; Dahlstrom, Jane E; Ohms, Stephen; Chen, Long; Dheen, S Thameem; Rangasamy, Danny

    2014-01-01

    Long Interspersed Elements (L1 elements) are biologically active retrotransposons that are capable of autonomous replication using their own reverse transcriptase (RT) enzyme. Expression of the normally repressed RT has been implicated in cancer cell growth. However, at present, little is known about the expression of L1-encoded RT activity or the molecular changes that are associated with RT activity in the development of breast cancer. Here, we report that RT activity is widespread in breast cancer cells. The expression of RT protein decreased markedly in breast cancer cells after treatment with the antiretroviral drug, efavirenz. While the majority of cells showed a significant reduction in proliferation, inhibition of RT was also accompanied by cell-specific differences in morphology. MCF7 cells displayed elongated microtubule extensions that adhered tightly to their substrate, while a large fraction of the T47D cells that we studied formed long filopodia projections. These morphological changes were reversible upon cessation of RT inhibition, confirming their dependence on RT activity. We also carried out gene expression profiling with microarrays and determined the genes that were differentially expressed during the process of cellular differentiation. Genes involved in proliferation, cell migration, and invasive activity were repressed in RT-inhibited cells. Concomitantly, genes involved in cell projection, formation of vacuolar membranes, and cell-to-cell junctions were significantly upregulated in RT-inhibited cells. qRT-PCR examination of the mRNA expression of these genes in additional cell lines yielded close correlation between their differential expression and the degree of cellular differentiation. Our study demonstrates that the inhibition of L1-encoded RT can reduce the rate of proliferation and promote differentiation of breast cancer cells. Together, these results provide a direct functional link between the expression of L1 retrotransposons and

  4. Crispene E, a cis-clerodane diterpene inhibits STAT3 dimerization in breast cancer cells.

    PubMed

    Mantaj, Julia; Rahman, S M Abdur; Bokshi, Bishwajit; Hasan, Choudhury M; Jackson, Paul J M; Parsons, Richard B; Rahman, Khondaker M

    2015-04-01

    Crispene E, a new clerodane-type diterpene, inhibited STAT3 dimerization in a cell-free fluorescent polarisation assay and was found to have significant toxicity against STAT3-dependent MDA-MB 231 breast cancer cell line and selectively inhibited the expression of STAT3 and STAT3 target genes cyclin D1, Fascin and bcl-2. Molecular docking studies suggest the molecule inhibits STAT3 by interacting with its SH2 domain. The compound has been isolated from Tinospora crispa and characterized using standard spectroscopic techniques. PMID:25721973

  5. Combination of Potassium Pentagamavunon-0 and Doxorubicin Induces Apoptosis and Cell Cycle Arrest and Inhibits Metastasis in Breast Cancer Cells.

    PubMed

    Putri, Herwandhani; Jenie, Riris Istighfari; Handayani, Sri; Kastian, Ria Fajarwati; Meiyanto, Edy

    2016-01-01

    A salt compound of a curcumin analogue, potassium pentagamavunon-0 (K PGV-0) has been synthesized to improve solubility of pentagamavunon-0 which has been proven to have anti-proliferative effects on several cancer cells. The purpose of this study was to investigate cytotoxic activity and metastasis inhibition by K PGV- 0 alone and in combination with achemotherapeutic agent, doxorubicin (dox), in breast cancer cells. Based on MTT assay analysis, K PGV-0 showed cytotoxic activity in T47D and 4T1 cell lines with IC50 values of 94.9 μM and 49.0±0.2 μM, respectively. In general, K PGV-0+dox demonstrated synergistic effects and decreased cell viability up to 84.7% in T47D cells and 62.6% in 4T1 cells. Cell cycle modulation and apoptosis induction were examined by flow cytometry. K PGV-0 and K PGV-0+dox caused cell accumulation in G2/M phase and apoptosis induction. Regarding cancer metastasis, while K PGV-0 alone did not show any inhibition of 4T1 cell migration, K PGV-0+dox exerted inhibition. K PGV-0 and its combination with dox inhibited the activity of MMP-9 which has a pivotal role in extracellular matrix degradation. These results show that a combination of K PGV-0 and doxorubicin inhibits cancer cell growth through cell cycling, apoptosis induction, and inhibition of cell migration and MMP-9 activity. Therefore, K PGV-0 may have potential for development as a co-chemotherapeutic agent. PMID:27268651

  6. Invited article: inhibition of B cell functions: implications for neurology.

    PubMed

    Dalakas, Marinos C

    2008-06-01

    B cells are involved in the pathophysiology of many neurologic diseases, either in a causative or contributory role, via production of autoantibodies, cytokine secretion, or by acting as antigen-presenting cells leading to T cell activation. B cells are clonally expanded in various CNS disorders, such as multiple sclerosis (MS), paraneoplastic CNS disorders, or stiff-person syndrome, and are activated to produce pathogenic autoantibodies in demyelinating neuropathies and myasthenia. B cell activating factor (BAFF) and a proliferating inducing ligand (APRIL), key cytokines for B cell survival, are strongly unregulated in MS brain and in muscles of inflammatory myopathies. Modulation of B cell functions using a series of monoclonal antibodies against CD20+ B cells or the molecules that increase B cell survival, such as BAFF/APRIL and their receptors BAFF-R, TACI, and BCMA, provide a rational approach to the treatment of the aforementioned neurologic disorders. In controlled studies, rituximab, a B cell-depleting monoclonal antibody, has been encouraging in MS and paraproteinemic anti-MAG demyelinating neuropathy, exerting long-lasting remissions. In uncontrolled series, benefit has been reported in several disorders. B cell depletion is a well-tolerated therapeutic option currently explored in the treatment of several autoimmune neurologic disorders.

  7. The JAK2 inhibitor AZD1480 inhibits hepatitis A virus replication in Huh7 cells.

    PubMed

    Jiang, Xia; Kanda, Tatsuo; Nakamoto, Shingo; Saito, Kengo; Nakamura, Masato; Wu, Shuang; Haga, Yuki; Sasaki, Reina; Sakamoto, Naoya; Shirasawa, Hiroshi; Okamoto, Hiroaki; Yokosuka, Osamu

    2015-0