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1

Radiosensitization by fullerene-C60 dissolved in squalene on human malignant melanoma through lipid peroxidation and enhanced mitochondrial membrane potential  

NASA Astrophysics Data System (ADS)

We examined fullerene-C60 dissolved in squalene (C60/Sqe) for the ability to potentiate the radiosensitization under X-ray irradiation on human malignant melanoma HMV-II cells, which were treated with C60/Sqe and thereafter irradiated with X-ray. The cell proliferation for C60/Sqe was inhibited more markedly than for Sqe alone. Meanwhile, cell proliferation was almost unaltered for C60/squalane (Sqa) or Sqa, a hydrogenated form of Sqe, as compared to no-additive control. Thus radiosensitization of C60/Sqe is attributed to peroxidation of unsaturated bonds of squalene by X-ray-excited C60 in contrast to squalane. The fluorescence images of HMV-II cells stained with Rhodamine123, an indicator for mitochondrial membrane potential, were monitored for 6 h after X-ray irradiation. C60/Sqe obviously exhibited more augmented fluorescence intensity on perinuclear region of HMV-II cells than Sqe alone. TBARS assay showed that the lipid peroxidation level as malondialdehyde-equivalent increased by combination of C60/Sqe and X-ray dose-dependently on X-ray doses. C60/Sqe exhibited lipid peroxidation more markedly by 1.2-fold than Sqe alone. Thus the level of lipid peroxidation of squalene was sufficiently higher in C60/Sqe than in Sqe in the absence of C60 under X-ray irradiation, suggesting the combination of C60/Sqe and X-ray irradiation induced radiosensitization on HMV-II cells by peroxidation of absorbed Sqe in mitochondrial membrane via oxidative stress mediated by fullerene-C60.

Kato, Shinya; Kimura, Masatsugu; Miwa, Nobuhiko

2014-04-01

2

Book Review: Human Radiosensitivity  

SciTech Connect

This well written report reviews the evidence for variation in human sensitivity to ionizing radiation from epidemiological, clinical, animal, and experimental studies. The report also considers the mechanism(s) of radiation sensitivity and the ethical implications of current and potential knowledge that might be gained in the future. The report is concisely written, considers a large number of historical as well as recent studies, and features a ‘ bullet like ’ summary at the end of each chapter that captures the salient points.

Morgan, William F.

2013-11-01

3

Phase I\\/II Clinical Study of Pulsed Paclitaxel Radiosensitization for Thoracic Malignancy: A Therapeutic Approach on the Basis of Preclinical Research of Human Cancer Cell Lines1  

Microsoft Academic Search

Purpose: A Phase I\\/II clinical study using pulsed low- dose paclitaxel and radiation for thoracic malignancy was conducted. The study was based on preclinical research of the effects of paclitaxel on apoptosis and the cell cycle in human cancer cell lines. Experimental Design: Three human epithelial cancer cell lines were investigated for preclinical study. Cells were analyzed for apoptosis and

Yuhchyau Chen; Kishan Pandya; Peter C. Keng; David Johnstone; Jigang Li; Yi-Jang Lee; Therese Smudzin; Paul Okunieff

2003-01-01

4

Intra-arterial bromodeoxyuridine radiosensitization of malignant gliomas  

SciTech Connect

In the 1950's it was first observed that mammalian cells exposed to the halogenated deoxyuridines were more sensitive to ultraviolet light and radiation than untreated cells. This prompted early clinical trials with bromodeoxyuridine (BUdR) which showed mixed results. More recently, several Phase I studies, while establishing the feasibility of continuous intravenous (IV) infusion of BUdR, have reported significant dose limiting skin and bone marrow toxicities and have questioned the optimal method of BUdR delivery. To exploit the high mitotic activity of malignant gliomas relative to surrounding normal brain tissue, we have developed a permanently implantable infusion pump system for safe, continuous intraarterial (IA) internal carotid BUdR delivery. Since July 1985, 23 patients with malignant brain tumors (18 grade 4, 5 grade 3) have been treated in a Phase I clinical trial using IA BUdR (400-600 mg/m2/day X 8 1/2 weeks) and focal external beam radiotherapy (59.4 Gy at 1.8 Gy/day in 6 1/2 weeks). Following initial biopsy/surgery the infusion pump system was implanted; BUdR infusion began 2 weeks prior to and continued throughout the 6 1/2 week course of radiotherapy. There have been no vascular complications. Side-effects in all patients have included varying degrees of anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, and conjunctivitis. Myelosuppression requiring dose reduction occurred in one patient. An overall Kaplan-Meier estimated median survival of 20 months has been achieved. As in larger controlled series, histologic grade and age are prognostically significant. We have shown in a Phase I study that IA BUdR radiosensitization is safe, tolerable, may lead to improved survival, and appears to be an efficacious primary treatment of malignant gliomas.

Hegarty, T.J.; Thornton, A.F.; Diaz, R.F.; Chandler, W.F.; Ensminger, W.D.; Junck, L.; Page, M.A.; Gebarski, S.S.; Hood, T.W.; Stetson, P.L. (Univ. of Michigan Medical Center, Ann Arbor (USA))

1990-08-01

5

SU11657 Enhances Radiosensitivity of Human Meningioma Cells  

SciTech Connect

Purpose: To analyze the effect of the multireceptor tyrosine kinase inhibitor SU11657 (primarily vascular endothelial growth factor, platelet-derived growth factor) in combination with irradiation in freshly isolated primary human meningioma cells. Methods and Materials: Tumor specimens were obtained from meningioma patients undergoing surgery at the Department of Neurosurgery, University of Heidelberg, Germany. For the present study only cells up to passage 6 were used. Benign and atypical meningioma cells and human umbilical vein endothelial cells (HUVEC) were treated with SU11657 alone and in combination with 6-MV photons (0-10 Gy). Clonogenic survival and cell proliferation were determined alone and in coculture assays to determine direct and paracrine effects. Results: Radiation and SU11657 alone reduced cell proliferation in atypical and benign meningioma cells as well as in HUVEC in a dose-dependent manner. SU11657 alone also reduced clonogenic survival of benign and atypical meningioma cells. SU11657 increased radiosensitivity of human meningioma cells in clonogenic survival and cell number/proliferation assays. The anticlonogenic and antiproliferative effects alone and the radiosensitization effects of SU11657 were more pronounced in atypical meningioma cells compared with benign meningioma cells. Conclusion: Small-molecule tyrosine kinase inhibitors like SU11657 are capable of amplifying the growth inhibitory effects of irradiation in meningioma cells. These data provide a rationale for further clinical evaluation of this combination concept, especially in atypical and malignant meningioma patients.

Milker-Zabel, Stefanie [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany)], E-mail: stefanie_milker-zabel@med.uni-heidelberg.de; Bois, Angelika Zabel-du [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany); Ranai, Gholamreza [Department of Neurosurgery, University of Heidelberg, Heidelberg (Germany); Trinh, Thuy [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany); Department of Radiation Oncology, German Cancer Research Center, Heidelberg (Germany); Unterberg, Andreas [Department of Neurosurgery, University of Heidelberg, Heidelberg (Germany); Debus, Juergen [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany); Lipson, Kenneth E. [3M Pharmaceuticals, St. Paul, MN (United States); Abdollahi, Amir; Huber, Peter E. [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany); Department of Radiation Oncology, German Cancer Research Center, Heidelberg (Germany)

2008-03-15

6

Suppression of autophagy augments the radiosensitizing effects of STAT3 inhibition on human glioma cells.  

PubMed

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. PMID:25220423

Yuan, Xiaopeng; Du, Jie; Hua, Song; Zhang, Haowen; Gu, Cheng; Wang, Jie; Yang, Lei; Huang, Jianfeng; Yu, Jiahua; Liu, Fenju

2015-01-15

7

Hyaluronan in human malignancies  

SciTech Connect

Hyaluronan, a major macropolysaccharide in the extracellular matrix of connective tissues, is intimately involved in the biology of cancer. Hyaluronan accumulates into the stroma of various human tumors and modulates intracellular signaling pathways, cell proliferation, motility and invasive properties of malignant cells. Experimental and clinicopathological evidence highlights the importance of hyaluronan in tumor growth and metastasis. A high stromal hyaluronan content is associated with poorly differentiated tumors and aggressive clinical behavior in human adenocarcinomas. Instead, the squamous cell carcinomas and malignant melanomas tend to have a reduced hyaluronan content. In addition to the stroma-cancer cell interaction, hyaluronan can influence stromal cell recruitment, tumor angiogenesis and epithelial-mesenchymal transition. Hyaluronan receptors, hyaluronan synthases and hyaluronan degrading enzymes, hyaluronidases, are involved in the modulation of cancer progression, depending on the tumor type. Furthermore, intracellular signaling and angiogenesis are affected by the degradation products of hyaluronan. Hyaluronan has also therapeutic implications since it is involved in multidrug resistance.

Sironen, R.K. [Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland) [Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland); Department of Pathology, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio (Finland); Tammi, M.; Tammi, R. [Institute of Biomedicine, Anatomy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland)] [Institute of Biomedicine, Anatomy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland); Auvinen, P.K. [Department of Oncology, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio (Finland)] [Department of Oncology, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio (Finland); Anttila, M. [Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland) [Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland); Department of Gynecology and Obstetrics, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio (Finland); Kosma, V-M., E-mail: Veli-Matti.Kosma@uef.fi [Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland); Department of Pathology, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio (Finland)

2011-02-15

8

Radiosensitization of human bronchogenic carcinoma cells by interferon beta  

SciTech Connect

The effects of interferons on the radiosensitivity of in vitro human bronchogenic carcinoma cells was investigated. Human fibroblast-derived interferon (IFN-beta) was found to sensitize cells to gamma irradiation while either HuIFN-alpha or mouse IFN-alpha/beta did not. The observed radiosensitization was supra-additive and resulted in a decrease in the shoulder width of the radiation dose-cell survival curve but did not affect the slope. The degree of radiosensitization of the various IFNs tested paralleled the antiproliferative effects of these IFNs on this cell line.

Gould, M.N.; Kakria, R.C.; Olson, S.; Borden, E.C.

1984-01-01

9

2-Deoxy-D-glucose and 6-aminonicotinamide-mediated Nrf2 down regulation leads to radiosensitization of malignant cells via abrogation of GSH-mediated defense.  

PubMed

Enhanced level of nuclear erythroid-related factor-2 (Nrf2) has been associated with cancer chemo/radioresistance. Therefore, the role of Nrf2 in radiosensitization of malignant cells induced by a combination of 2-deoxy-D-Glucose (2-DG) and 6-aminonicotinamide (6-AN) was investigated. Two established human malignant cells lines namely KB (head and neck squamous carcinoma) and BMG-1 (cerebral glioma) were used. Following treatment with a combination of 2-DG (5 mM) and 6-AN (5 ?M), irradiated (2Gy) KB and BMG-1 cells were assessed for protein level of Nrf2, Keap1 and ?-glutamylcysteine synthetase (?-GCS) by western blotting and mRNA expression of ?-GCS, glutathione reductase (GR) and glutathione peroxidase (GPx1) by RT-PCR at 24 hours post treatment. A significant decrease in the level of Nrf2 with a concomitant increase in Keap1 was observed in both the irradiated malignant cells at 24 hours following treatment with combination (2-DG + 6-AN). Down regulation of ?-GCS, GR and GPx1 at 24 hours following treatment with combination (2-DG + 6-AN) resulted in abrogation of glutathione (GSH)-mediated defense in both the irradiated malignant cells. Eventual accumulation of ROS led to radiosensitization of both the malignant cells. These results indicate that deregulated Nrf2-Keap1 signalling leads to the radiosensitization of malignant cells due to abrogated glutathione defense. Metabolic modification-mediated down regulation of Nfr2 and its downstream signalling may have a potential of improving tumour radiotherapy. PMID:22946929

Sharma, Pradeep Kumar; Varshney, Rajeev

2012-12-01

10

Hypothermia-Enhanced Human Tumor Cell Radiosensitivity  

Microsoft Academic Search

Ablation of neoplastic disease by freezing has found increasing utility as a potential therapeutic modality. To assess the effect of cooling temperatures on cellular radiation response, an established human cervical carcinoma cell line (HTB35) was subjected to holding temperatures of 0, 5, or 15°C for up to 24 h before irradiation. Survival was measured byin vitroclonogenic assay of colonies containing

Steven A. Burton; William R. Paljug; Shalom Kalnicki; E. Day Werts

1997-01-01

11

Inhibition of Rho pathways induces radiosensitization and oxygenation in human glioblastoma xenografts  

Microsoft Academic Search

We previously demonstrated in vitro that inhibiting the biological pathways of the small GTPase Rho radiosensitizes the human glioma U87 cell line. The aim of this study was to determine if Rho might be involved in the control of in vivo radiosensitivity altogether by controlling cellular radioresistance and by modifying tumor microenvironment. We demonstrate here that the in vivo induction

Isabelle Ader; Caroline Delmas; Jacques Bonnet; Philippe Rochaix; Gilles Favre; Christine Toulas; Elizabeth Cohen-Jonathan-Moyal; El Cohen-Jonathan

2003-01-01

12

Radiosensitivity of human haematopoietic stem/progenitor cells.  

PubMed

The haematopoietic system is regenerative tissue with a high proliferative potential; therefore, haematopoietic stem cells (HSCs) are sensitive to extracellular oxidative stress caused by radiation and chemotherapeutic agents. An understanding of this issue can help predict haematopoietic recovery from radiation exposure as well as the extent of radiation damage to the haematopoietic system. In the present study, the radiosensitivity of human lineage-committed myeloid haematopoietic stem/progenitor cells (HSPCs), including colony-forming unit-granulocyte macrophage, burst-forming unit-erythroid and colony-forming unit-granulocyte-erythroid-macrophage-megakaryocyte cells, which are contained in adult individual peripheral blood (PB) and fetus/neonate placental/umbilical cord blood (CB), were studied. The PB of 59 healthy individual blood donors and the CB of 42 neonates were investigated in the present study. HSPCs prepared from PB and CB were exposed to 0.5 or 2 Gy x-irradiation. The results showed that large individual differences exist in the surviving fraction of cells. In the case of adult PB, a statistically significant negative correlation was observed between the surviving fraction observed at a dose of 0.5 Gy and the age of the blood donors; however, none of these correlations were observed after 2 Gy x-irradiation. In addition, seasonal and gender variation were observed in the surviving fraction of CB HSPCs. The present results suggest that there are large individual differences in the surviving fraction of HSPCs contained in both adult PB and fetus/neonate CB. In addition, some factors, including the gender, age and season of birth, affect the radiosensitivity of HSPCs, especially with a relatively low-dose exposure. PMID:23295782

Kato, Kengo; Omori, Atsuko; Kashiwakura, Ikuo

2013-03-01

13

Selective radiosensitization and cytotoxicity of human melanoma cells using halogenated deoxycytidines and tetrahydrouridine  

SciTech Connect

The halogenated pyrimidines 5-chloro-2'-deoxycytidine (CldCyd) and 5-bromo-2'-deoxycytidine (BrdCyd) can act as radiosensitizers and cytotoxic agents. It was hypothesized that tumor cells and normal cells might use different metabolic pathways to incorporate these halogenated deoxycytidines into DNA. This difference could potentially be exploited to produce selective radiosensitization and cytotoxicity of human tumor cells compared to normal human fibroblasts. This hypothesis was tested using two human melanoma cell lines and two normal fibroblast cell lines. Either CldCyd or BrdCyd alone caused both cytotoxicity and radiosensitization of tumor and normal cells. The addition of the cytidine deaminase inhibitor tetrahydrouridine (H4U) significantly protected the normal cells but had relatively little effect on the tumor cells. These data indicate that it may be possible to exploit differences between the pyrimidine metabolism of normal cells and melanoma cells to improve the therapeutic index of halogenated pyrimidines both as radiosensitizers and as cytotoxic agents.

Lawrence, T.S.; Davis, M.A.

1989-05-01

14

Association between cellular radiosensitivity and G1/G2 checkpoint proficiencies in human cholangiocarcinoma cell lines.  

PubMed

Cholangiocarcinoma is a destructive malignancy with a poor prognosis and lack of effective medical treatment. Radiotherapy is an alternative treatment for patients with unresectable cholangiocarcinoma. However, there are limited data on the radiation responsiveness of individual cholangiocarcinoma cells, which is a key factor that influences radiation treatment outcome. In this study, we found that cholangiocarcinoma cell lines differ remarkably in their radiosensitivity. The variation of radiosensitivity of cholangiocarcinoma cells correlates with their p53 status and existing G1 and/or G2 checkpoint defects. We also demonstrated the potential of checkpoint kinase Chk1/2 inhibition on the enhancement of the radiosensitivity of cholangiocarcinoma cells. Thus, this study provides useful information for predicting radiation response and provides evidence for the enchantment of radiotherapeutic efficiency by targeting checkpoint kinase Chk1/2 in some subpopulations of cholangiocarcinoma patients. PMID:24969815

Hematulin, Arunee; Sagan, Daniel; Sawanyawisuth, Kanlayanee; Seubwai, Wunchana; Wongkham, Sopit

2014-09-01

15

Siah1 proteins enhance radiosensitivity of human breast cancer cells  

PubMed Central

Background Siah proteins play an important role in cancer progression. We evaluated the effect of Siah1, its splice variants Siah1L and the Siah1 mutant with the RING finger deleted (Siah1?R) on radiosensitization of human breast cancer cells. Methods The status of Siah1 and Siah1L was analysed in five breast cancer cell lines. To establish stable cells, SKBR3 cells were transfected with Siah1, Siah-1L and Siah1?R. Siah1 function was suppressed by siRNA in MCF-7 cells. The impact of Siah1 overexpression and silencing on apoptosis, proliferation, survival, invasion ability and DNA repair was assessed in SKBR3 and MCF-7 cells, also in regards to radiation. Results Siah1 and Siah1L mRNA expression was absent in four of five breast cancer cells lines analysed. Overexpression of Siah1 and Siah1L enhanced radiation-induced apoptosis in stable transfected SKBR3 cells, while Siah1?R failed to show this effect. In addition, Siah1 and Siah1L significantly reduced cell clonogenic survival and proliferation. Siah1L sensitization enhancement ratio values were over 1.5 and 4.0 for clonogenic survival and proliferation, respectively, pointing to a highly cooperative and potentially synergistic fashion with radiation. Siah1 or Siah1L significantly reduced invasion ability of SKBR3 and suppressed Tcf/Lef factor activity. Importantly, Siah1 siRNA demonstrated opposite effects in MCF-7 cells. Siah1 and Siah1L overexpression resulted in inhibition of DNA repair as inferred by increased levels of DNA double-strand breaks in irradiated SKBR3 cells. Conclusion Our results reveal for the first time how overexpression of Siah1L and Siah1 can determine radiosensitivity of breast cancer cells. These findings suggest that development of drugs augmenting Siah1 and Siah1L activity could be a novel approach in improving tumor cell kill. PMID:20682032

2010-01-01

16

Fulvestrant radiosensitizes human estrogen receptor-positive breast cancer cells  

SciTech Connect

Highlights: ? Fulvestrant radiosensitizes MCF-7 cells. ? Fulvestrant increases G1 arrest and decreases S phase in MCF-7 cells. ? Fulvestrant down-regulates DNA-PKcs and RAD51 in MCF-7 cells. -- Abstract: The optimal sequencing for hormonal therapy and radiation are yet to be determined. We utilized fulvestrant, which is showing promise as an alternative to other agents in the clinical setting of hormonal therapy, to assess the cellular effects of concomitant anti-estrogen therapy (fulvestrant) with radiation (F + RT). This study was conducted to assess the effects of fulvestrant alone vs. F + RT on hormone-receptor positive breast cancer to determine if any positive or negative combined effects exist. The effects of F + RT on human breast cancer cells were assessed using MCF-7 clonogenic and tetrazolium salt colorimetric (MTT) assays. The assays were irradiated with a dose of 0, 2, 4, 6 Gy ± fulvestrant. The effects of F + RT vs. single adjuvant treatment alone on cell-cycle distribution were assessed using flow cytometry; relative expression of repair proteins (Ku70, Ku80, DNA-PKcs, Rad51) was assessed using Western Blot analysis. Cell growth for radiation alone vs. F + RT was 0.885 ± 0.013 vs. 0.622 ± 0.029 @2 Gy, 0.599 ± 0.045 vs. 0.475 ± 0.054 @4 Gy, and 0.472 ± 0.021 vs. 0.380 ± 0.018 @6 Gy RT (p = 0.003). While irradiation alone induced G2/M cell cycle arrest, the combination of F + RT induced cell redistribution in the G1 phase and produced a significant decrease in the proportion of cells in G2 phase arrest and in the S phase in breast cancer cells (p < 0.01). Furthermore, levels of repair proteins DNA-PKcs and Rad51 were significantly decreased in the cells treated with F + RT compared with irradiation alone. F + RT leads to a decrease in the surviving fraction, increased cell cycle arrest, down regulating of nonhomologous repair protein DNA-PKcs and homologous recombination repair protein RAD51. Thus, our findings suggest that F + RT increases breast cancer cell radiosensitivity compared with radiation alone. These findings have salient implications for designing clinical trials using fulvestrant and radiation therapy.

Wang, Jing, E-mail: wangstella5@163.com [Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province (China) [Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province (China); Department of Oncology, Affiliated Hospital of Qingdao University Medical College, Shandong Province (China); Yang, Qifeng, E-mail: qifengy@gmail.com [Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province (China)] [Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province (China); Haffty, Bruce G., E-mail: hafftybg@umdnj.edu [Department of Radiation Oncology, UMDNJ-Robert Wood Johnson School of Medicine, Cancer Institute of New Jersey, NB (United States); Li, Xiaoyan, E-mail: xiaoyanli1219@gmail.com [Department of Oncology, Affiliated Hospital of Qingdao University Medical College, Shandong Province (China)] [Department of Oncology, Affiliated Hospital of Qingdao University Medical College, Shandong Province (China); Moran, Meena S., E-mail: meena.moran@yale.edu [Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT (United States)

2013-02-08

17

Expression of Cellular Oncogenes in Human Malignancies  

NASA Astrophysics Data System (ADS)

Cellular oncogenes have been implicated in the induction of malignant transformation in some model systems in vitro and may be related to malignancies in vivo in some vertebrate species. This article describes a study of the expression of 15 cellular oncogenes in fresh human tumors from 54 patients, representing 20 different tumor types. More than one cellular oncogene was transcriptionally active in all of the tumors examined. In 14 patients it was possible to study normal and malignant tissue from the same organ. In many of these patients, the transcriptional activity of certain oncogenes was greater in the malignant than the normal tissue. The cellular fes (feline sarcoma) oncogene, not previously known to be transcribed in mammalian tissue, was found to be active in lung and hematopoietic malignancies.

Slamon, Dennis J.; Dekernion, Jean B.; Verma, Inder M.; Cline, Martin J.

1984-04-01

18

A combination of 2-deoxy-D-glucose and 6-aminonicotinamide induces oxidative stress mediated selective radiosensitization of malignant cells via mitochondrial dysfunction.  

PubMed

Oxidative stress-mediated mitochondrial dysfunction is known to induce intrinsic pathway of apoptosis. Previously, we have shown that a combination of metabolic modifiers 2-deoxy-D-glucose (2-DG) and 6-aminonicotinamide (6-AN) results in oxidative stress-mediated radiosensitization of malignant cells via noncoordinated expression of antioxidant defense. We now show that the combination (2-DG?+?6-AN?+?2Gy) induces significant alterations in mitochondrial membrane potential and oxidative damage to lipid and proteins selectively in malignant cells resulting in the release of cytochrome c from mitochondria and increase in Bax/Bcl-2 ratio stimulating intrinsic pathway of apoptosis, besides enhancing the mitotic death linked to cytogenetic damage. These results highlight the role of mitochondrial dysfunction in selective radiosensitization by 2-DG?+?6-AN, besides inhibition of energy-linked DNA repair processes and generation of oxidative stress reported earlier. PMID:21660566

Bhardwaj, Richa; Sharma, Pradeep Kumar; Jadon, Suryaprakash Singh; Varshney, Rajeev

2011-10-01

19

Minimally cytotoxic doses of temozolomide produce radiosensitization in human glioblastoma cells regardless of MGMT expression1  

PubMed Central

Concurrent treatment with the methylating agent temozolomide (TMZ) during radiotherapy (RT) has yielded the first significant improvement in survival of adult glioblastomas (GBMs) in the last three decades. However, improved survival is observed in a minority of patients, most frequently those whose tumors display CpG methylation of the MGMT (O6-methylguanine-DNA methyltransferase) promoter, and adult GBMs remain invariably fatal. Some, though not all, pre-clinical studies have shown that TMZ can increase radiosensitivity in GBM cells that lack MGMT, the sole activity in human cells that removes O6-meG from DNA. Here, we systematically examined the TMZ dose dependence of radiation killing in established GBM cell lines that differ in ability to remove O6-meG or tolerate its lethality. Our results show that minimally cytotoxic doses of TMZ can produce dose-dependent radiosensitization in MGMT-deficient cells, MGMT-proficient cells, and MGMT-deficient cells that lack mismatch repair, a process that renders cells tolerant of the lethality of O6-meG. In cells that either possess or lack MGMT activity, radiosensitization requires exposure to TMZ before but not after radiation, and is accompanied by formation of double-strand breaks within 45 min of radiation. Moreover, suppressing alkyladenine-DNA glycosylase, the only activity in human cells that excises 3-meA from DNA, reduces the TMZ dose dependence of radiosensitization, indicating that radiosensitization is mediated by 3-meA as well as by O6-meG. These results provide novel information on which to base further mechanistic study of radiosensitization by TMZ in human GBM cells, and to develop strategies to improve the outcome of concurrent TMZ-RT. PMID:20457618

Bobola, Michael S.; Kolstoe, Douglas D.; Blank, A.; Silber, John R.

2010-01-01

20

Malignant syphilis with human immunodeficiency virus infection  

PubMed Central

Malignant syphilis or Lues maligna, commonly reported in the pre-antibiotic era, has now seen a resurgence with the advent of human immunodeficiency virus (HIV). Immunosuppression and sexual promiscuity set the stage for this deadly association of HIV and Treponema pallidum that can manifest atypically and can prove to cause diagnostic problems. We report one such case in a 30-year-old female who responded favorably to treatment with penicillin. PMID:23130209

Rajan, Jiby; Prasad, P. V. S.; Chockalingam, K.; Kaviarasan, P. K.

2011-01-01

21

Overview of Radiosensitivity of Human Tumor Cells to Low-Dose-Rate Irradiation  

SciTech Connect

Purpose: We compared clonogenic survival in 27 human tumor cell lines that vary in genotype after low-dose-rate (LDR) or high-dose rate (HDR) irradiation. We measured susceptibility to LDR-induced redistribution in the cell cycle in eight of these cell lines. Methods and Materials: We measured clonogenic survival after up to 96 hours of LDR (0.25 Gy/h) irradiation. We compared these with clonogenic survival after HDR irradiation (50 Gy/h). Using flow cytometry, we measured LDR-induced redistribution as a function of time during LDR irradiation in eight of these cell lines. Results: Coefficients that describe clonogenic survival after both LDR and HDR irradiation segregate into four radiosensitivity groups that associate with cell genotype: mutant (mut)ATM, wild-type TP53, mutTP53, and an unidentified gene in radioresistant glioma cells. The LDR and HDR radiosensitivity correlates at lower doses ({approx}2 Gy HDR, {approx}6 Gy LDR), but not at higher doses (HDR > 4 Gy; LDR > 6 Gy). The rate of LDR-induced loss of clonogenic survival changes at approximately 24 hours; wild-type TP53 cells become more resistant and mutTP53 cells become more sensitive. Redistribution induced by LDR irradiation also changes at approximately 24 hours. Conclusions: Radiosensitivity of human tumor cells to both LDR and HDR irradiation is genotype dependent. Analysis of coefficients that describe cellular radiosensitivity segregates 27 cell lines into four statistically distinct groups, each associating with specific genotypes. Changes in cellular radiosensitivity and redistribution in the cell cycle are strongly time dependent. Our data establish a genotype-dependent time-dependent model that predicts clonogenic survival, explains the inverse dose-rate effect, and suggests possible clinical applications.

Williams, Jerry R. [Molecular Radiation Biology Program, Department of Radiation Medicine, Loma Linda Medical Center, Loma Linda, CA (United States); Laboratory of Radiobiology, Johns Hopkins School of Medicine, Baltimore, MD (United States)], E-mail: jrwilliams_france@yahoo.com; Zhang Yonggang; Zhou Haoming [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD (United States); Gridley, Daila S. [Molecular Radiation Biology Program, Department of Radiation Medicine, Loma Linda Medical Center, Loma Linda, CA (United States); Koch, Cameron J. [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA (United States); Slater, James M. [Molecular Radiation Biology Program, Department of Radiation Medicine, Loma Linda Medical Center, Loma Linda, CA (United States); Little, John B. [Center for Radiation Sciences and Environmental Health, Harvard School of Public Health, Boston, MA (United States)

2008-11-01

22

MicroRNA-218 enhances the radiosensitivity of human cervical cancer via promoting radiation induced apoptosis.  

PubMed

We previously reported frequent loss of microRNA-218 (miR-218) in cervical cancer, which was associated with tumor progression and poor prognosis. As microRNAs were found invovled in the regulation of radiosensitivity in various human cancers, we therefore aim to investigate the effects of miR-218 on radiosensitivity of cervical cancer in the present study. The clonogenic survival assay demonstrated that loss of miR-218 could predict radioresistance in the primary cervical cancer cells (R(2)=0.6516, P<0.001). In vitro, abundant miR-218 increased the radiosensitivity in cervical cancer cells (P<0.001 for HeLa, P=0.009 for SiHa, P=0.016 for C33A and P=0.01 for CaSki). Upregulation of miR-218 significantly enhanced the radiation-induced apoptosis, which was further enhanced by the combination of miR-218 overexpression and radiation In xenograft growth assay, combination of miR-218 overexpression and radiation notably induced cellular apoptosis and suppressed tumor growth. In conclusion, we demonstrated that miR-218 resensitized cervical cancer cells to radiation via promoting cellular apoptosis. Moreover, we proved that miR-218 as a potent predictor of radiosensitivity in cervical cancer, especially for those patients with loss of miR-218. PMID:24843318

Yuan, Wang; Xiaoyun, Han; Haifeng, Qiu; Jing, Li; Weixu, Hu; Ruofan, Dong; Jinjin, Yu; Zongji, Shen

2014-01-01

23

MicroRNA-218 Enhances the Radiosensitivity of Human Cervical Cancer via Promoting Radiation Induced Apoptosis  

PubMed Central

We previously reported frequent loss of microRNA-218 (miR-218) in cervical cancer, which was associated with tumor progression and poor prognosis. As microRNAs were found invovled in the regulation of radiosensitivity in various human cancers, we therefore aim to investigate the effects of miR-218 on radiosensitivity of cervical cancer in the present study. The clonogenic survival assay demonstrated that loss of miR-218 could predict radioresistance in the primary cervical cancer cells (R2=0.6516, P<0.001). In vitro, abundant miR-218 increased the radiosensitivity in cervical cancer cells (P<0.001 for HeLa, P=0.009 for SiHa, P=0.016 for C33A and P=0.01 for CaSki). Upregulation of miR-218 significantly enhanced the radiation-induced apoptosis, which was further enhanced by the combination of miR-218 overexpression and radiation In xenograft growth assay, combination of miR-218 overexpression and radiation notably induced cellular apoptosis and suppressed tumor growth. In conclusion, we demonstrated that miR-218 resensitized cervical cancer cells to radiation via promoting cellular apoptosis. Moreover, we proved that miR-218 as a potent predictor of radiosensitivity in cervical cancer, especially for those patients with loss of miR-218. PMID:24843318

Yuan, Wang; Xiaoyun, Han; Haifeng, Qiu; Jing, Li; Weixu, Hu; Ruofan, Dong; Jinjin, Yu; Zongji, Shen

2014-01-01

24

Therapeutic and Radiosensitizing Effects of Armillaridin on Human Esophageal Cancer Cells  

PubMed Central

Background. Armillaridin (AM) is isolated from Armillaria mellea. We examined the anticancer activity and radiosensitizing effect on human esophageal cancer cells. Methods. Human squamous cell carcinoma (CE81T/VGH and TE-2) and adenocarcinoma (BE-3 and SKGT-4) cell lines were cultured. The MTT assay was used for cell viability. The cell cycle was analyzed using propidium iodide staining. Mitochondrial transmembrane potential was measured by DiOC6(3) staining. The colony formation assay was performed for estimation of the radiation surviving fraction. Human CE81T/VGH xenografts were established for evaluation of therapeutic activity in vivo. Results. AM inhibited the viability of four human esophageal cancer cell lines with an estimated concentration of 50% inhibition (IC50) which was 3.4–6.9??M. AM induced a hypoploid cell population and morphological alterations typical of apoptosis in cells. This apoptosis induction was accompanied by a reduction of mitochondrial transmembrane potential. AM accumulated cell cycle at G2/M phase and enhanced the radiosensitivity in CE81T/VGH cells. In vivo, AM inhibited the growth of CE81T/VGH xenografts without significant impact on body weight and white blood cell counts. Conclusion. Armillaridin could inhibit growth and enhance radiosensitivity of human esophageal cancer cells. There might be potential to integrate AM with radiotherapy for esophageal cancer treatment. PMID:23864890

Chi, Chih-Wen; Chen, Chien-Chih; Chen, Yu-Jen

2013-01-01

25

DNMT (DNA methyltransferase) inhibitors radiosensitize human cancer cells by suppressing DNA repair activity  

PubMed Central

Background Histone modifications and DNA methylation are two major factors in epigenetic phenomenon. Unlike the histone deacetylase inhibitors, which are known to exert radiosensitizing effects, there have only been a few studies thus far concerning the role of DNA methyltransferase (DNMT) inhibitors as radiosensitizers. The principal objective of this study was to evaluate the effects of DNMT inhibitors on the radiosensitivity of human cancer cell lines, and to elucidate the mechanisms relevant to that process. Methods A549 (lung cancer) and U373MG (glioblastoma) cells were exposed to radiation with or without six DNMT inhibitors (5-azacytidine, 5-aza-2'-deoxycytidine, zebularine, hydralazine, epigallocatechin gallate, and psammaplin A) for 18 hours prior to radiation, after which cell survival was evaluated via clonogenic assays. Cell cycle and apoptosis were analyzed via flow cytometry. Expressions of DNMT1, 3A/3B, and cleaved caspase-3 were detected via Western blotting. Expression of ?H2AX, a marker of radiation-induced DNA double-strand break, was examined by immunocytochemistry. Results Pretreatment with psammaplin A, 5-aza-2'-deoxycytidine, and zebularine radiosensitized both A549 and U373MG cells. Pretreatment with psammaplin A increased the sub-G1 fraction of A549 cells, as compared to cells exposed to radiation alone. Prolongation of ?H2AX expression was observed in the cells treated with DNMT inhibitors prior to radiation as compared with those treated by radiation alone. Conclusions Psammaplin A, 5-aza-2'-deoxycytidine, and zebularine induce radiosensitivity in both A549 and U373MG cell lines, and suggest that this effect might be associated with the inhibition of DNA repair. PMID:22429326

2012-01-01

26

The radiosensitizing effect of CpG ODN107 on human glioma cells is tightly related to its antiangiogenic activity via suppression of HIF-1?/VEGF pathway.  

PubMed

Malignant glioma displays invasive growth and is difficult to be completely excised; surgery combined with subsequent radiotherapy is a standard treatment for patients. CpG oligodeoxynucleotides (CpG ODN) can enhance radiotherapeutic effect in some tumors. Angiogenesis is crucial for tumor progression and metastasis. Anti-angiogenic strategy thus may be effective for tumor treatment. Herein, the antiangiogenic activity and radiosensitizing effect of CpG ODN107 on glioma were investigated. Our results showed that the growth of glioma cell line U87 was significantly inhibited by CpG ODN107 (10?g/ml) in combination with irradiation (5Gy) in vitro. In orthotopic implantation model of nude mice, the survival rate of mice significantly increased after treatment with CpG ODN107 (0.083mg/kg) in combination with radiotherapy (10Gy) as compared with treatment with local radiotherapy alone. CpG ODN107 in combination with radiotherapy significantly decreased microvessel density (MVD), VEGF level and HIF-1? expression in orthotopic implantation glioma. In conclusion, CpG ODN107 significantly increased the radiosensitivity of U87 human glioma cells in vitro and in vivo. The radiosensitizing effect of CpG ODN 107 is tightly related to its anti-angiogenic activity via suppression of HIF-1?/VEGF pathway. PMID:23791618

Liu, Dan; Cao, Guanqun; Cen, Yanyan; Liu, Tao; Peng, Wei; Sun, Jianguo; Li, Xiaoli; Zhou, Hong

2013-10-01

27

5-Iodo-2-Pyrimidinone-2?Deoxyribose–Mediated Cytotoxicity and Radiosensitization in U87 Human Glioblastoma Xenografts  

Microsoft Academic Search

Purpose: 5-Iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is a novel orally administered (p.o.) prodrug of 5-iododeoxyuridine. Because p.o. IPdR is being considered for clinical testing as a radiosensitizer in patients with high-grade gliomas, we performed this in vivo study of IPdR-mediated cytotoxicity and radiosensitization in a human glioblastoma xenograft model, U87. Methods and Materials: Groups of 8 or 9 athymic male nude mice (6-8

Timothy J. Kinsella; Michael T. Kinsella; Yuji Seo; Gregory Berk

2007-01-01

28

Lin28-let7 Modulates Radiosensitivity of Human Cancer Cells With Activation of K-Ras  

SciTech Connect

Purpose: To evaluate the potential of targeting Lin28-let7 microRNA regulatory network for overcoming the radioresistance of cancer cells having activated K-Ras signaling. Methods and Materials: A549 lung carcinoma cells and ASPC1 pancreatic cancer cells possessing K-RAS mutation were transfected with pre-let7a microRNA or Lin28 siRNA, respectively. Clonogenic assay, quantitative reverse transcription polymerase chain reaction, and Western analysis were performed. The effects of Lin28 on SQ20B cells having wild-type K-RAS, and a normal fibroblast were also assessed. Results: The overexpression of let-7a decreased expression of K-Ras and radiosensitized A549 cells. Inhibition of Lin28, a repressor of let-7, attenuated K-Ras expression and radiosensitized A549 and ASPC1 cells. Neither SQ20B cells expressing wild-type K-RAS nor HDF, the normal human fibroblasts, were radiosensitized by this approach. Conclusions: The Lin28-let7 regulatory network may be a potentially useful therapeutic target for overcoming the radioresistance of human cancers having activated K-Ras signaling.

Oh, Jee-Sun.; Kim, Jae-Jin; Byun, Ju-Yeon [Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnamsi (Korea, Republic of); Kim, In-Ah, E-mail: inah228@snu.ac.k [Department of Radiation Oncology, Cancer Research Institute, Seoul National University, Seoul (Korea, Republic of)

2010-01-15

29

Molecularly Targeted Radiosensitization of Human Prostate Cancer by Modulating Inhibitor of Apoptosis  

PubMed Central

Purpose The inhibitor of apoptosis proteins (IAPs) are overexpressed in hormone-refractory prostate cancer, rendering the cancer cells resistant to radiation. This study aims to investigate the radiosensitizing effect of small molecule IAP-inhibitor both in vitro and in vivo in androgen-independent prostate cancer, and the possible mechanism of radiosensitization. Experimental Design Radiosensitization of SH-130 in human prostate cancer DU-145 cells was determined by clonogenic survival assay. Combination effect of SH-130 and ionizing radiation was evaluated by apoptosis assays. Pull-down and immunoprecipitation assay were employed to investigate the interaction between SH-130 and IAPs. DU-145 xenografts in nude mice were treated with SH-130, radiation or in combination, and tumor suppression effect was determined by caliper measurement or bioluminescence imaging. NF-?B activation was detected by luciferase reporter assay and quantitative real-time PCR. Results SH-130 potently enhanced radiation-induced caspase activation and apoptosis in DU-145 cells. Both XIAP and cIAP-1 can be pulled down by SH-130, but not inactive SH-123. Moreover, SH-130 interrupted interaction between XIAP/cIAP-1 and Smac. In a nude mouse xenograft model, SH-130 potently sensitized the DU-145 tumors to X-ray radiation without increasing systemic toxicity. The combination therapy suppressed tumor growth more significantly than either treatment alone, with over 80% of complete tumor regression. Furthermore, SH-130 partially blocked TNF?- and radiation-induced NF-?B activation in DU-145 cells. Conclusions Our results demonstrate that small-molecule inhibitors of IAPs can overcome apoptosis-resistance and radiosensitize human prostate cancer with high levels of IAPs. Molecular modulation of IAPs may improve the outcome of prostate cancer radiotherapy. PMID:19047096

Dai, Yao; Liu, Meilan; Tang, Wenhua; DeSano, Jeffrey; Burstein, Ezra; Davis, Mary; Pienta, Kenneth; Lawrence, Theodore; Xu, Liang

2008-01-01

30

Rosiglitazone enhances the radiosensitivity of p53-mutant HT-29 human colorectal cancer cells  

SciTech Connect

Combined-modality treatment has improved the outcome in cases of various solid tumors, and radiosensitizers are used to enhance the radiotherapeutic efficiency. Rosiglitazone, a synthetic ligand of peroxisome proliferator-activated receptors {gamma} used in the treatment of type-2 diabetes, has been shown to reduce tumor growth and metastasis in human cancer cells, and may have the potential to be used as a radiosensitizer in radiotherapy for human colorectal cancer cells. In this study, rosiglitazone treatment significantly reduced the cell viability of p53-wild type HCT116 cells but not p53-mutant HT-29 cells. Interestingly, rosiglitazone pretreatment enhanced radiosensitivity in p53-mutant HT-29 cells but not HCT116 cells, and prolonged radiation-induced G{sub 2}/M arrest and enhanced radiation-induced cell growth inhibition in HT-29 cells. Pretreatment with rosiglitazone also suppressed radiation-induced H2AX phosphorylation in response to DNA damage and AKT activation for cell survival; on the contrary, rosiglitazone pretreatment enhanced radiation-induced caspase-8, -9, and -3 activation and PARP cleavage in HT-29 cells. In addition, pretreatment with a pan-caspase inhibitor, zVAD-fmk, attenuated the levels of caspase-3 activation and PARP cleavage in radiation-exposed cancer cells in combination with rosiglitazone pretreatment. Our results provide proof for the first time that rosiglitazone suppresses radiation-induced survival signals and DNA damage response, and enhances the radiation-induced apoptosis signaling cascade. These findings can assist in the development of rosiglitazone as a novel radiosensitizer.

Chiu, Shu-Jun, E-mail: chiusj@mail.tcu.edu.tw [Department of Life Science, Tzu Chi University, Hualien, Taiwan (China) [Department of Life Science, Tzu Chi University, Hualien, Taiwan (China); Institute of Radiation Sciences, Tzu Chi Technology College, Hualien, Taiwan (China); Hsaio, Ching-Hui; Tseng, Ho-Hsing; Su, Yu-Han [Department of Life Science, Tzu Chi University, Hualien, Taiwan (China)] [Department of Life Science, Tzu Chi University, Hualien, Taiwan (China); Shih, Wen-Ling [Graduate Institute of Biotechnology, National Pingtung University of Science and Technology, Pingtung, Taiwan (China)] [Graduate Institute of Biotechnology, National Pingtung University of Science and Technology, Pingtung, Taiwan (China); Lee, Jeng-Woei; Chuah, Jennifer Qiu-Yu [Department of Life Science, Tzu Chi University, Hualien, Taiwan (China)] [Department of Life Science, Tzu Chi University, Hualien, Taiwan (China)

2010-04-09

31

Monoclonal antibodies to malignant human gliomas.  

PubMed

Operationally specific monoclonal antibodies (MAbs) reactive with tumor but not normal adult tissues offer great potential for diagnosis and therapy of CNS neoplasms. Two targets for specific MAb localization were chosen for this study: (1) glioma-associated gangliosides GM2 [II3NeuAc-GgOse3Cer], GD2 [II3(NeuAc)2-GgOse3Cer], GD3[II3(NeuAc)2-LacCer], 3'-isoLM1 [IV3NeuAc-LcOse4Cer], and 3',6'-isoLD1 [IV3NeuAc,III6NeuAc-LcOse4Cer] and (2) epidermal growth factor receptor (EGFR) variant molecules. Epitopic specificity of isolated ganglioside hybridomas was determined with FAB-MS defined ganglioside standards. All MAb are IgM. Assay of 14 cytologic specimens and 31 frozen sections of primary CNS neoplasms revealed staining with anti-GD3 (14/14, 31/31), anti-GM2 (9/14, 26/31), and anti-GD2 (6/14, 24/30), respectively. 3'-isoLM1 and 3',6' isoLD1, which exhibit a restricted oncofetal expression pattern and are not detectable in adult human brain, are present in 15/31 primary CNS neoplasms and in 1/8 human glioma xenografts, as detected by MAbs SL-50 and DMAb-14, respectively. EGFR proteins, the second target, have unique amino acid spans resulting from gene deletion in the amplified EGFR gene present in subsets of malignant human gliomas. Antibodies against EGFR deletion-mutant Type III show highly restricted activity with a subset of glioma biopsies (6/35) expressing the mutant EGFR. These reagents should be useful for in vitro and in vivo diagnosis and, potentially, for treatment of malignant brain tumors. PMID:1384525

Wikstrand, C J; Fredman, P; Svennerholm, L; Humphrey, P A; Bigner, S H; Bigner, D D

1992-10-01

32

Aberrant methylation of Reprimo in human malignancies.  

PubMed

Reprimo is a new candidate mediator of p53-mediated cell cycle arrest at the G2 phase. Loss of Reprimo gene expression accompanied by its promoter methylation was identified in pancreatic and lung cancers. Our aim was to examine the methylation status of Reprimo in a broad range of cancers. We examined Reprimo expression by RT-PCR and the DNA methylation status of the Reprimo promoter by MSP in 39 tumor cell lines. Loss or downregulation of Reprimo expression was frequent (62%), and we confirmed that transcriptional repression of Reprimo was caused by hypermethylation (overall concordance 92%). Treatment of expression-negative cells with 5-aza-2'-deoxycytidine restored Reprimo expression. We then examined aberrant methylation of Reprimo in 645 tumors representing 16 tumor types. Promoter methylation of Reprimo was found in 79% of gastric cancers, 62% of gallbladder cancers, 57% of lymphomas, 56% of colorectal cancers, 40% of esophageal adenocarcinomas, 37% of breast cancers and 31% of leukemias. Methylation frequencies in ovarian cancers, bladder cancers, cervical cancers, brain tumors, malignant mesotheliomas and pediatric tumors were lower (0-20%). Reprimo methylation was rarely detected in nonmalignant tissues (0-11%) except for gastric epithelia. While colorectal polyps were also frequently methylated (27%), chronic cholecystitis samples were infrequently methylated (4%). Furthermore, we failed to identify Reprimo mutation in colorectal and gastric cancer cell lines and 50 primary colorectal cancers. Aberrant methylation of Reprimo with loss of expression is a common event and may contribute to the pathogenesis of some types of human malignancy. PMID:15700311

Takahashi, Takao; Suzuki, Makoto; Shigematsu, Hisayuki; Shivapurkar, Narayan; Echebiri, Chinyere; Nomura, Masaharu; Stastny, Victor; Augustus, Meena; Wu, Chew-Wun; Wistuba, Ignacio I; Meltzer, Stephen J; Gazdar, Adi F

2005-07-01

33

HIF-1? inhibition by siRNA or chetomin in human malignant glioma cells: effects on hypoxic radioresistance and monitoring via CA9 expression  

PubMed Central

Background Hypoxia induces activation of the HIF-1 pathway and is an essential characteristic of malignant gliomas. Hypoxia has been linked to tumor progression, therapy resistance and poor prognosis. However, little is known about the impact of HIF-1? inhibition on radioresistance of malignant glioma. Methods In this study, we investigated the effects of the inhibition of HIF-1? on cell survival and radiosensitivity in U251MG and U343MG glioma cells, using two different strategies. HIF-1? inhibition was achieved by siRNA targeting of HIF-1? or via chetomin, a disruptor of interactions between HIF-1? and p300. The inhibition of the HIF-1 pathway was monitored by quantitative real-time PCR and Western blot analyses of the expression levels of HIF-1? and CA9. CA9 expression was investigated as a potential indicator of the efficacy of HIF-1 inhibition and the resulting radiosensitivity of malignant glioma cell lines was determined by clonogenic assay after irradiation under normoxic (2-10 Gy) or hypoxic (2-15 Gy) conditions. Results Although siRNA and chetomin show distinct modes of action, both attenuated the hypoxia-induced radioresistance of malignant glioma cell lines U251MG (DMF10: 1.35 and 1.18) and U343MG (DMF10: 1.78 and 1.48). However, siRNA and chetomin showed diverse effects on radiosensitivity under normoxic conditions in U251MG (DMF10: 0.86 and 1.35) and U343MG (DMF10: 1.33 and 1.02) cells. Conclusions Results from this in vitro study suggest that inhibition of HIF-1? is a promising strategy to sensitize human malignant gliomas to radiotherapy and that CA9 could serve as an indicator of effective HIF-1-related radiosensitization. PMID:21050481

2010-01-01

34

PTEN: Multiple Functions in Human Malignant Tumors  

PubMed Central

PTEN is the most important negative regulator of the PI3K signaling pathway. In addition to its canonical, PI3K inhibition-dependent functions, PTEN can also function as a tumor suppressor in a PI3K-independent manner. Indeed, the PTEN network regulates a broad spectrum of biological functions, modulating the flow of information from membrane-bound growth factor receptors to nuclear transcription factors, occurring in concert with other tumor suppressors and oncogenic signaling pathways. PTEN acts through its lipid and protein phosphatase activity and other non-enzymatic mechanisms. Studies conducted over the past 10?years have expanded our understanding of the biological role of PTEN, showing that in addition to its ability to regulate proliferation and cell survival, it also plays an intriguing role in regulating genomic stability, cell migration, stem cell self-renewal, and tumor microenvironment. Changes in PTEN protein levels, location, and enzymatic activity through various molecular mechanisms can generate a continuum of functional PTEN levels in inherited syndromes, sporadic cancers, and other diseases. PTEN activity can indeed, be modulated by mutations, epigenetic silencing, transcriptional repression, aberrant protein localization, and post-translational modifications. This review will discuss our current understanding of the biological role of PTEN, how PTEN expression and activity are regulated, and the consequences of PTEN dysregulation in human malignant tumors. PMID:25763354

Milella, Michele; Falcone, Italia; Conciatori, Fabiana; Cesta Incani, Ursula; Del Curatolo, Anais; Inzerilli, Nicola; Nuzzo, Carmen M. A.; Vaccaro, Vanja; Vari, Sabrina; Cognetti, Francesco; Ciuffreda, Ludovica

2015-01-01

35

Increasing radiosensitivity with the downregulation of cofilin-1 in U251 human glioma cells.  

PubMed

The aim of the present study was to examine the association between cofilin?1 (CFL1) and radioresistance in human glioma U251 cells. CFL1 expression was downregulated and upregulated in U251 cells through the transfection of CFL1?small interfering (si)RNA and pcDNA3.1?CFL1, respectively. The radiosensitivity of U251 cells and established radioresistant U251 cells (RR?U251) was evaluated using cell viability, migration and invasion ability assays. Cell cycle distribution was also examined. The results showed that CFL1 expression was significantly increased in RR?U251 cells; in addition, the cell viability, migration and invasion ability of RR?U251 cells were significantly enhanced compared to those of the normal U251 cells, whereas the number of cells arrested in G2 phase was markedly decreased. In CFL1?silenced RR?U251 and CFL1?silenced U251 cells, the cell viability, migration and invasion abilities were significantly downregulated and the number of cells arrested in G2 phase was increased compared to that of the untransfected cells. In U251 cells overexpressing CFL1, cell viability, migration and invasion abilities were markedly upregulated and the number of cells arrested in G2 phase was decreased. In conclusion, the results of the present study suggested that downregulation of CFL1 may increase radiosensitivity in U251 cells. PMID:25529407

Du, Hua-Qing; Chen, Ling; Wang, Ying; Wang, Li-Jun; Yan, Hua; Liu, Hong-Yi; Xiao, Hong

2015-05-01

36

MiR-124 Radiosensitizes Human Colorectal Cancer Cells by Targeting PRRX1  

PubMed Central

One of the challenges in the treatment of colorectal cancer patients is that these tumors show resistance to radiation. MicroRNAs (miRNAs) are involved in essential biological activities, including chemoresistance and radioresistance. Several research studies have indicated that miRNA played an important role in sensitizing cellular response to ionizing radiation (IR). In this study, we found that miR-124 was significantly down-regulated both in CRC-derived cell lines and clinical CRC samples compared with adjacent non-tumor colorectal tissues, MiR-124 could sensitize human colorectal cancer cells to IR in vitro and in vivo. We identified PRRX1, a new EMT inducer and stemness regulator as a novel direct target of miR-124 by using target prediction algorithms and luciferase assay. PRRX1 knockdown could sensitize CRC cells to IR similar to the effects caused by miR-124. Overexpression of PRRX1 in stably overexpressed-miR-124 cell lines could rescue the effects of radiosensitivity enhancement brought by miR-124. Taking these observations into consideration, we illustrated that miR-124 could increase the radiosensitivity of CRC cells by blocking the expression of PRRX1, which indicated miR-124 could act as a great therapeutic target for CRC patients. PMID:24705396

Huang, Jing; Gao, Fei; Lin, Xiaoshan; He, Lian; Li, Dan; Li, Zhijun; Ding, Yi; Chen, Longhua

2014-01-01

37

Increasing radiosensitivity with the downregulation of cofilin-1 in U251 human glioma cells  

PubMed Central

The aim of the present study was to examine the association between cofilin-1 (CFL1) and radioresistance in human glioma U251 cells. CFL1 expression was downregulated and upregulated in U251 cells through the transfection of CFL1-small interfering (si)RNA and pcDNA3.1-CFL1, respectively. The radiosensitivity of U251 cells and established radioresistant U251 cells (RR-U251) was evaluated using cell viability, migration and invasion ability assays. Cell cycle distribution was also examined. The results showed that CFL1 expression was significantly increased in RR-U251 cells; in addition, the cell viability, migration and invasion ability of RR-U251 cells were significantly enhanced compared to those of the normal U251 cells, whereas the number of cells arrested in G2 phase was markedly decreased. In CFL1-silenced RR-U251 and CFL1-silenced U251 cells, the cell viability, migration and invasion abilities were significantly downregulated and the number of cells arrested in G2 phase was increased compared to that of the untransfected cells. In U251 cells overexpressing CFL1, cell viability, migration and invasion abilities were markedly upregulated and the number of cells arrested in G2 phase was decreased. In conclusion, the results of the present study suggested that downregulation of CFL1 may increase radiosensitivity in U251 cells. PMID:25529407

DU, HUA-QING; CHEN, LING; WANG, YING; WANG, LI-JUN; YAN, HUA; LIU, HONG-YI; XIAO, HONG

2015-01-01

38

Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells.  

PubMed

The aim of this study was to assess niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase (PARP) inhibitor, for its ability to radiosensitize human tumor cells. Human tumor cells derived from lung, breast and prostate cancers were tested for radiosensitization by niraparib using clonogenic survival assays. Both p53 wild-type and p53-defective lines were included. The ability of niraparib to alter the repair of radiation-induced DNA double strand breaks (DSBs) was determined using detection of ?-H2AX foci and RAD51 foci. Clonogenic survival analyses indicated that micromolar concentrations of niraparib radiosensitized tumor cell lines derived from lung, breast, and prostate cancers independently of their p53 status but not cell lines derived from normal tissues. Niraparib also sensitized tumor cells to H2O2 and converted H2O2-induced single strand breaks (SSBs) into DSBs during DNA replication. These results indicate that human tumor cells are significantly radiosensitized by the potent and selective PARP-1 inhibitor, niraparib, in the in vitro setting. The mechanism of this effect appears to involve a conversion of sublethal SSBs into lethal DSBs during DNA replication due to the inhibition of base excision repair by the drug. Taken together, our findings strongly support the clinical evaluation of niraparib in combination with radiation. PMID:24970803

Bridges, Kathleen A; Toniatti, Carlo; Buser, Carolyn A; Liu, Huifeng; Buchholz, Thomas A; Meyn, Raymond E

2014-07-15

39

Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells  

PubMed Central

The aim of this study was to assess niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase (PARP) inhibitor, for its ability to radiosensitize human tumor cells. Human tumor cells derived from lung, breast and prostate cancers were tested for radiosensitization by niraparib using clonogenic survival assays. Both p53 wild-type and p53-defective lines were included. The ability of niraparib to alter the repair of radiation-induced DNA double strand breaks (DSBs) was determined using detection of ?-H2AX foci and RAD51 foci. Clonogenic survival analyses indicated that micromolar concentrations of niraparib radiosensitized tumor cell lines derived from lung, breast, and prostate cancers independently of their p53 status but not cell lines derived from normal tissues. Niraparib also sensitized tumor cells to H2O2 and converted H2O2-induced single strand breaks (SSBs) into DSBs during DNA replication. These results indicate that human tumor cells are significantly radiosensitized by the potent and selective PARP-1 inhibitor, niraparib, in the in vitro setting. The mechanism of this effect appears to involve a conversion of sublethal SSBs into lethal DSBs during DNA replication due to the inhibition of base excision repair by the drug. Taken together, our findings strongly support the clinical evaluation of niraparib in combination with radiation. PMID:24970803

Bridges, Kathleen A.; Toniatti, Carlo; Buser, Carolyn A.; Liu, Huifeng; Buchholz, Thomas A.; Meyn, Raymond E.

2014-01-01

40

HDAC inhibition radiosensitizes human normal tissue cells and reduces DNA Double-Strand Break repair capacity.  

PubMed

HDAC inhibitors (HDACi) are gaining increasing attention in the treatment of cancer, particularly in view of their therapeutic effectiveness and assumed mild toxicity profile. While numerous studies have investigated the role of HDACi in tumor cells, little is known about their effects on normal tissue cells. We studied the effect of suberoylanilide hydroxamic acid (SAHA), MS275, sodium-butyrate and valproic acid in healthy human fibroblasts and found HDACi-treatment to go along with increased radiosensitivity and reduced DSB repair capacity. In view of the potential genotoxic effects of HDACi-treatment, particularly when being administered long-term for chronic disease or when given to children, to women of childbearing age or their partners or in combination with radiotherapy, an extensive education of patients and prescribing physicians as well as a stringent definition of clinical indications is urgently required. PMID:19956891

Purrucker, Jan C; Fricke, Andreas; Ong, Mei Fang; Rübe, Christian; Rübe, Claudia E; Mahlknecht, Ulrich

2010-01-01

41

Downregulation of high mobility group box 1 modulates telomere homeostasis and increases the radiosensitivity of human breast cancer cells.  

PubMed

The functions of the high mobility group box 1 (HMGB1) in tumor cells include replenishing telomeric DNA and maintaining cell immortality. There is a negative correlation between human telomerase reverse transcriptase (hTERT) and radiosensitivity in tumor cells. Our aim was to elucidate the relationship among HMGB1, telomere homeostasis and radiosensitivity in MCF-7 cells. In this study, we established stably transfected control (MCF-7-NC) and HMGB1 knockdown (MCF-7-shHMGB1) cell lines. The expression of HMGB1 mRNA and the relative telomere length were examined by real-time PCR. Radiosensitivity was detected by clonogenic assay. The protein expressions were determined by western blot analysis. The telomerase activity was detected by PCR-ELISA. Proliferation ability was examined by CCK-8 assay. Cell cycle and apoptosis were examined by flow cytometry. DNA damage foci were detected by immunofluorescence. ShRNA-mediated downregulation of HMGB1 expression increased the radiosensitivity of MCF-7 cells, and reduced the accumulation of hTERT and cyclin D1. Moreover, knockdown of HMGB1 in MCF-7 cells inhibited telomerase activity and cell proliferation, while increasing the extent of apoptosis. Downregulation of HMGB1 modulated telomere homeostasis by changing the level of telomere-binding proteins, such as TPP1 (PTOP), TRF1 and TRF2. This downregulation also inhibited the ATM and ATR signaling pathways. The current data demonstrate that knockdown of HMGB1 breaks telomere homeostasis, enhances radiosensitivity, and suppresses the repair of DNA damage in human breast cancer cells. These results suggested that HMGB1 might be a potential radiotherapy target in human breast cancer. PMID:25501936

Ke, Shaobo; Zhou, Fuxiang; Yang, Hui; Wei, Yuehua; Gong, Jun; Mei, Zijie; Wu, Lin; Yu, Haijun; Zhou, Yunfeng

2015-03-01

42

Radiosensitization of Oropharyngeal Squamous Cell Carcinoma Cells by Human Papillomavirus 16 Oncoprotein E6*I  

SciTech Connect

Purpose: Patients with oropharyngeal squamous cell carcinoma (OSCC) whose disease is associated with high-risk human papillomavirus (HPV) infection have a significantly better outcome than those with HPV-negative disease, but the reasons for the better outcome are not known. We postulated that they might relate to an ability of HPV proteins to confer a better response to radiotherapy, a commonly used treatment for OSCC. Methods and Materials: We stably expressed the specific splicing-derived isoforms, E6*I and E6*II, or the entire E6 open reading frame (E6total), which gives rise to both full length and E6*I isoforms, in OSCC cell lines. Radiation resistance was measured in clonogenicity assays, p53 activity was measured using transfected reporter genes, and flow cytometry was used to analyze cell cycle and apoptosis. Results: E6*I and E6total sensitized the OSCC cells to irradiation, E6*I giving the greatest degree of radiosensitization (approximately eightfold lower surviving cell fraction at 10 Gy), whereas E6*II had no effect. In contrast to radiosensitivity, E6*I was a weaker inhibitor than E6total of tumor suppressor p53 transactivator activity in the same cells. Flow cytometric analyses showed that irradiated E6*I expressing cells had a much higher G2M:G1 ratio than control cells, indicating that, after G2, cells were diverted from the cell cycle to programmed cell death. Conclusion: This study supports a role for E6*I in the enhanced responsiveness of HPV-positive oropharyngeal carcinomas to p53-independent radiation-induced death.

Pang, Ervinna [Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, NSW (Australia); Discipline of Infectious Diseases and Immunology, University of Sydney, NSW (Australia); Delic, Naomi C. [Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, NSW (Australia); Discipline of Dermatology, University of Sydney, NSW (Australia); Hong, Angela; Zhang Mei [Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, NSW (Australia); Department of Radiation Oncology, Royal Prince Alfred Hospital, NSW (Australia); Rose, Barbara R. [Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, NSW (Australia); Discipline of Infectious Diseases and Immunology, University of Sydney, NSW (Australia); Lyons, J. Guy, E-mail: guy.lyons@sydney.edu.a [Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, NSW (Australia); Discipline of Dermatology, University of Sydney, NSW (Australia)

2011-03-01

43

Combined EGFR and autophagy modulation impairs cell migration and enhances radiosensitivity in human glioblastoma cells.  

PubMed

Glioblastoma (GBM) remains the most aggressive and lethal brain tumor due to its molecular heterogeneity and high motility and invasion capabilities of its cells, resulting in high resistance to current standard treatments (surgery, followed by ionizing radiation combined with Temozolomide chemotherapy administration). Locus amplification, gene overexpression, and genetic mutations of epidermal growth factor receptor (EGFR) are hallmarks of GBM that can ectopically activate downstream signaling oncogenic cascades such as PI3K/Akt/mTOR pathway. Importantly, alteration of this pathway, involved also in the regulation of autophagy process, can improve radioresistance in GBM cells, thus promoting the aggressive phenotype of this tumor. In this work, the endogenous EGFR expression profile and autophagy were modulated to increase radiosensitivity behavior of human T98G and U373MG GBM cells. Our results primarily indicated that EGFR interfering induced radiosensitivity according to a decrease of the clonogenic capability of the investigated cells, and an effective reduction of the in vitro migratory features. Moreover, EGFR interfering resulted in an increase of Temozolomide (TMZ) cytotoxicity in T98G TMZ-resistant cells. In order to elucidate the involvement of the autophagy process as pro-death or pro-survival role in cells subjected to EGFR interfering, the key autophagic gene ATG7 was silenced, thereby producing a transient block of the autophagy process. This autophagy inhibition rescued clonogenic capability of irradiated and EGFR-silenced T98G cells, suggesting a pro-death autophagy contribution. To further confirm the functional interplay between EGFR and autophagy pathways, Rapamycin-mediated autophagy induction during EGFR modulation promoted further impairment of irradiated cells, in terms of clonogenic and migration capabilities. Taken together, these results might suggest a novel combined EGFR-autophagy modulation strategy, to overcome intrinsic GBM radioresistance, thus improving the efficacy of standard treatments. J. Cell. Physiol. 229: 1863-1873, 2014. © 2014 Wiley Periodicals, Inc. PMID:24691646

Palumbo, Silvia; Tini, Paolo; Toscano, Marzia; Allavena, Giulia; Angeletti, Francesca; Manai, Federico; Miracco, Clelia; Comincini, Sergio; Pirtoli, Luigi

2014-11-01

44

Radiosensitization of Human Leukemic HL-60 Cells by ATR Kinase Inhibitor (VE-821): Phosphoproteomic Analysis  

PubMed Central

DNA damaging agents such as ionizing radiation or chemotherapy are frequently used in oncology. DNA damage response (DDR)—triggered by radiation-induced double strand breaks—is orchestrated mainly by three Phosphatidylinositol 3-kinase-related kinases (PIKKs): Ataxia teleangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK) and ATM and Rad3-related kinase (ATR). Their activation promotes cell-cycle arrest and facilitates DNA damage repair, resulting in radioresistance. Recently developed specific ATR inhibitor, VE-821 (3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide), has been reported to have a significant radio- and chemo-sensitizing effect delimited to cancer cells (largely p53-deficient) without affecting normal cells. In this study, we employed SILAC-based quantitative phosphoproteomics to describe the mechanism of the radiosensitizing effect of VE-821 in human promyelocytic leukemic cells HL-60 (p53-negative). Hydrophilic interaction liquid chromatography (HILIC)-prefractionation with TiO2-enrichment and nano-liquid chromatography—tandem mass spectrometry (LC-MS/MS) analysis revealed 9834 phosphorylation sites. Proteins with differentially up-/down-regulated phosphorylation were mostly localized in the nucleus and were involved in cellular processes such as DDR, all phases of the cell cycle, and cell division. Moreover, sequence motif analysis revealed significant changes in the activities of kinases involved in these processes. Taken together, our data indicates that ATR kinase has multiple roles in response to DNA damage throughout the cell cycle and that its inhibitor VE-821 is a potent radiosensitizing agent for p53-negative HL-60 cells. PMID:25003641

Šalovská, Barbora; Fabrik, Ivo; ?urišová, Kamila; Link, Marek; Vávrová, Ji?ina; ?ezá?ová, Martina; Tichý, Aleš

2014-01-01

45

Mechanical deterioration underlies malignant behavior of aneurysmal human ascending aorta  

Microsoft Academic Search

Objective: The human ascending aorta becomes markedly prone to rupture and dissection at a diameter of 6 cm. The mechanical substrate for this malignant behavior is unknown. This investigation applied engineering analysis to human ascending aortic aneurysms and compared their structural characteristics with those of normal aortas. Methods: We measured the mechanical characteristics of the aorta by direct epi- aortic

George Koullias; Maryann Tranquilli; Dimitris P. Korkolis; Paul Barash; John A. Elefteriades

46

Hypoxia-targeted triple suicide gene therapy radiosensitizes human colorectal cancer cells  

PubMed Central

The hypoxic microenvironment, an important feature of human solid tumors but absent in normal tissue, may provide an opportunity for cancer-specific gene therapy. The purpose of the present study was to investigate whether hypoxia-driven triple suicide gene TK/CD/UPRT expression enhances cytotoxicity to ganciclovir (GCV) and 5-fluorocytosine (5-FC), and sensitizes human colorectal cancer to radiation in vitro and in vivo. Stable transfectant of human colorectal HCT8 cells was established which expressed hypoxia-inducible vectors (HRE-TK/eGFP and HRE-CD/UPRT/mDsRed). Hypoxia-induced expression/function of TK, CD and UPRT was verified by western blot analysis, flow cytometry, fluorescent microscopy and cytotoxicity assay of GCV and 5-FC. Significant radiosensitization effects were detected after 5-FC and GCV treatments under hypoxic conditions. In the tumor xenografts, the distribution of TK/eGFP and CD/UPRT/mDsRed expression visualized with fluorescence microscopy was co-localized with the hypoxia marker pimonidazole positive staining cells. Furthermore, administration of 5-FC and GCV in mice in combination with local irradiation resulted in tumor regression, as compared with prodrug or radiation treatments alone. Our data suggest that the hypoxia-inducible TK/GCV+CDUPRT/5-FC triple suicide gene therapy may have the ability to specifically target hypoxic cancer cells and significantly improve the tumor control in combination with radiotherapy. PMID:24912473

HSIAO, HUNG TSUNG; XING, LIGANG; DENG, XUELONG; SUN, XIAORONG; LING, C. CLIFTON; LI, GLORIA C.

2014-01-01

47

Late ROS-accumulation and Radiosensitivity in CuZnSOD Overexpressing Human Glioma Cells  

PubMed Central

This study investigates the hypothesis that CuZn-superoxide dismutase (SOD1) overexpression confers radioresistance to human glioma cells by regulating the late accumulation of reactive oxygen species (ROS) and G2/M checkpoint pathway. U118-9 human glioma cells (wild type, neo vector control, and stably overexpressing SOD1) were irradiated (0-10 Gy) and assayed for cell survival, cellular ROS levels, cell cycle phase distributions, and cyclin B1 expression. SOD1 overexpressing cells were radioresistant compared to wild type (wt) and neo vector control (neo) cells. Irradiated wt and neo cells showed a significant increase (~2-fold) in DHE-fluorescence beginning at 2 d post-irradiation, which remained elevated at 8 d post-irradiation. Interestingly, the late accumulation of ROS was suppressed in irradiated SOD1-overexpressing cells. The increase in ROS levels was followed by a decrease in cell growth and viability, and an increase in the percentage of cells with sub G1 DNA content. SOD1 overexpression enhanced radiation-induced G2-accumulation within 24 h post-irradiation, which was accompanied with a decrease in cyclin B1 mRNA and protein levels. These results support the hypothesis that long after the radiation exposure a “metabolic redox-response” regulates radiosensitivity of human glioma cells. PMID:18790046

Gao, Zhen; Sarsour, Ehab H.; Kalen, Amanda L.; Li, Ling; Kumar, Maneesh G.; Goswami, Prabhat C.

2008-01-01

48

Antisense oligonucleotides targeting human telomerase mRNA increases the radiosensitivity of nasopharyngeal carcinoma cells.  

PubMed

Nasopharyngeal carcinoma (NPC) is associated with a high incidence rate in South China and is predominantly treated with radiotherapy; however, the survival rate remains low. The therapeutic effects of radiation and chemotherapy may be enhanced when combined with anti?sense oligonucleotides targeting human telomerase RNA (hTR ASODN). However, the influence of hTR ASODN on the anti?tumor effects of radiation in NPC remain unknown. The present study investigated the effects of hTR ASODN on the proliferation and radiosensitivity of NPC cells, and further explored the underlying mechanisms. hTR ASODN significantly inhibited the proliferation and decreased the telomere length of CNE?2 human NPC cells. Furthermore, combined treatment of hTR ASODN with radiation significantly enhanced anti?tumor efficacy. The apoptotic rate and cleavage of caspase 9 were increased in the cells treated with the combined therapy, as compared with the cells treated with hTR ASODN or radiotherapy alone. In conclusion, these results suggest that hTR ASODN may inhibit the proliferation of NPC cells and enhance the anti?tumor effects of radiation by inducing cell apoptosis. Therefore hTR ASODN may be a potential adjuvant agent for the treatment of NPC combined with radiation therapy, and these findings are of translational importance. PMID:25523013

Yu, Change; Yu, Ying; Xu, Zumin; Li, Haiwen; Yang, Dongyan; Xiang, Mei; Zuo, Yufang; Li, Shuhui; Chen, Zihong; Yu, Zhonghua

2015-04-01

49

The Chemopreventive Agent Curcumin Is a Potent Radiosensitizer of Human Cervical Tumor Cells via Increased Reactive Oxygen Species Production and Overactivation of the Mitogen-Activated Protein Kinase Pathway  

PubMed Central

Cervical cancer is the second most common malignancy among women worldwide and is highly radioresistant, often resulting in local treatment failure. For locally advanced disease, radiation is combined with low-dose chemotherapy; however, this modality often leads to severe toxicity. Curcumin, a polyphenol extracted from rhizomes of the plant Curcuma longa, is a widely studied chemopreventive agent that was shown to have a low toxicity profile in three human clinical trials. Here, we show that pretreatment of two cervical carcinoma cell lines, HeLa and SiHa, with curcumin before ionizing radiation (IR) resulted in significant dose-dependent radiosensitization of these cells. It is noteworthy that curcumin failed to radiosensitize normal human diploid fibroblasts. Although in tumor cells, curcumin did not significantly affect IR-induced activation of AKT and nuclear factor-?B, we found that it caused a significant increase in the production of reactive oxygen species, which further led to sustained extracellular signal-regulated kinase (ERK) 1/2 activation. The antioxidant compound N-acetylcysteine blocked the curcumin-induced increased reactive oxygen species (ROS), sustained activation of ERK1/2, and decreased survival after IR in HeLa cells, implicating a ROS-dependent mechanism for curcumin radiosensitivity. Moreover, PD98059 (2?-amino-3?-methoxyflavone)-, PD184352- [2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide], and U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynylthio)butadiene]-specific inhibitors of mitogen-activated protein kinase kinase 1/2 (MEK1/2) blocked curcumin-mediated radiosensitization, demonstrating that the sustained ERK1/2 activation resulting from ROS generation leads to curcumin-mediated radiosensitization. Together, these results suggest a novel mechanism for curcumin-mediated radiosensitization involving increased ROS and ERK1/2 activation and suggest that curcumin application (either systemically or topically) may be an effective radiation modifying modality in the treatment of cervical cancer. PMID:18252805

Javvadi, Prashanthi; Segan, Andrew T.; Tuttle, Stephen W.; Koumenis, Constantinos

2011-01-01

50

Radiosensitization of human glioma cells in vitro and in vivo with acyclovir and mutant HSV-TK75 expressed from adenovirus  

Microsoft Academic Search

Purpose: We recently reported that an adenovirus-expressing mutant HSV-TK75 (AdCMV-TK75) radiosensitized rat syngeneic gliomas in combination with low concentrations of acyclovir (ACV) much more effectively than a virus expressing wild-type herpes simplex virus thymidine kinase (HSV-TK). In this report we have examined whether similar radiosensitizing effects are also seen with human glioma cells in vitro and in vivo.Methods and Materials:

Elizabeth Rosenberg; William Hawkins; Matthew Holmes; Cyrus Amir; Rupert K Schmidt-Ullrich; Peck-Sun Lin; Kristoffer Valerie

2002-01-01

51

Specific Chromosomal Abnormalities in Malignant Human Gliomas1  

Microsoft Academic Search

Karyotypic analysis of 54 malignant human gliomas (5 anaplastic asina-)tomas, 43 glioblastoma multiformes, 3 gliosarcomas, 2 giant cell glioblastomas, 1 anaplastic mixed glioma) has demonstrated that 12 tumors contained normal stemlines or only lacked one sex chromosome. The 42 tumors with abnormal karyotypes included 38 tumors which could be completely analyzed. Six of these 38 cases had near-triploid or near-

Sandra H. Bigner; Joachim Mark; Peter C. Burger; M. Stephen; Dennis E. Bullan; Lawrence H. Muhlbaier; Dareil D. Bigner

1988-01-01

52

Ionizing Radiation Activates AMP-Activated Kinase (AMPK): A Target for Radiosensitization of Human Cancer Cells  

SciTech Connect

Purpose: Adenosine monophosphate (AMP)-activated kinase (AMPK) is a molecular energy sensor regulated by the tumor suppressor LKB1. Starvation and growth factors activate AMPK through the DNA damage sensor ataxia-telangiectasia mutated (ATM). We explored the regulation of AMPK by ionizing radiation (IR) and its role as a target for radiosensitization of human cancer cells. Methods and Materials: Lung, prostate, and breast cancer cells were treated with IR (2-8 Gy) after incubation with either ATM or AMPK inhibitors or the AMPK activator metformin. Then, cells were subjected to either lysis and immunoblotting, immunofluorescence microscopy, clonogenic survival assays, or cell cycle analysis. Results: IR induced a robust phosphorylation and activation of AMPK in all tumor cells, independent of LKB1. IR activated AMPK first in the nucleus, and this extended later into cytoplasm. The ATM inhibitor KU-55933 blocked IR activation of AMPK. AMPK inhibition with Compound C or anti-AMPK {alpha} subunit small interfering RNA (siRNA) blocked IR induction of the cell cycle regulators p53 and p21{sup waf/cip} as well as the IR-induced G2/M arrest. Compound C caused resistance to IR, increasing the surviving fraction after 2 Gy, but the anti-diabetic drug metformin enhanced IR activation of AMPK and lowered the surviving fraction after 2 Gy further. Conclusions: We provide evidence that IR activates AMPK in human cancer cells in an LKB1-independent manner, leading to induction of p21{sup waf/cip} and regulation of the cell cycle and survival. AMPK appears to (1) participate in an ATM-AMPK-p21{sup waf/cip} pathway, (2) be involved in regulation of the IR-induced G2/M checkpoint, and (3) may be targeted by metformin to enhance IR responses.

Sanli, Toran; Rashid, Ayesha; Liu Caiqiong [Department of Oncology, Juravinski Cancer Center and McMaster University, Hamilton, Ontario (Canada)

2010-09-01

53

Targeting FAK Radiosensitizes 3-Dimensional Grown Human HNSCC Cells Through Reduced Akt1 and MEK1/2 Signaling  

SciTech Connect

Purpose: Focal adhesion kinase (FAK), a main regulator of integrin signaling and cell migration, is frequently overexpressed and hyperphosphorylated in human head-and-neck squamous cell carcinoma (HNSCC). We have previously shown that pharmacologic FAK inhibition leads to radiosensitization of 3-dimensionally grown HNSCC cell lines. To further evaluate the role of FAK in radioresistance and as a potential cancer target, we examined FAK and FAK downstream signaling in HNSCC cell lines grown in more physiologic extracellular matrix-based 3-dimensional cell cultures. Methods and Materials: Seven HNSCC cell lines were grown in 3-dimensional extracellular matrix and the clonogenic radiation survival, expression, and phosphorylation of FAK, paxillin, Akt1, extracellular signal-regulated kinase (ERK)1/2, and MEK1/2 were analyzed after siRNA-mediated knockdown of FAK, Akt1, MEK1, FAK+Akt1, or FAK+MEK1 compared with controls or stable overexpression of FAK. The role of MEK1/2 for clonogenic survival and signaling was investigated using the MEK inhibitor U0126 with or without irradiation. Results: FAK knockdown moderately or significantly enhanced the cellular radiosensitivity of 3-dimensionally grown HNSCC cells. The FAK downstream targets paxillin, Akt1, and ERK1/2 were substantially dephosphorylated under FAK depletion. FAK overexpression, in contrast, increased radiation survival and paxillin, Akt1, and ERK1/2 phosphorylation. The degree of radiosensitization upon Akt1, ERK1/2, or MEK1 depletion or U0126 was superimposable to FAK knockdown. Combination knockdown conditions (ie, Akt1/FAK, MEK1/FAK, or U0126/FAK) failed to provide additional radiosensitization. Conclusions: Our data provide further evidence for FAK as important determinant of radiation survival, which acts in the same signaling axis as Akt1 and ERK1/2. These data strongly support our hypothesis that FAK is a relevant molecular target for HNSCC radiotherapy.

Hehlgans, Stephanie [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany) [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany); Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt am Main (Germany); Institute of Radiopharmacy, Helmholtz Center Dresden-Rossendorf, Dresden (Germany); Eke, Iris [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany)] [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany); Cordes, Nils, E-mail: Nils.Cordes@OncoRay.de [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany) [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany); Institute of Radiopharmacy, Helmholtz Center Dresden-Rossendorf, Dresden (Germany); Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany)

2012-08-01

54

NOTCH Mutations: Multiple Faces in Human Malignancies.  

PubMed

NOTCH proteins have been implicated in multiple cellular functions, such as stem cell maintenance and cell fate determination. Initially identified as proto-oncogenes because they promote the development of certain types of leukemia, inactivating mutations of NOTCH were later reported. Together with the potential distinct functions of NOTCH family members, their ligands and associated niches, the precise roles of NOTCH in human cancers, particularly solid tumors, remain unsettled. In oral squamous cell carcinoma (OSCC), mutations of NOTCH1 are found in 10% to 15% tumors from Caucasian patients, mostly inactivating mutations. Recent studies of OSCC from Chinese patients, however, showed mutation rates of NOTCH1 about 50% with a considerable portion of potential activating mutations. These findings add another twist into the already complex picture of NOTCH alterations in human cancers, calling for further investigation to uncover what role exactly these molecules play in cancer initiation and progression to develop strategies targeting NOTCH signaling for cancer prevention and treatment. Cancer Prev Res; 8(4); 259-61. ©2015 AACR. See related article by Izumchenko et al., p. 277. PMID:25712049

Mao, Li

2015-04-01

55

Radiosensitivity of human ovarian carcinoma and melanoma cells to ?-rays and protons  

PubMed Central

Introduction Proton radiation offers physical advantages over conventional radiation. Radiosensitivity of human 59M ovarian cancer and HTB140 melanoma cells was investigated after exposure to ?-rays and protons. Material and methods Irradiations were performed in the middle of a 62 MeV therapeutic proton spread out Bragg peak with doses ranging from 2 to 16 Gy. The mean energy of protons was 34.88 ±2.15 MeV, corresponding to the linear energy transfer of 4.7 ±0.2 keV/µm. Irradiations with ?-rays were performed using the same doses. Viability, proliferation and survival were assessed 7 days after both types of irradiation while analyses of cell cycle and apoptosis were performed 48 h after irradiation. Results Results showed that ?-rays and protons reduced the number of viable cells for both cell lines, with stronger inactivation achieved after irradiation with protons. Surviving fractions for 59M were 0.91 ±0.01 for ?-rays and 0.81 ±0.01 for protons, while those for HTB140 cells were 0.93 ±0.01 for ?-rays and 0.86 ±0.01 for protons. Relative biological effectiveness of protons, being 2.47 ±0.22 for 59M and 2.08 ±0.36 for HTB140, indicated that protons provoked better cell elimination than ?-rays. After proton irradiation proliferation capacity of the two cell lines was slightly higher as compared to ?-rays. Proliferation was higher for 59M than for HTB140 cells after both types of irradiation. Induction of apoptosis and G2 arrest detected after proton irradiation were more prominent in 59M cells. Conclusions The obtained results suggest that protons exert better antitumour effects on ovarian carcinoma and melanoma cells than ?-rays. The dissimilar response of these cells to radiation is related to their different features. PMID:25097591

Keta, Otilija; Todorovi?, Danijela; Popovi?, Nataša; Kori?anac, Lela; Cuttone, Giacomo; Petrovi?, Ivan

2014-01-01

56

Role of human papillomavirus and its detection in potentially malignant and malignant head and neck lesions: updated review  

Microsoft Academic Search

Head and neck malignancies are characterized by a multiphasic and multifactorial etiopathogenesis. Tobacco and alcohol consumption are the most common risk factors for head and neck malignancy. Other factors, including DNA viruses, especially human papilloma virus (HPV), may also play a role in the initiation or development of these lesions. The pathways of HPV transmission in the head and neck

Ajay Kumar Chaudhary; Mamta Singh; Shanthy Sundaram; Ravi Mehrotra

2009-01-01

57

Eliminating malignant contamination from therapeutic human spermatogonial stem cells  

PubMed Central

Spermatogonial stem cell (SSC) transplantation has been shown to restore fertility in several species and may have application for treating some cases of male infertility (e.g., secondary to gonadotoxic therapy for cancer). To ensure safety of this fertility preservation strategy, methods are needed to isolate and enrich SSCs from human testis cell suspensions and also remove malignant contamination. We used flow cytometry to characterize cell surface antigen expression on human testicular cells and leukemic cells (MOLT-4 and TF-1a). We demonstrated via FACS that EpCAM is expressed by human spermatogonia but not MOLT-4 cells. In contrast, HLA-ABC and CD49e marked >95% of MOLT-4 cells but were not expressed on human spermatogonia. A multiparameter sort of MOLT-4–contaminated human testicular cell suspensions was performed to isolate EpCAM+/HLA-ABC–/CD49e– (putative spermatogonia) and EpCAM–/HLA-ABC+/CD49e+ (putative MOLT-4) cell fractions. The EpCAM+/HLA-ABC–/CD49e– fraction was enriched for spermatogonial colonizing activity and did not form tumors following human-to–nude mouse xenotransplantation. The EpCAM–/HLA-ABC+/CD49e+ fraction produced tumors following xenotransplantation. This approach could be generalized with slight modification to also remove contaminating TF-1a leukemia cells. Thus, FACS provides a method to isolate and enrich human spermatogonia and remove malignant contamination by exploiting differences in cell surface antigen expression. PMID:23549087

Dovey, Serena L.; Valli, Hanna; Hermann, Brian P.; Sukhwani, Meena; Donohue, Julia; Castro, Carlos A.; Chu, Tianjiao; Sanfilippo, Joseph S.; Orwig, Kyle E.

2013-01-01

58

Human papillomaviruses: targeting differentiating epithelial cells for malignant transformation  

Microsoft Academic Search

Human papillomavirus (HPV) infections play a crucial role in the pathogenesis of cervical neoplasia. Insights into the mechanisms by which HPV infection can, in a small numbers of cases, result in malignancy, comes from the observation that three proteins encoded by high-risk genital HPVs, E6, E7 and to a lesser extent E5, target factors that control the cell cycle and

Frauke Fehrmann; Laimonis A Laimins

2003-01-01

59

Cytotoxic and radiosensitizing effects of FAK targeting in human glioblastoma cells in vitro.  

PubMed

Glioblastoma multiforme (GBM) is a highly aggressive and extremely lethal cancer and novel molecular therapies are required for optimized multimodal therapy regimes. While focal adhesion kinase (FAK) is regarded as a therapeutic target, its radiosensitizing potential remains to be elucidated in glioblastoma. Thus, FAK was inhibited using the pharmaco-logical inhibitor TAE226 and cytotoxicity and radiosensitization of glioblastoma cells were investigated in vitro. Monolayer and suspension cell cultures of a panel of glioblastoma cell lines (A172, LN229, U87MG, U138MG, U343MG, DD-HT7607, and DD-T4) were treated with increasing TAE226 concentrations (0-10 µM) alone or in combination with X-rays (0-6 Gy). Subsequently, clonogenic cell survival, expression and the phosphorylation of FAK downstream signaling, apoptosis and autophagy were analyzed. Efficient FAK inhibition by TAE226 mediated significant cytotoxicity and reduced sphere formation in a dose- and time-dependent manner. Two out of seven glioblastoma cell lines showed radiosensitization. Apoptotic induction by TAE226 was cell line-dependent. The results demonstrated that pharmacological FAK inhibitor TAE226 efficiently reduced clonogenicity and sphere formation in glioblastoma cells without generally modifying their radiosensitivity. However, future studies are necessary to define the potential of FAK inhibition by TAE226 or other pharmacological inhibitors in combination with radiochemotherapy. PMID:25625667

Storch, Katja; Sagerer, Andre; Cordes, Nils

2015-04-01

60

Simultaneous Inhibition of EGFR and PI3K Enhances Radiosensitivity in Human Breast Cancer  

SciTech Connect

Purpose: Mutations in the epidermal growth factor receptor (EGFR)/phosphoinositide 3-kinase (PI3K)/Akt signaling transduction pathway are common in cancer. This pathway is imperative to the radiosensitivity of cancer cells. We aimed to investigate the radiosensitizing effects of the simultaneous inhibition of EGFR and PI3K in breast cancer cells. Methods and Materials: MCF-7 cell lines with low expression of EGFR and wild-type PTEN and MDA-MB-468 cell lines with high expression of EGFR and mutant PTEN were used. The radiosensitizing effects by the inhibition of EGFR with AG1478 and/or PI3K with Ly294002 were determined by colony formation assay, Western blot was used to investigate the effects on downstream signaling. Flow cytometry was used for apoptosis and cell cycle analysis. Mice-bearing xenografts of MDA-MB-468 breast cancer cells were also used to observe the radiosensitizing effect. Results: Simultaneous inhibition of EGFR and PI3K greatly enhanced radiosensitizing effect in MDA-MB-468 in terms of apoptosis and mitotic death, either inhibition of EGFR or PI3K alone could enhance radiosensitivity with a dose-modifying factor (DMF{sub SF2}) of 1.311 and 1.437, radiosensitizing effect was further enhanced by simultaneous inhibition of EGFR and PI3K with a DMF{sub SF2} at 2.698. DNA flow cytometric analysis indicated that dual inhibition combined with irradiation significantly induced G0/G1 phase arrest in MDA-MB-468 cells. The expression of phosphor-Akt and phosphor-Erk1/2 (induced by irradiation and PI3K inhibitor) were fully attenuated by simultaneous treatment with both inhibitors in combination with irradiation. In addition, dual inhibition combined with irradiation induced dramatic tumor growth delay in MDA-MB-468 xenografts. Conclusions: Our study indicated that simultaneous inhibition of EGFR and PI3K could further sensitize the cancer cells to irradiation compared to the single inhibitor with irradiation in vitro and in vivo. The approach may have important therapeutic implication in the treatment of a subset of breast cancer patients with high expression of EGFR and deficient function of PTEN.

Li Ping; Zhang Qing [Department of Radiation Oncology, 6th People's Hospital of Jiao Tong University, Shanghai 200233 (China); Torossian, Artour [Vanderbilt University, School of Medicine, Nashville, TN (United States); Li Zhaobin; Xu Wencai [Department of Radiation Oncology, 6th People's Hospital of Jiao Tong University, Shanghai 200233 (China); Lu Bo [Department of Radiation Oncology, Thomas Jefferson University and Hospitals, Inc. Philadelphia, PA (United States); Fu Shen, E-mail: fushen1117@gmail.com [Department of Radiation Oncology, 6th People's Hospital of Jiao Tong University, Shanghai 200233 (China)

2012-07-01

61

Celecoxib Enhances the Radiosensitizing Effect of 7-Hydroxystaurosporine (UCN-01) in Human Lung Cancer Cell Lines  

SciTech Connect

Purpose: 7-Hydroxystaurosporine (UCN-01), a Chk1-specific inhibitor, showed promising in vitro and in vivo chemo- or radiosensitizing activity. However, there have been concerns about its limited therapeutic efficacy and risk of side effects. A method of enhancing the treatment efficacy of UCN-01 while not increasing its side effects on normal tissue may therefore be required to apply this drug in clinical settings. Celecoxib is a cyclooxygenase-2 (COX-2)-specific inhibitor that downregulates ataxia telangiectasia and rad3-related (ATR) protein, an upstream kinase of Chk1. In this study, we investigated whether the addition of celecoxib can potentiate the radiosensitizing effect of UCN-01. Methods and Materials: The cooperative radiosensitizing effects and the underlying molecular mechanisms of UCN-01 plus celecoxib were determined by clonogenic assay, tumor growth delay assay, flow cytometry, and Western blotting. Synergism of the three agents combined (UCN-01 plus celecoxib plus radiation) were evaluated using median drug effect analysis and drug-independent action model analysis. Results: The combination of UCN-01 and celecoxib could induce synergistic cytotoxicity and radiosensitizing effects in in vitro and in vivo systems. The combination of both drugs also cooperatively inhibited IR-induced G{sub 2}/M arrest, and increased the G{sub 2} to mitotic transition. Conclusions: Combined treatment with UCN-01 and celecoxib can exert synergistically enhanced radiosensitizing effects via cooperative inhibition of the ionizing radiation-activated G{sub 2} checkpoint. We propose that this combination strategy may be useful in clinical applications of UCN-01 for radiotherapy of cancer patients.

Kim, Young-Mee; Jeong, In-Hye [Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Pyo, Hongryull, E-mail: Quasar93@yahoo.co.kr [Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

2012-07-01

62

Serum Sialyltransferase and Liver Catalase Activity in Cachectic Nude Mice Bearing a Human Malignant Melanoma1  

Microsoft Academic Search

Cachexia is rare in nude mice bearing human malignant tumors even when the transplanted tumors become as large as the body size of the host. In our series on heterotransplantation of a variety of human malignant tumors into nude mice, a malignant melanoma (SEKI) was found to induce severe body weight loss in the host at the early stage of

Yukio Kondo; Kanji Sato; Yoshito Ueyama; Nakaaki Ohsawa

63

Phenotypes and Karyotypes of Human Malignant Mesothelioma Cell Lines  

PubMed Central

Background Malignant mesothelioma is an aggressive tumour of serosal surfaces most commonly pleura. Characterised cell lines represent a valuable tool to study the biology of mesothelioma. The aim of this study was to develop and biologically characterise six malignant mesothelioma cell lines to evaluate their potential as models of human malignant mesothelioma. Methods Five lines were initiated from pleural biopsies, and one from pleural effusion of patients with histologically proven malignant mesothelioma. Mesothelial origin was assessed by standard morphology, Transmission Electron Microscopy (TEM) and immunocytochemistry. Growth characteristics were assayed using population doubling times. Spectral karyotyping was performed to assess chromosomal abnormalities. Authentication of donor specific derivation was undertaken by DNA fingerprinting using a panel of SNPs. Results Most of cell lines exhibited spindle cell shape, with some retaining stellate shapes. At passage 2 to 6 all lines stained positively for calretinin and cytokeratin 19, and demonstrated capacity for anchorage-independent growth. At passage 4 to 16, doubling times ranged from 30–72 hours, and on spectral karyotyping all lines exhibited numerical chromosomal abnormalities ranging from 41 to 113. Monosomy of chromosomes 8, 14, 22 or 17 was observed in three lines. One line displayed four different karyotypes at passage 8, but only one karyotype at passage 42, and another displayed polyploidy at passage 40 which was not present at early passages. At passages 5–17, TEM showed characteristic features of mesothelioma ultrastructure in all lines including microvilli and tight intercellular junctions. Conclusion These six cell lines exhibit varying cell morphology, a range of doubling times, and show diverse passage-dependent structural chromosomal changes observed in malignant tumours. However they retain characteristic immunocytochemical protein expression profiles of mesothelioma during maintenance in artificial culture systems. These characteristics support their potential as in vitro model systems for studying cellular, molecular and genetic aspects of mesothelioma. PMID:23516439

Relan, Vandana; Morrison, Leanne; Parsonson, Kylie; Clarke, Belinda E.; Duhig, Edwina E.; Windsor, Morgan N.; Matar, Kevin S.; Naidoo, Rishendran; Passmore, Linda; McCaul, Elizabeth; Courtney, Deborah; Yang, Ian A.; Fong, Kwun M.; Bowman, Rayleen V.

2013-01-01

64

Poor Prognosis Associated With Human Papillomavirus ?7 Genotypes in Cervical Carcinoma Cannot Be Explained by Intrinsic Radiosensitivity  

SciTech Connect

Purpose: To investigate the relationship between human papillomavirus (HPV) genotype and outcome after radiation therapy and intrinsic radiosensitivity. Methods and Materials: HPV genotyping was performed on cervix biopsies by polymerase chain reaction using SPF-10 broad-spectrum primers, followed by deoxyribonucleic acid enzyme immunoassay and genotyping by reverse hybridization line probe assay (LiPA{sub 25}) (version 1) (n=202). PapilloCheck and quantitative reverse transcription-polymerase chain reaction were used to genotype cervix cancer cell lines (n=16). Local progression-free survival after radiation therapy alone was assessed using log-rank and Cox proportionate hazard analyses. Intrinsic radiosensitivity was measured as surviving fraction at 2 Gy (SF2) using clonogenic assays. Results: Of the 202 tumors, 107 (53.0%) were positive for HPV16, 29 (14.4%) for HPV18, 9 (4.5%) for HPV45, 23 (11.4%) for other HPV genotypes, and 22 (10.9%) were negative; 11 (5.5%) contained multiple genotypes, and 1 tumor was HPV X (0.5%). In 148 patients with outcome data, those with HPV?9-positive tumors had better local progression-free survival compared with ?7 patients in univariate (P<.004) and multivariate (hazard ratio 1.54, 95% confidence interval 1.11-1.76, P=.021) analyses. There was no difference in the median SF2 of ?9 and ?7 cervical tumors (n=63). In the cell lines, 9 were ?7 and 4 ?9 positive and 3 negative. There was no difference in SF2 between ?9 and ?7 cell lines (n=14). Conclusion: The reduced radioresponsiveness of ?7 cervical tumors is not related to intrinsic radiosensitivity.

Hall, John S.; Iype, Rohan; Armenoult, Lucile S.C. [Translational Radiobiology Group, Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester (United Kingdom)] [Translational Radiobiology Group, Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester (United Kingdom); Taylor, Janet [Translational Radiobiology Group, Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester (United Kingdom) [Translational Radiobiology Group, Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester (United Kingdom); Applied Computational Biology and Bioinformatics Group, Paterson Institute for Cancer Research, Manchester (United Kingdom); Miller, Crispin J. [Applied Computational Biology and Bioinformatics Group, Paterson Institute for Cancer Research, Manchester (United Kingdom)] [Applied Computational Biology and Bioinformatics Group, Paterson Institute for Cancer Research, Manchester (United Kingdom); Davidson, Susan [Christie National Health Service Foundation Trust, Manchester (United Kingdom)] [Christie National Health Service Foundation Trust, Manchester (United Kingdom); Sanjose, Silvia de; Bosch, Xavier [Cancer Epidemiology Research Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat (Spain)] [Cancer Epidemiology Research Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat (Spain); Stern, Peter L. [Immunology Group, Paterson Institute for Cancer Research, Manchester (United Kingdom)] [Immunology Group, Paterson Institute for Cancer Research, Manchester (United Kingdom); West, Catharine M.L., E-mail: Catharine.West@manchester.ac.uk [Translational Radiobiology Group, Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester (United Kingdom)

2013-04-01

65

Oxygen- and temperature-dependent cytotoxic and radiosensitizing effects of cis-dichlorodiammineplatinum(II) on human NHIK 3025 cells in vitro  

SciTech Connect

The radiosensitizing effect of the chemotherapeutic drug cis-dichlorodiammineplatinum(II) (cis-DDP) was tested on human NHIK 3025 cells cultivated in vitro. cis-DDP was found to exert a radiomodifying effect under hypoxic but not under aerobic conditions. These results confirm that cis-DDP may act as a radiosensitizer of hypoxic cells; however, the radiosensitizing effect was seen only at concentrations of cis-DDP having a considerable cytotoxic activity, and for practical reasons concerning survival level the highest drug concentration that was investigated was 15 microM at 37/sup 0/C. The radiosensitizing effect was of a dose-modifying type and with a dose-modifying factor (DMF) of 1.2 at 15 microM in hypoxic cells. The radiosensitizing as well as the cytotoxic effect of cis-DDP was found to be strongly temperature dependent. Isoeffect doses of cis-DDP was reduced with a factor of 3 at 22 as compared to 37/sup 0/C. We also found that hypoxic cells were less sensitive to cis-DDP than cells treated in the presence of oxygen. To test the correlation between cytotoxicity and radiosensitization on the one hand and cellular uptake of cis-DDP on the other, cell-associated Pt was measured by atomic absorption spectroscopy. From these studies the cytotoxicity of cis-DDP at 22 and 37/sup 0/C under aerobic conditions was found to be the same as long as the amount of cell-associated Pt (i.e., the cellular uptake) was the same. However, whether the cells were treated under hypoxic or aerobic conditions, the cellular uptake of Pt was the same. While the radiosensitizing effect was present at 37 and at 40/sup 0/C, no such effect could be found at 22/sup 0/C.

Melvik, J.E.; Pettersen, E.O.

1988-06-01

66

Heterogeneity and immunophenotypic plasticity of malignant cells in human liposarcomas  

PubMed Central

Liposarcomas are tumors arising in white adipose tissue (WAT) with avidity for local recurrence. Aggressive dedifferentiated liposarcomas (DDLS) may arise from well-differentiated subtypes (WDLS) upon disease progression, however, this key issue is unresolved due in large part to knowledge gaps about liposarcoma cellular composition. Here, we wished to improve insights into liposarcoma cellular hierarchy. Tumor section analysis indicated that the populations, distinguishable based on expression of CD34 (a marker of adipocyte progenitors) and CD36 (a marker of adipocyte differentiation), occupy distinct intra-tumoral locations in both WDLS and DDLS. Taking advantage of these markers, we separated cells from a panel of fresh human surgical specimens by fluorescence-activated cell sorting (FACS). Based on chromosome analysis and the culture phenotypes of the composing populations, we demonstrate that malignant cells comprise four mesenchymal populations distinguished by expression of CD34 and CD36, while vascular (CD31+) and hematopoietic (CD45+) components are non-neoplastic. Finally, we show that mouse xenografts are derivable from both CD36-negative and CD36-positive DDLS cells, and that each population recreates the heterogeneity of CD36 expression in vivo. Combined, our results show that malignant cells in WDLS and DDLS can be classified according to distinct stages of adipogenesis and indicate immonophenotypic plasticity of malignant liposarcoma cells. PMID:23770802

Zhang, Yan; Young, Eric D.; Bill, Katelynn; Belousov, Roman; Peng, Tingsheng; Lazar, Alexander J; Pollock, Raphael E; Simmons, Paul J.; Lev, Dina; Kolonin, Mikhail G.

2013-01-01

67

Ectopically hTERT expressing adult human mesenchymal stem cells are less radiosensitive than their telomerase negative counterpart  

SciTech Connect

During the past several years increasing evidence indicating that the proliferation capacity of mammalian cells is highly radiosensitive, regardless of the species and the tissue of origin of the cells, has accumulated. It has also been shown that normal bone marrow cells of mice have a similar radiosensitivity to other mammalian cells so far tested. In this study, we investigated the genetic effects of ionizing radiation (2.5-15 Gy) on normal human mesenchymal stem cells and their telomerised counterpart hMSC-telo1. We evaluated overall genomic integrity, DNA damage/repair by applying a fluorescence-detected alkaline DNA unwinding assay together with Western blot analyses for phosphorylated H2AX and Q-FISH was applied for investigation of telomeric damage. Our results indicate that hMSC and TERT-immortalized hMSCs can cope with relatively high doses of {gamma}-rays and that overall DNA repair is similar in the two cell lines. The telomeres were extensively destroyed after irradiation in both cell types suggesting that telomere caps are especially sensitive to radiation. The TERT-immortalized hMSCs showed higher stability at telomeric regions than primary hMSCs indicating that cells with long telomeres and high telomerase activity have the advantage of re-establishing the telomeric caps.

Serakinci, Nedime [Department of Human Genetics, University of Aarhus, Aarhus (Denmark) and Institute of Medical Biology, Department of Anatomy and Neurobiology, Southern Denmark University, Odense (Denmark)]. E-mail: nserakinci@health.sdu.dk; Christensen, Rikke [Department of Human Genetics, University of Aarhus, Aarhus (Denmark); Graakjaer, Jesper [Department of Clinical Genetics, Vejle County Hospital, Vejle (Denmark); Cairney, Claire J. [Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK, Beatson Laboratories, Garscube Estate, Glasgow (United Kingdom); Keith, W. Nicol [Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK, Beatson Laboratories, Garscube Estate, Glasgow (United Kingdom); Alsner, Jan [Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus (Denmark); Saretzki, Gabriele [Henry Wellcome Laboratory for Biogerontology, Newcastle General Hospital, University of Newcastle upon Tyne, Newcastle (United Kingdom); Kolvraa, Steen [Department of Clinical Genetics, Vejle County Hospital, Vejle (Denmark)

2007-03-10

68

Bowman-Birk proteinase inhibitor (BBI) modulates radiosensitivity and radiation-induced differentiation of human fibroblasts in culture.  

PubMed

The radiosensitivity and differentiation pattern of cultured normal human fibroblasts was analysed as a function of treatment of the cells with the Bowman-Birk proteinase inhibitor (BBI). Upon irradiation with doses from 0 to 8 Gy normal human fibroblasts are induced to a premature terminal differentiation within 14-21 days of postirradiation incubation. Treatment of the cells with 10 microM BBI for 2 h prior to the irradiation procedure resulted in a significant shift of the radiation survival curve, increased SF2 values 0.63 vs. 0.84 and the cell type composition of the test fibroblast cultures. Upon pretreatment with BBI the radiation-induced premature terminal differentiation of progenitor fibroblasts to postmitotic fibrocytes could significantly be inhibited. Based on this data, it can be postulated that BBI may serve as a radioprotector of normal fibroblasts which are involved in radiation-induced tissue injuries like radiation fibrosis. PMID:7597212

Dittmann, K; Löffler, H; Bamberg, M; Rodemann, H P

1995-02-01

69

5-Iodo-2-Pyrimidinone-2'-Deoxyribose-Mediated Cytotoxicity and Radiosensitization in U87 Human Glioblastoma Xenografts  

SciTech Connect

Purpose: 5-Iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is a novel orally administered (p.o.) prodrug of 5-iododeoxyuridine. Because p.o. IPdR is being considered for clinical testing as a radiosensitizer in patients with high-grade gliomas, we performed this in vivo study of IPdR-mediated cytotoxicity and radiosensitization in a human glioblastoma xenograft model, U87. Methods and Materials: Groups of 8 or 9 athymic male nude mice (6-8 weeks old) were implanted with s.c. U87 xenograft tumors (4 x 10{sup 6} cells) and then randomized to 10 treatment groups receiving increasing doses of p.o. IPdR (0, 100, 250, 500, and 1000 mg/kg/d) administered once daily (q.d.) x 14 days with or without radiotherapy (RT) (0 or 2 Gy/d x 4 days) on days 11-14 of IPdR treatment. Systemic toxicity was determined by body weight measurements during and after IPdR treatment. Tumor response was assessed by changes in tumor volumes. Results: IPdR alone at doses of {>=}500 mg/kg/d resulted in moderate inhibition of tumor growth. The combination of IPdR plus RT resulted in a significant IPdR dose-dependent tumor growth delay, with the maximum radiosensitization using {>=}500 mg/kg/d. IPdR doses of 500 and 1000 mg/kg/d resulted in transient 5-15% body weight loss during treatment. Conclusions: In U87 human glioblastoma s.c. xenografts, p.o. IPdR given q.d. x 14 days and RT given 2 Gy/d x 4 days (days 11-14 of IPdR treatment) results in a significant tumor growth delay in an IPdR dose-dependent pattern. The use of p.o. IPdR plus RT holds promise for Phase I/II testing in patients with high-grade gliomas.

Kinsella, Timothy J. [Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (United States)], E-mail: timothy.kinsella@UHhospitals.org; Kinsella, Michael T.; Seo, Yuji [Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (United States); Berk, Gregory [Hana Biosciences, South San Francisco, CA (United States)

2007-11-15

70

Pharmacokinetics of the hypoxic radiosensitizers misonidazole and demethylmisonidazole after intraperitoneal administration in humans  

SciTech Connect

The hypoxic radiosensitizers misonidazole or demethylmisonidazole were administered i.p. in a 2-liter volume to 6 patients affected by advanced ovarian carcinoma, and the pharmacokinetic course of the two drugs was studied. The clearance of misonidazole and demethylmisonidazole from the peritoneal fluid was 19.1 and 12.4 ml/min, respectively. At 3 hr after drug administration, both radiosensitizers had peritoneal fluid concentrations more than 8 times larger than in the plasma. The concentration x time exposure in the peritoneal fluid was 3.2 times larger than in plasma for misonidazole and 7.6 times for demethylmisonidazole. The advantage of i.p. delivery compared with systemic delivery decreases with distance from the peritoneal surface, but the advantage may be maintained for up to 1 mm or 100 cell layers. These differences between the two routes of administration provide a rational basis for the expectation that a substantial increase of the therapeutic benefits of misonidazole and demethylmisonidazole in potentiating radiation therapy or chemotherapy can be expected in treating tumors confined to the i.p. space.

Gianni, L.; Jenkins, J.F.; Greene, R.F.; Lichter, A.S.; Myers, C.E.; Collins, J.M.

1983-02-01

71

Radiosensitization of Human Vascular Endothelial Cells Through Hsp90 Inhibition With 17-N-Allilamino-17-Demethoxygeldanamycin  

SciTech Connect

Purpose: In addition to invasive tumor cells, endothelial cells (ECs) of the tumor vasculature are an important target for anticancer radiotherapy. The purpose of the present work is to investigate how 17-N-allilamino-17-demethoxygeldanamycin (17AAG), known as an anticancer drug inhibiting heat shock protein 90 (Hsp90), modifies radiation responses of human vascular ECs. Methods and Materials: The ECs cultured from human umbilical veins were exposed to {gamma}-irradiation, whereas some EC samples were pretreated with growth factors and/or 17AAG. Postirradiation cell death/survival and morphogenesis were assessed by means of terminal deoxynucleotidyl transferase biotin-deoxyuridine triphosphate nick end labeling or annexin V staining and clonogenic and tube-formation assays. The 17AAG-affected expression and phosphorylation of radioresistance-related proteins were probed by means of immunoblotting. Dominant negative or constitutively activated Akt was transiently expressed in ECs to manipulate Akt activity. Results: It was found that nanomolar concentrations of 17AAG sensitize ECs to relatively low doses (2-6 Gy) of {gamma}-irradiation and abolish the radioprotective effects of vascular endothelial growth factor and basic fibroblast growth factor. The drug-induced radiosensitization of ECs seems to be caused by prevention of Hsp90-dependent phosphorylation (activation) of Akt that results in blocking the radioprotective phosphatidylinositol 3-kinase/Akt pathway. Conclusions: Clinically achievable concentrations of 17AAG can decrease the radioresistance intrinsic to vascular ECs and minimize the radioprotection conferred upon them by tumor-derived growth factors. These findings characterize 17AAG as a promising radiosensitizer for the tumor vasculature.

Kabakov, Alexander E. [Department of Radiation Biochemistry, Medical Radiology Research Center, Obninsk (Russian Federation)], E-mail: aekabakov@hotmail.com; Makarova, Yulia M.; Malyutina, Yana V. [Department of Radiation Biochemistry, Medical Radiology Research Center, Obninsk (Russian Federation)

2008-07-01

72

Raman spectroscopic identification of normal and malignant human stomach cells  

NASA Astrophysics Data System (ADS)

Micro-Raman spectroscopy is employed to identify the normal and malignant human stomach cells. For the cancer cell, the reduced intensity of the Raman peak at 1250 cm^(-1) indicates that the protein secondary structure transforms from ?-sheet or disordered structures to ?-helical, while the increased intensity of the symmetric PO2 stretching vibration mode at 1094 cm^(-1) shows the increased DNA content. The ratio of the intensity at 1315 cm^(-1) to that at 1340 cm^(-1) reduces from 1.8 for the normal cell to 1.1 for the cancer cell in the course of canceration, and the ratio of the intensity at 1655 cm^(-1) to that at 1450 cm^(-1) increases from 1.00 for the cancer cell to 1.26 for the normal cell which indicates that the canceration of stomach cell may induce saturation of the lipid chain.

Yang, Jipeng; Guo, Jianyu; Wu, Liangping; Sun, Zhenrong; Cai, Weiying; Wang, Zugeng

2005-12-01

73

Butyrate modulates antioxidant enzyme expression in malignant and non-malignant human colon tissues.  

PubMed

The induction of antioxidant enzymes is an important mechanism in colon cancer chemoprevention, but the response of human colon tissue to butyrate, a gut fermentation product derived from dietary fiber, remains largely unknown. Therefore, our study investigated the effect of a butyrate treatment on catalase (CAT) and superoxide dismutase (SOD2) in matched human colon tissues of different transformation stages (n?=?3-15 in each group) ex vivo. By performing quantitative real-time PCR, Western blot, and spectrophotometric measurements, we found an increase in SOD2 at expression and activity level in colonic adenocarcinomas (mRNA: 1.96-fold; protein: 1.41-fold, activity: 1.8-fold; P?malignant tissues, greater variations in response to butyrate were observed. Furthermore, both enzymes showed an age-dependent decrease in activity in normal colon epithelium (CAT: r?=?-0.49, P?=?0.09; SOD2: r?=?-0.58, P?=?0.049). In conclusion, butyrate exhibited potential antioxidant features ex vivo but cellular consequences need to be investigated more in depth. © 2014 Wiley Periodicals, Inc. PMID:24677319

Jahns, Franziska; Wilhelm, Anne; Jablonowski, Nadja; Mothes, Henning; Greulich, Karl Otto; Glei, Michael

2015-04-01

74

ZnFe2O4 nanoparticles as radiosensitizers in radiotherapy of human prostate cancer cells.  

PubMed

Nanoparticles of high-Z elements exhibit stronger photoelectric effects than soft tissues under gamma irradiation. Hence, they can be used as effective radiosensitizers for increasing the efficiency of current radiotherapy. In this work, superparamagnetic zinc ferrite spinel (ZnFe2O4) nanoparticles were synthesized by a hydrothermal reaction method and used as radiosensitizers in cancer therapy. The magnetic nanoparticles showed fast separation from solutions (e.g., ~1 min for 2 mg mL(-1) of the nanoparticles in ethanol) by applying an external magnetic field (~1T). The ZnFe2O4 nanoparticles were applied in an in vitro radiotherapy of lymph node carcinoma of prostate cells (as high radioresistant cells) under gamma irradiation of (60)Co source. The nanoparticles exhibited no significant effects on the cancer cells up to the high concentration of 100 ?g mL(-1), in the absence of gamma irradiation. The gamma irradiation alone (2Gy dose) also showed no significant effects on the cells. However, gamma irradiation in the presence of 100 ?g mL(-1) ZnFe2O4 nanoparticles resulted in ~53% inactivation of the cells (~17 times higher than the inactivation that occurred under gamma irradiation alone) after 24h. The higher cell inactivation was assigned to interaction of gamma radiation with nanoparticles (photoelectric effect), resulting in a high level electron release in the media of the radioresistant cells. Our results indicated that ZnFe2O4 nanoparticles not only can be applied in increasing the efficiency of radiotherapy, but also can be easily separated from the cell environment by using an external magnetic field after the radiotherapy. PMID:25492003

Meidanchi, Alireza; Akhavan, Omid; Khoei, Samideh; Shokri, Ali A; Hajikarimi, Zahra; Khansari, Nakisa

2015-01-01

75

Human malignant glioma cells expressing functional formylpeptide receptor recruit endothelial progenitor cells for neovascularization  

Microsoft Academic Search

Endothelial progenitor cells (EPCs) are involved in tumor neovascularization with undefined mechanisms. In this study, we explored the role of formylpeptide receptor, a G protein-coupled receptor, expressed by human malignant glioma cells in neovascularization of malignant glioma. EPCs were isolated from human umbilical cord blood and their migratory capability and tubulogenesis induced by the supernatant of U87 glioblastoma (GBM) cell

Cheng-ping Xu; Hua-rong Zhang; Fei-lan Chen; Xiao-hong Yao; Zi-qing Liang; Rong Zhang; Youhong Cui; Cheng Qian; Xiu-wu Bian

2010-01-01

76

Human herpes simplex viruses in benign and malignant thyroid tumours.  

PubMed

To test the hypothesis that herpes viruses may have a role in thyroid neoplasia, we analysed thyroid tissues from patients with benign (44) and malignant (65) lesions for HSV1 and HSV2 DNA. Confirmatory studies included direct sequencing, analysis of viral gene expression, and activation of viral-inducible signalling pathways. Expression of viral entry receptor nectin-1 was examined in human samples and in cancer cell lines. In vitro experiments were performed to explore the molecular mechanisms underlying thyroid cancer cell susceptibility to HSV. HSV DNA was detected in 43/109 (39.4%) examined samples. HSV capsid protein expression correlated with HSV DNA status. HSV-positive tumours were characterized by activation of virus-inducible signalling such as interferon-beta expression and nuclear NFkappaB expression. Lymphocyte infiltration and oncocytic cellular features were common in HSV-positive tumours. HSV1 was detected with the same frequency in benign and malignant thyroid tumours. HSV2 was significantly associated with papillary thyroid cancer and the presence of lymph node metastases. The expression of HSV entry receptor nectin-1 was increased in thyroid tumours compared to normal thyroid tissue and further increased in papillary thyroid cancer. Nectin-1 expression was detected in all examined thyroid cancer cell lines. Nectin-1 expression in cancer cells correlated with their susceptibility to HSV. Inhibition of PI3K/AKT or MAPK/ERK signalling did not affect the level of nectin-1 expression but decreased thyroid cancer cell susceptibility to HSV. These findings showed that HSV is frequently detected in thyroid cancer. During tumour progression, thyroid cells acquire increased susceptibility to HSV due to increased expression of viral entry mediator nectin-1 and activation of mitogenic signalling in cancer cells. PMID:20455254

Jensen, Kirk; Patel, Aneeta; Larin, Alexander; Hoperia, Victoria; Saji, Motoyasu; Bauer, Andrew; Yim, Kevin; Hemming, Val; Vasko, Vasyl

2010-06-01

77

Radiosensitizing effect of gold nanoparticles in carbon ion irradiation of human cervical cancer cells  

SciTech Connect

Noble metal nanoparticles have received considerable attention in biotechnology for their role in bio sensing due to surface plasmon resonance, medical diagnostics due to better imaging contrast and therapy. The radiosensitization effect of gold nanoparticles (AuNP) has been gaining popularity in radiation therapy of cancer cells. The better depth dose profile of energetic ion beam proves its superiority over gamma radiation for fighting against cancer. In the present work, the glucose capped gold nanoparticles (Glu-AuNP) were synthesised and internalized in the HeLa cells. Transmission electron microscopic analysis of ultrathin sections of Glu-AuNP treated HeLa cells confirmed the internalization of Glu-AuNPs. Control HeLa cells and Glu-AuNp treated HeLa cells were irradiated at different doses of 62 MeV 12C ion beam (LET - 290keV/{mu}m) at BIO beam line of using 15UD Pelletron accelerator at Inter University Accelerator Centre, New Delhi, India. The survival fraction was assessed by colony forming assay which revealed that the dose of carbon ion for 90% cell killing in Glu-AuNP treated HeLa cells and control HeLa cells are 2.3 and 3.2 Gy respectively. This observation shows {approx} 28% reduction of {sup 12}C{sup 6+} ion dose for Glu-AuNP treated HeLa cells as compared to control HeLa cells.

Kaur, Harminder; Avasthi, D. K.; Pujari, Geetanjali; Sarma, Asitikantha [Inter University Accelerator Centre, Aruna Asaf Ali Marg, Post box-10502, New Delhi-110067 (India)

2013-07-18

78

Radiosensitizing effect of gold nanoparticles in carbon ion irradiation of human cervical cancer cells  

NASA Astrophysics Data System (ADS)

Noble metal nanoparticles have received considerable attention in biotechnology for their role in bio sensing due to surface plasmon resonance, medical diagnostics due to better imaging contrast and therapy. The radiosensitization effect of gold nanoparticles (AuNP) has been gaining popularity in radiation therapy of cancer cells. The better depth dose profile of energetic ion beam proves its superiority over gamma radiation for fighting against cancer. In the present work, the glucose capped gold nanoparticles (Glu-AuNP) were synthesised and internalized in the HeLa cells. Transmission electron microscopic analysis of ultrathin sections of Glu-AuNP treated HeLa cells confirmed the internalization of Glu-AuNPs. Control HeLa cells and Glu-AuNp treated HeLa cells were irradiated at different doses of 62 MeV 12C ion beam (LET - 290keV/?m) at BIO beam line of using 15UD Pelletron accelerator at Inter University Accelerator Centre, New Delhi, India. The survival fraction was assessed by colony forming assay which revealed that the dose of carbon ion for 90% cell killing in Glu-AuNP treated HeLa cells and control HeLa cells are 2.3 and 3.2 Gy respectively. This observation shows ˜ 28% reduction of 12C6+ ion dose for Glu-AuNP treated HeLa cells as compared to control HeLa cells.

Kaur, Harminder; Avasthi, D. K.; Pujari, Geetanjali; Sarma, Asitikantha

2013-07-01

79

CpG ODN107 potentiates radiosensitivity of human glioma cells via TLR9-mediated NF-?B activation and NO production.  

PubMed

Radiotherapy is a standard treatment for glioma patient with or without surgery; radiosensitizer can increase tumor sensitivity for radiotherapy. Herein, a synthetic oligodeoxynucleotide containing unmethylated CpG dinucleotides (CpG ODN107) as a radiosensitizer was investigated in vitro and in vivo, and the possible mechanisms were studied in vitro. In the present experiments, the human glioma U87 cell line used herein was resistant to 5 Gy of ?-ray irradiation. The results showed that 10 ?g/ml of CpG ODN107 in combination with irradiation significantly inhibited cell proliferation both in MTT assay and colony formation experiments. Tumor growth was inhibited by CpG ODN107 in combination with local irradiation but not by local irradiation or CpG ODN107 alone in human glioma xenograft model in nude mice. The inhibition ratio of tumor growth produced by CpG ODN107 (1.7, 5, and 15 mg/kg) in combination with irradiation was 27.3, 67.0, and 65.5 %, respectively. Further molecular mechanisms were studied in vitro. The results showed that the expressions of iNOS, NO, TLR9 mRNA, and NF-?B p50/p65 increased in the cells treated with CpG ODN107 in combination with irradiation. CpG ODN107 in combination with irradiation did not induce apoptosis but induced cell cycle arrest at G(1) phase. The said results demonstrated that CpG ODN107 possessed a radiosensitizing effect via TLR9-mediated NF-?B activation and NO production in the tumor cells, leading to cell cycle arrest. Therefore, CpG ODN107 is a potential candidate as radiosensitizer for human glioma. PMID:22739939

Li, Xiaoli; Liu, Dan; Liu, Xin; Jiang, Weiwei; Zhou, Weiying; Yan, Wei; Cen, Yanyan; Li, Bin; Cao, Guanqun; Ding, Guofu; Pang, Xueli; Sun, Jianguo; Zheng, Jiang; Zhou, Hong

2012-10-01

80

VorinostatSAHA Promotes Hyper-Radiosensitivity in Wild Type p53 Human Glioblastoma Cells  

PubMed Central

Glioblastoma multiforme (GBM) is a very aggressive and locally invasive tumor. The current standard of care is partial brain radiation therapy (60 Gy) concurrently with the alkylating agent temozolomide (TMZ). However, patients’ survival remains poor (6-12 months) mainly due to local and diffuse (distant) recurrence. The possibility to promote hyper radiosensitivity (HRS) with low dose radiation may contribute to improve outcome. Here, we evaluated the effect of VorinostatSAHA and TMZ on glioblastoma cells’ sensitivity to low dose radiation. Clonogenic survivals were performed on D54 (p53 and PTEN wild type) and U118 (p53 and PTEN mutants) cells exposed to clinically relevant doses of VorinostatSAHA and TMZ and increasing radiation doses. Apoptosis was measured by the activation of caspase-3 and the role of p53 and PTEN were evaluated with the p53 inhibitor pifithrin ? and the PI3K/AKT pathway inhibitor LY29002. VorinostatSAHA promoted HRS at doses as low as 0.25 Gy in the D54 but not the U118 cells. Killing efficiency was associated with caspase-3 activation, delayed H2AX phosphorylation and abrogation of a radiation -induced G2 arrest. Inhibiting p53 function with pifithrin ? prevented the promotion of HRS by VorinostatSAHA. Moreover, LY29002, a PI-3K inhibitor, restored promotion of HRS by VorinostatSAHA in the p53 mutant U118 cells to levels similar to the p53 wild type cells. TMZ also promoted HRS at doses as low as 0.15 Gy. These finding indicate that HRS can be promoted in p53 wild type glioblastoma cells through a functional PTEN to delay DNA repair and sensitize cells to low dose radiation. Promotion of HRS thus appears to be a viable approach for GBM that could be used as a basis to develop new Phase I/II studies. PMID:25379568

Diss, Eric; Nalabothula, NarasimhaRao; Nguyen, Duc; Chang, Elizabeth; Kwok, Young; Carrier, France

2014-01-01

81

Vorinostat(SAHA) Promotes Hyper-Radiosensitivity in Wild Type p53 Human Glioblastoma Cells.  

PubMed

Glioblastoma multiforme (GBM) is a very aggressive and locally invasive tumor. The current standard of care is partial brain radiation therapy (60 Gy) concurrently with the alkylating agent temozolomide (TMZ). However, patients' survival remains poor (6-12 months) mainly due to local and diffuse (distant) recurrence. The possibility to promote hyper radiosensitivity (HRS) with low dose radiation may contribute to improve outcome. Here, we evaluated the effect of Vorinostat(SAHA) and TMZ on glioblastoma cells' sensitivity to low dose radiation. Clonogenic survivals were performed on D54 (p53 and PTEN wild type) and U118 (p53 and PTEN mutants) cells exposed to clinically relevant doses of Vorinostat(SAHA) and TMZ and increasing radiation doses. Apoptosis was measured by the activation of caspase-3 and the role of p53 and PTEN were evaluated with the p53 inhibitor pifithrin ? and the PI3K/AKT pathway inhibitor LY29002. Vorinostat(SAHA) promoted HRS at doses as low as 0.25 Gy in the D54 but not the U118 cells. Killing efficiency was associated with caspase-3 activation, delayed H2AX phosphorylation and abrogation of a radiation -induced G2 arrest. Inhibiting p53 function with pifithrin ? prevented the promotion of HRS by Vorinostat(SAHA). Moreover, LY29002, a PI-3K inhibitor, restored promotion of HRS by Vorinostat(SAHA) in the p53 mutant U118 cells to levels similar to the p53 wild type cells. TMZ also promoted HRS at doses as low as 0.15 Gy. These finding indicate that HRS can be promoted in p53 wild type glioblastoma cells through a functional PTEN to delay DNA repair and sensitize cells to low dose radiation. Promotion of HRS thus appears to be a viable approach for GBM that could be used as a basis to develop new Phase I/II studies. PMID:25379568

Diss, Eric; Nalabothula, NarasimhaRao; Nguyen, Duc; Chang, Elizabeth; Kwok, Young; Carrier, France

2014-01-15

82

Embryonic stem cell (ESC)-mediated transgene delivery induces growth suppression, apoptosis and radiosensitization, and overcomes temozolomide resistance in malignant gliomas  

Microsoft Academic Search

High-grade gliomas are among the most lethal of all cancers. Despite considerable advances in multimodality treatment, including surgery, radiotherapy and chemotherapy, the overall prognosis for patients with this disease remains dismal. Currently available treatments necessitate the development of more effective tumor-selective therapies. The use of gene therapy for malignant gliomas is promising, as it allows in situ delivery and selectively

I M Germano; L Emdad; Z A Qadeer; E Binello; M Uzzaman

2010-01-01

83

September 28, 2005: Mechanisms Leading to the Formation of Human Malignancies  

Cancer.gov

Mechanisms Leading to the Formation of Human Malignancies Star Speakers Robert Weinberg, PhD Member, Whitehead Institute for Biomedical Research Daniel K. Ludwig and American Cancer Society Research Professor of Molecular Biology Dept. of Biology, Massachusetts

84

Depletion of Securin Induces Senescence After Irradiation and Enhances Radiosensitivity in Human Cancer Cells Regardless of Functional p53 Expression  

SciTech Connect

Purpose: Radiotherapy is one of the best choices for cancer treatment. However, various tumor cells exhibit resistance to irradiation-induced apoptosis. The development of new strategies to trigger cancer cell death besides apoptosis is necessary. This study investigated the role of securin in radiation-induced apoptosis and senescence in human cancer cells. Methods and Materials: Cell survival was determined using clonogenic assays. Western blot analysis was used to analyze levels of securin, caspase-3, PARP, p53, p21, Rb, gamma-H2AX, and phospho-Chk2. Senescent cells were analyzed using a beta-galactosidase staining assay. A securin-expressed vector (pcDNA-securin) was stably transfected into securin-null HCT116 cells. Securin gene knockdown was performed by small interfering RNA and small hairpin RNA in HCT116 and MDA-MB-231 cells, respectively. Results: Radiation was found to induce apoptosis in securin wild type HCT116 cells but induced senescence in securin-null cells. Restoration of securin reduced senescence and increased cell survival in securin-null HCT116 cells after irradiation. Radiation-induced gamma-H2AX and Chk2 phosphorylation were induced transiently in securin-wild-type cells but exhibited sustained activation in securin-null cells. Securin gene knockdown switches irradiation-induced apoptosis to senescence in both HCT116 p53-null and MDA-MB-231 cells. Conclusions: Our results demonstrated that the level of securin expression plays a determining role in the radiosensitivity and fate of cells. Depletion of securin impairs DNA repair after irradiation, increasing DNA damage and promoting senescence in the residual surviving cells regardless of functional p53 expression. The knockdown of securin may contribute to a novel radiotherapy protocol for the treatment of human cancer cells that are resistant to irradiation.

Chen Wenshu; Yu Yichu [Department of Life Science, Tzu Chi University, Hualien, Taiwan (China); Lee Yijang [Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan (China); Chen, J.-H. [Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan (China); Hsu, H.-Y. [Department of Life Science, Tzu Chi University, Hualien, Taiwan (China); Chiu, S.-J., E-mail: chiusj@mail.tcu.edu.t [Department of Life Science, Tzu Chi University, Hualien, Taiwan (China); Institute of Radiation Sciences, Tzu Chi Technology College, Hualien, Taiwan (China)

2010-06-01

85

The Sodium Iodide Symporter (NIS) and Potential Regulators in Normal, Benign and Malignant Human Breast Tissue  

Microsoft Academic Search

IntroductionThe presence, relevance and regulation of the Sodium Iodide Symporter (NIS) in human mammary tissue remains poorly understood. This study aimed to quantify relative expression of NIS and putative regulators in human breast tissue, with relationships observed further investigated in vitro.MethodsHuman breast tissue specimens (malignant n = 75, normal n = 15, fibroadenoma n = 10) were analysed by RQ-PCR

James Ryan; Catherine E. Curran; Emer Hennessy; John Newell; John C. Morris; Michael J. Kerin; Roisin M. Dwyer; Marian Ludgate

2011-01-01

86

Normal human colon cells suppress malignancy when fused with colon cancer cells  

SciTech Connect

Normal human colon mucosa cells and cells obtained from histologically normal tissues near that cancer were fused with human colon cancer cells. Resultant hybrid populations of normal and malignant cell fusions behaved as nonmalignant cells in culture, were unable to grow in soft agar, did not express tumor-associated antigens, and were nontumorigenic in nude mice. Autofusion of the cancer cell population led to a phenotype intermediate between normal and malignant cells. That is, the cultures had a much lower plating efficiency in soft agar, and the tumors had a longer latency and slower growth rate in nude mice. This is the first cell culture system to demonstrate that normal epithelial cells can suppress malignancy of their autologous cancer cells, and is a prelude to more extensive studies of genetic events involved in malignant conversion of human colonic epithelium.

Johnson, T.L.; Moyer, M.P. (Univ. of Texas Health Science Center, San Antonio (USA))

1990-11-01

87

Pleiotropic roles of Notch signaling in normal, malignant, and developmental hematopoiesis in the human.  

PubMed

The Notch signaling pathway is evolutionarily conserved across species and plays an important role in regulating cell differentiation, proliferation, and survival. It has been implicated in several different hematopoietic processes including early hematopoietic development as well as adult hematological malignancies in humans. This review focuses on recent developments in understanding the role of Notch signaling in the human hematopoietic system with an emphasis on hematopoietic initiation from human pluripotent stem cells and regulation within the bone marrow. Based on recent insights, we summarize potential strategies for treatment of human hematological malignancies toward the concept of targeting Notch signaling for fate regulation. PMID:25252682

Kushwah, Rahul; Guezguez, Borhane; Lee, Jung Bok; Hopkins, Claudia I; Bhatia, Mickie

2014-11-01

88

Cytotoxicity of human umbilical cord blood-derived mesenchymal stem cells against human malignant glioma cells  

Microsoft Academic Search

Background  Mesenchymal stem cells (MSCs) represent a potential useful source for cell-based glioma therapies because these cells evidence\\u000a both orthodox and unorthodox plasticity and also show tropism for cancer. In this study, the authors attempted to access the\\u000a cytotoxicity of human umbilical cord blood (hUCB)-derived MSCs, with or without cytokine activations against malignant glioma\\u000a cells.\\u000a \\u000a \\u000a \\u000a Materials and methods  hUCB-derived MSCs were activated

Seok-Gu Kang; Sin Soo Jeun; Jung Yeon Lim; Seong Muk Kim; Yoon Sun Yang; Won IL Oh; Pil-Woo Huh; Chun Kun Park

2008-01-01

89

A combination of 2-deoxy-D-glucose and 6-aminonicotinamide induces cell cycle arrest and apoptosis selectively in irradiated human malignant cells.  

PubMed

Previously, we have shown that a combination of metabolic modifiers 2-deoxy-D-glucose (2-DG) and 6-aminonicotinamide (6-AN) results in oxidative stress mediated radiosensitization of malignant cells via mitochondrial dysfunction and non-coordinated expression of antioxidant defense, besides inhibition of repair and recovery. In the present study, our objective was to study, in a panel of human malignant cells of various origins (lung carcinoma, squamous carcinoma, oral carcinoma, and glioblastoma), if the inhibitory activity of combination (2-DG+6-AN+2 Gy) against tumor growth could be considered a general phenomenon and to determine its effect on the cell cycle. The results revealed that combination (2-DG+6-AN+2 Gy) treatment result in significant cell growth inhibition and induced ROS generation in all cancer cells studied. The anti-proliferative effect was related to the ability of combination (2-DG+6-AN+2 Gy) to provoke growth inhibition at the G2/M arrest and apoptosis. Furthermore, combination (2-DG+6-AN+2 Gy) induced G2/M arrest is closely correlated to decreased cyclin A, cyclin B1, and cdc2 levels. PMID:22328137

Bhardwaj, Richa; Sharma, Pradeep K; Jadon, S P S; Varshney, Rajeev

2012-08-01

90

Radiosensitization induced by the anti-epidermal growth factor receptor monoclonal antibodies cetuximab and nimotuzumab in A431 cells.  

PubMed

Epidermal growth factor receptors (EGFR) are overexpressed in a wide range of malignancies including head and neck, colon, and breast cancers. It has been identified that carcinomas with high expression levels of EGFR are more resistant to radiotherapy. Therefore, inhibiting nuclear translocation of EGFR to increase the radiosensitivity of malignant cells expressing EGFR offers the potential for increasing the therapeutic index of radiotherapy. The purpose of the present study was to quantify and to compare the radiosensitizing properties of the well-known anti-EGFR antibodies, cetuximab and nimotuzumab in human epidermoid A431 overexpressing EGFR cells. Cells were treated with two concentrations of the antibodies and then irradiated with a single dose of 4 Gy. The results indicated that the two antibodies induced radiosensitization increasing the percentage of dead/dying cells and the yield of ?-H2AX foci 24 h after irradiation. Whereas cetuximab exhibited a significant increase in radiosensitization at the highest concentration, the effects of nimotuzumab were more modest. A correlation between ?-H2AX foci signals and dead/dying cells was observed. The disparity in modulation of radiation-induced DNA damage by the two antibodies could be associated with the level of their respective intrinsic cytotoxic properties. Overall, the findings highlight the potential therapeutic benefit of combination therapy with anti-EGFR antibodies and radiotherapy for relevant carcinomas. PMID:22231391

González, Jorge Ernesto; Barquinero, Joan Francesc; Lee, Manuel; García, Omar; Casaco, Angel

2012-01-15

91

In vitro measurements of ultraweak luminescence of human malignant tumors and healthy tissues  

NASA Astrophysics Data System (ADS)

In vitro measurements of levels of ultraweak luminescence were carried out using healthy and malignant tissues obtained from 63 patients undergoing surgical operations for cancers of colon, stomach and breast. The results obtained support recent reports that there is a difference in mean intensities of the ultraweak luminescence emitted from healthy and malignant tissues. This work demonstrates, however, that because of a large scatter among the intensities detected for samples obtained from different patients the differences found for the mean intensities cannot serve as a parameter for differentiating between the malignant and normal human tissues.

Chwirot, B. W.; Chwirot, S.; Jedrzejczyk, W.; Pozniak, V.; Dziczek, D.; Michniewicz, Z.; Jackowski, M.; Raczynska, A. M.; Winczakiewicz, J.

2001-07-01

92

Targeting eradication of malignant cells derived from human bone marrow mesenchymal stromal cells  

SciTech Connect

Human bone marrow mesenchymal stromal cells (hBMSC) have been shown to participate in malignant transformation. However, hampered by the low frequency of malignant transformation of hBMSC, we do not yet know how to prevent malignant transformation of implanted hBMSC. In this study, in order to establish a model for the eradication of hBMSC-derived malignant cells, a gene fusion consisting of a human telomerase (hTERT) promoter modified with both c-Myc and myeloid zinc finger protein2 (MZF-2) binding elements and followed by the E. coli cytosine deaminase (CD) and luciferase genes was stably transferred into hBMSC via lentiviral transduction; n-phosphonacelyl-L-aspartic acid (PALA) selection was used to generate malignant cell colonies derived from transduced hBMSC after treatment with the carcinogenic reagent BPDE. Cells that were amplified after PALA selection were used for transplantation and 5-FC pro-drug cytotoxicity tests. The results showed that PALA-resistant malignant cells could be generated from hBMSC co-induced with lentiviral transduction and treatment with Benzo(a)pyrene Diol Epoxide (BPDE); the modification of c-Myc and MZF-2 binding elements could remarkably enhance the transcriptional activities of the hTERT promoter in malignant cells, whereas transcriptional activity was depressed in normal hBMSC; malignant cells stably expressing CD under the control of the modified hTERT promoter could be eliminated by 5-FC administration. This study has provided a method for targeted eradication of malignant cells derived from hBMSC.

Yang, Yingbin [Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044 (China) [Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044 (China); School of Life Science, Southwest University, Chongqing 400715 (China); Cai, Shaoxi, E-mail: sxcai@cqu.edu.cn [Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044 (China)] [Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044 (China); Yang, Li [Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044 (China) [Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044 (China); College of Pharmacy, Jinan University, Guangzhou 510632 (China); Yu, Shuhui [Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044 (China) [Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044 (China); Library of Southwest University, Chongqing 400715 (China); Jiang, Jiahuan; Yan, Xiaoqing [Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044 (China)] [Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044 (China); Zhang, Haoxing [School of Life Science, Southwest University, Chongqing 400715 (China)] [School of Life Science, Southwest University, Chongqing 400715 (China); Liu, Lan [Department of Laboratory of Medicine, Children's Hospital of Chongqin Medical University, Chongqing 400014 (China)] [Department of Laboratory of Medicine, Children's Hospital of Chongqin Medical University, Chongqing 400014 (China); Liu, Qun [College of Life Science and Technology, Southwest University for Nationalities, Chengdu 610041 (China)] [College of Life Science and Technology, Southwest University for Nationalities, Chengdu 610041 (China); Du, Jun [Center of Microbiology, Biochemistry, and Pharmacology, School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510080 (China)] [Center of Microbiology, Biochemistry, and Pharmacology, School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510080 (China); Cai, Shaohui [College of Pharmacy, Jinan University, Guangzhou 510632 (China)] [College of Pharmacy, Jinan University, Guangzhou 510632 (China); Sung, K.L. Paul [Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044 (China) [Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044 (China); Departments of Orthopaedic Surgery and Bioengineering, University of California, SD 0412 (United States)

2010-12-10

93

Malignant transformation of diploid human fibroblasts by transfection of oncogenes: Progress report, July 1986June 1989  

Microsoft Academic Search

Although there is good evidence that carcinogen exposure is a major cause of human cancer, it has proven impossible to transform normal human fibroblasts or epithelial cells in culture into malignant cells by treating them with carcinogens. This failure may reflect an inability to identify and isolate cells containing one or more premalignant changes so that these can be expanded

J. J. McCormick; V. M. Maher

1989-01-01

94

Radiosensitizing and anti-proliferative effects of resveratrol in two human cervical tumor cell lines.  

PubMed

Resveratrol is a polyphenol isolated from the skins of grapes that has been shown to significantly alter the cellular physiology of tumor cells, as well as block the process of initiation and progression. At least one mechanism for the intracellular actions of resveratrol involves the suppression of prostaglandin (PG) biosynthesis. The involvement of PGs and other eicosanoids in the development of human cancer is well established. PGs are synthesized from arachidonic acid via the cyclooxygenase pathway and have multiple physiological and pathological functions. In addition, evidence has arisen suggesting that PGs may be implicated in the cytotoxic and/or cytoprotective response of tumor cells to ionizing radiation (IR). As such, we hypothesized that tumor cells may exhibit changes in the cellular response to IR following exposure to resveratrol, a naturally occurring compound that inhibits cyclooxygenase-1 (COX-1) activity. Thus, clonogenic cell survival assays were performed using irradiated HeLa and SiHa cells pretreated with resveratrol prior to IR exposure, and resulted in enhanced tumor cell killing by IR in a dose-dependent manner. Further analysis of COX-1 inhibition indicated that resveratrol pretreatment: (1), inhibited cell division as assayed by growth curves; and (2), induced an early S phase cell cycle checkpoint arrest, as demonstrated by fluorescence-activated cell sorting, as well as bromodeoxyuridine pulse-chase analysis. These results suggest that resveratrol alters both cell cycle progression and the cytotoxic response to IR in two cervical tumor cell lines. PMID:11741744

Zoberi, Imran; Bradbury, C Matthew; Curry, Heather A; Bisht, Kheem S; Goswami, Prabhat C; Roti Roti, Joseph L; Gius, David

2002-01-25

95

The enhancement of radiosensitivity in human esophageal squamous cell carcinoma cells by zoledronic acid and its potential mechanism.  

PubMed

Esophageal squamous cell carcinoma (ESCC) has a low 5-year patient survival rate. Radiotherapy, as a preoperative or postoperative treatment of surgery, has a crucial role in improving local control and survival of ESCC. Various chemotherapeutic and biologic agents have been used as radio-sensitizers in combination with radiotherapy. Here, we demonstrate that zoledronic acid (ZOL) has a radio-sensitizing effect on ESCC cells. Exposure of ESCC cancer cells to ZOL plus radiation resulted in increased cell death through arresting the cell cycle between S and G2/M phases. ZOL appeared to inhibit proliferation, tube formation and invasion of endothelial cells. These anti-angiogenetic effects were more marked concurrently with irradiation. In addition, synergistic suppressive effects on VEGF expression were observed after combined treatment. Our data suggest that the combination of ZOL and radiation is a promising therapeutic strategy to enhance radiation therapy for ESCC patients. PMID:23334334

You, Yanjie; Liu, Jianfeng; Wang, Zhizhong; Zhang, Yuan; Ran, Yonggang; Guo, Xu; Liu, Huimin; Wang, Haibo

2014-01-01

96

Biomarkers for enhancing the radiosensitivity of nasopharyngeal carcinoma  

PubMed Central

Nasopharyngeal carcinoma (NPC) is a common head and neck malignancy. The incidence of NPC is higher in Southern China and Southeast Asia compared with Western countries. Given its high radiosensitivity, the standard treatment for NPC is radiotherapy. However, radioresistance remains a serious obstacle to successful treatment. Radioresistance can cause local recurrence and distant metastases in some patients after treatment by radiation. Thus, special emphasis has been given to the discovery of effective radiosensitizers. This review aims to discuss the biomarkers, classified according to the main mechanisms of radiosensitization, which can enhance the sensitivity of NPC cells to ionizing radiation.

Chen, Wei; Hu, Guo-Hua

2015-01-01

97

Combined cord blood and bone marrow transplantation from the same human leucocyte antigen-identical sibling donor for children with malignant and non-malignant diseases.  

PubMed

Umbilical cord blood (UCB) from an human leucocyte antigen (HLA)-identical sibling can be used for transplantation of patients with malignant and non-malignant diseases. However, the low cellular content of most UCB units represents a limitation to this approach. An option to increase cell dose is to harvest bone marrow (BM) cells from the same donor and infuse them along with the UCB. We studied 156 children who received such a combined graft between 1992 and 2011. Median age was 7 years and 78% of patients (n = 122) were transplanted for non-malignant diseases, mainly haemoglobinopathies. Acute leukaemia (n = 26) was the most frequent malignant diagnosis. Most patients (91%) received myeloablative conditioning. Median donor age was 1·7 years, median infused nucleated cell dose was 24·4 × 10(7) /kg and median follow-up was 41 months. Sixty-days neutrophil recovery occurred in 96% of patients at a median of 17 d. The probabilities of grade-II-IV acute and chronic graft-versus-host disease (GVHD) were 19% and 10%, respectively. Four-year overall survival was 90% (68% malignant; 97% non-malignant diseases) with 3% probability of death. In conclusion, combined UCB and BM transplantation from an HLA-identical sibling donor is an effective treatment for children with malignant and non-malignant disorders with high overall survival and low incidence of GVHD. PMID:25521756

Tucunduva, Luciana; Volt, Fernanda; Cunha, Renato; Locatelli, Franco; Zecca, Marco; Yesilipek, Akif; Caniglia, Maurizio; Güngör, Tayfun; Aksoylar, Serap; Fagioli, Franca; Bertrand, Yves; Addari, Maria Carmen; de la Fuente, Josu; Winiarski, Jacek; Biondi, Andrea; Sengeloev, Henrik; Badell, Isabel; Mellgren, Karin; de Heredia, Cristina Díaz; Sedlacek, Petr; Vora, Ajay; Rocha, Vanderson; Ruggeri, Annalisa; Gluckman, Eliane

2015-04-01

98

Heterochromatin protein 1 expression is reduced in human thyroid malignancy.  

PubMed

Owing to the loss of heterochromatin integrity that occurs during thyroid tumorigenesis, the expression of Heterochromatin Protein 1 isoforms HP1? and HP1? was assessed by immunohistochemistry in 189 thyroid tumors and non-neoplastic tissues. Expression of HP1? was significantly decreased in all thyroid lesions, except in follicular adenomas, when compared with matched adjacent normal tissue. This loss of HP1? expression may in part be caused by microRNA dysregulation. An example is miR-205, a microRNA that is abundantly upregulated in thyroid carcinomas and shown to reduce the expression of HP1?. In contrast to HP1?, HP1? expression was only reduced in metastatic carcinomas and poorly differentiated lesions. These results suggest the reduction of HP1? followed by a decrease in HP1? contributes to the pathogenesis of thyroid carcinomas, and their loss is a potential marker of thyroid malignancy and metastatic potential, respectively. PMID:24840329

Tretiakova, Maria S; Bond, Sarah D; Wheeler, David; Contreras, Alejandro; Kocherginsky, Masha; Kroll, Todd G; Hale, Tracy K

2014-07-01

99

Downregulation of miR-210 expression inhibits proliferation, induces apoptosis and enhances radiosensitivity in hypoxic human hepatoma cells in vitro  

SciTech Connect

Hypoxia is a common feature of solid tumors and an important contributor to tumor radioresistance. miR-210 is the most consistently and robustly induced microRNA under hypoxia in different types of tumor cells and normal cells. In the present study, to explore the feasibility of miR-210 as an effective therapeutic target, lentiviral-mediated anti-sense miR-210 gene transfer technique was employed to downregulate miR-210 expression in hypoxic human hepatoma SMMC-7721, HepG2 and HuH7 cells, and phenotypic changes of which were analyzed. Hypoxia led to an increased hypoxia inducible factor-1{alpha} (HIF-1{alpha}) and miR-210 expression and cell arrest in the G{sub 0}/G{sub 1} phase in all cell lines. miR-210 downregulation significantly suppressed cell viability, induced cell arrest in the G{sub 0}/G{sub 1} phase, increased apoptotic rate and enhanced radiosensitivity in hypoxic human hepatoma cells. Moreover, apoptosis-inducing factor, mitochondrion-associated, 3 (AIFM3) was identified as a direct target gene of miR-210. AIFM3 downregulation by siRNA attenuated radiation induced apoptosis in miR-210 downregulated hypoxic human hepatoma cells. Taken together, these data suggest that miR-210 might be a potential therapeutic target and specific inhibition of miR-210 expression in combination with radiotherapy might be expected to exert strong anti-tumor effect on hypoxic human hepatoma cells. -- Highlights: Black-Right-Pointing-Pointer miR-210 downregulation radiosensitized hypoxic hepatoma. Black-Right-Pointing-Pointer AIFM3 was identified as a direct target gene of miR-210. Black-Right-Pointing-Pointer miR-210 might be a therapeutic target to hypoxic hepatoma.

Yang, Wei, E-mail: detachedy@yahoo.com.cn [Department of Radiobiology, School of Radiological Medicine and Protection, Soochow University, Suzhou (China)] [Department of Radiobiology, School of Radiological Medicine and Protection, Soochow University, Suzhou (China); Sun, Ting [Brain and Nerve Research Laboratory, The First Affiliated Hospital, Soochow University, Suzhou (China)] [Brain and Nerve Research Laboratory, The First Affiliated Hospital, Soochow University, Suzhou (China); Cao, Jianping; Liu, Fenju [Department of Radiobiology, School of Radiological Medicine and Protection, Soochow University, Suzhou (China)] [Department of Radiobiology, School of Radiological Medicine and Protection, Soochow University, Suzhou (China); Tian, Ye [Department of Radiotherapy and Oncology, The Second Affiliated Hospital, Soochow University, Suzhou (China)] [Department of Radiotherapy and Oncology, The Second Affiliated Hospital, Soochow University, Suzhou (China); Zhu, Wei [Department of Radiobiology, School of Radiological Medicine and Protection, Soochow University, Suzhou (China)] [Department of Radiobiology, School of Radiological Medicine and Protection, Soochow University, Suzhou (China)

2012-05-01

100

Biochemical Classification of Circulating Immune Complexes in Human Malignant Melanoma and Hematologic Neoplasms  

Microsoft Academic Search

Circulating immune complexes (CIC) in human cancer are known to be very heterogeneous in size and composition. In 95 staged malignant melanoma patients and 71 individuals with leukemia and lymphoma, this heterogeneity was analyzed biochemically in sera positive for CIC. CICs were measured by a multiassay system and individual complexes were isolated and analyzed by immunological and biochemical methods. Analyses

William D. Queen; Noor Bharwani; Elizabeth A. Phillips; Ben A. Ruether; Terry M. Phillips; Martin Jerry

1989-01-01

101

Establishment and characterization of five cell lines derived from human malignant gliomas  

Microsoft Academic Search

We established and characterized five cell lines derived from human malignant gliomas (four glioblastomas multiforme and one highly anaplastic astrocytoma). All cell lines exhibited tumor cell morphology and growth kinetics, and anchorage-independent growth in soft agar. Cytogenetic analysis revealed significant aneuploidy in all five cases as well as clonal chromosomal alterations unique to each cell line. No cell line was

J. T. Rutka; J. R. Giblin; D. Y. Dougherty; H. C. Liu; J. R. McCulloch; C. W. Bell; R. S. Stern; C. B. Wilson; M. L. Rosenblum

1987-01-01

102

Activation of Neural and Pluripotent Stem Cell Signatures Correlates with Increased Malignancy in Human Glioma  

Microsoft Academic Search

The presence of stem cell characteristics in glioma cells raises the possibility that mechanisms promoting the maintenance and self-renewal of tissue specific stem cells have a similar function in tumor cells. Here we characterized human gliomas of various malignancy grades for the expression of stem cell regulatory proteins. We show that cells in high grade glioma co-express an array of

Johan Holmberg; Xiaobing He; Inti Peredo; Abiel Orrego; Göran Hesselager; Christer Ericsson; Outi Hovatta; Sueli Mieko Oba-Shinjo; Suely Kazue Nagahashi Marie; Monica Nistér; Jonas Muhr; Joseph Najbauer

2011-01-01

103

Radiosensitization by Inhibiting STAT1 in Renal Cell Carcinoma  

SciTech Connect

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.

Hui Zhouguang [Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, Houston, TX (United States); Department of Radiation Oncology, Cancer Hospital (Institute), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing (China); Tretiakova, Maria [Department of Pathology, University of Chicago Pritzker School of Medicine, Chicago, IL (United States); Zhang Zhongfa; Li Yan [Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI (United States); Wang Xiaozhen [Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, Houston, TX (United States); Department of Radiation Oncology, Cancer Hospital (Institute), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing (China); Zhu, Julie Xiaohong [Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, Houston, TX (United States); Gao Yuanhong [Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, Houston, TX (United States); Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou (China); Mai Weiyuan [Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, Houston, TX (United States); Furge, Kyle [Laboratory of Computational Biology, Van Andel Research Institute, Grand Rapids, MI (United States); Qian Chaonan [Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI (United States); Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou (China); Amato, Robert [Department of Genitourinary Oncology, Methodist Hospital, Houston, TX (United States); Butler, E. Brian [Department of Radiation Oncology, Methodist Hospital and Methodist Hospital Research Institute, Houston, TX (United States)] (and others)

2009-01-01

104

SWI/SNF chromatin remodeling and human malignancies.  

PubMed

The SWI/SNF complexes, initially identified in yeast 20 years ago, are a family of multi-subunit complexes that use the energy of adenosine triphosphate (ATP) hydrolysis to remodel nucleosomes. Chromatin remodeling processes mediated by the SWI/SNF complexes are critical to the modulation of gene expression across a variety of cellular processes, including stemness, differentiation, and proliferation. The first evidence of the involvement of these complexes in carcinogenesis was provided by the identification of biallelic, truncating mutations of the SMARCB1 gene in malignant rhabdoid tumors, a highly aggressive childhood cancer. Subsequently, genome-wide sequencing technologies have identified mutations in genes encoding different subunits of the SWI/SNF complexes in a large number of tumors. SWI/SNF mutations, and the subsequent abnormal function of SWI/SNF complexes, are among the most frequent gene alterations in cancer. The mechanisms by which perturbation of the SWI/SNF complexes promote oncogenesis are not fully elucidated; however, alterations of SWI/SNF genes obviously play a major part in cancer development, progression, and/or resistance to therapy. PMID:25387058

Masliah-Planchon, Julien; Bièche, Ivan; Guinebretière, Jean-Marc; Bourdeaut, Franck; Delattre, Olivier

2015-01-01

105

Analysis of heteroantisera to cells from human malignant effusions by immunofluorescence and protein A binding.  

PubMed Central

Using cultured cells derived from human malignant effusions, hetero-antisera were raised in rabbits. The antisera were sequentially absorbed on various human non-tumour cells, reactivity being monitored by immunofluorescence and 125I-labelled staphylococcal protein A assays. The absorbed antisera possessed common reactivity to all tumour cells assayed. This reactivity was not histogenically determined, and our data suggest that it was not directed to oncofoetal antigens. Images Fig. 1 Fig. 2 Fig. 3 PMID:339939

Birchall, J. P.; Owen, J. J.; Owen, B. S.

1977-01-01

106

Transfer of malignant trait to immortalized human cells following exposure to human cancer serum.  

PubMed

BackgroundHuman cancer cells can transfer signaling molecules to neighboring and distant cells predisposing them to malignant transformation. This process might contribute to tumor progression and invasion through delivery of oncogenes or inhibitors of tumor suppressor genes, derived from the primary tumor cells, to susceptible target cells. The oncogenic potential of human cancer serum has been described in immortalized mouse fibroblasts but has not been shown yet in human cells The objective of this study was to determine whether metastatic cancer patient sera have the ability to induce neoplastic transformation in immortalized human embryonic kidney (HEK293) cells, human embryonic stem cells (hESCs), human mesenchymal stem cells (hMSCs) and human adult liver fibroblasts (hALFs).MethodsEarly passage HEK293 cells, hESCs, hMSCs and hALFs were exposed to cancer patient serum, or cancer cells-derived condition medium for 3 weeks. Treated cells were analyzed for cell proliferation and transformation both in vitro and in vivo.ResultsHEK293 cells exposed to cancer serum increased their proliferative capability and displayed characteristics of transformed cells, as evaluated by in vitro anchorage-independent growth assay and in vivo tumorigenesis in immunodeficient mice. The same phenotypes were acquired when these cells were cultured in cancer cell line conditioned medium suggesting that the putative oncogenic factors present in the serum might derive directly from the primary tumor. Histopathological analyses revealed that the tumors arising from cancer patient serum and conditioned medium-treated HEK293 cells were poorly differentiated and displayed a high proliferative index. In contrast, neither of these phenomena was observed in treated hMSCs and hALFs. Intriguingly enough, hESC-treated cells maintained their self-renewal and differentiation potentials, as shown by in vitro sphere formation assay and in vivo development of teratomas in immunodeficient mice.ConclusionOur results indicate that cancer patients serum is able to induce oncogenic transformation of HEK293 cells and maintain the self-renewal of hESCs. To our knowledge, this is the first study that demonstrates the oncogenic transformation potential of cancer patient serum on human cells. In depth characterization of this process and the molecular pathways involved are needed to confirm its validity and determine its potential use in cancer therapy. PMID:25266310

Abdouh, Mohamed; Zhou, Shufeng; Arena, Vincenzo; Arena, Manuel; Lazaris, Anthoula; Onerheim, Ronald; Metrakos, Peter; Arena, Goffredo

2014-09-30

107

Diverse mechanisms of AKT pathway activation in human malignancy  

PubMed Central

AKT/PKB (Protein Kinase B) are central proteins mediating signals from receptor tyrosine kinases and phosphatidylinositol 3-kinase. AKT kinases are involved in a number of important cellular processes including cell proliferation and survival, cell size in response to nutrient availability, tumor invasion/metastasis, and angiogenesis. Various components of the AKT signaling pathway are encoded by tumor suppressor genes and oncogenes whose loss or activation, respectively, plays an important role in tumorigenesis. The growing body of evidence connecting deregulated AKT signaling with sporadic human cancers and inherited cancer predisposition syndromes is discussed. We also highlight new findings regarding the involvement of activating mutations of AKT1, AKT2, and AKT3 in somatic overgrowth disorders: Proteus syndrome, hypoglycemia with hypertrophy, and hemimegalencephaly, respectively. In addition, we review recent literature documenting the various ways the AKT signaling pathway is activated in human cancers and consequences for molecularly targeted therapies. PMID:23297823

Cheung, Mitchell; Testa, Joseph R.

2013-01-01

108

On the radiosensitivity of man in space  

NASA Astrophysics Data System (ADS)

Astronauts' radiation exposure limits are based on experimental and epidemiological data obtained on Earth. It is assumed that radiation sensitivity remains the same in the extraterrestrial space. However, human radiosensitivity is dependent upon the response of the hematopoietic tissue to the radiation insult. It is well known that the immune system is affected by microgravity. We have developed a mathematical model of radiation-induced myelopoiesis which includes the effect of microgravity on bone marrow kinetics. It is assumed that cellular radiosensitivity is not modified by the space environment, but repopulation rates of stem and stromal cells are reduced as a function of time in weightlessness. A realistic model of the space radiation environment, including the HZE component, is used to simulate the radiation damage. A dedicated computer code was written and applied to solar particle events and to the mission to Mars. The results suggest that altered myelopoiesis and lymphopoiesis in microgravity might increase human radiosensitivity in space.

Esposito, R. D.; Durante, M.; Gialanella, G.; Grossi, G.; Pugliese, M.; Scampoli, P.; Jones, T. D.

109

p53 Mutations in Human Lymphoid Malignancies: Association with Burkitt Lymphoma and Chronic Lymphocytic Leukemia  

Microsoft Academic Search

We have investigated the frequency of p53 mutations in B- and T-cell human lymphoid malignancies, including acute lymphoblastic leukemia, the major subtypes of non-Hodgkin lymphoma, and chronic lymphocytic leukemia. p53 exons 5-9 were studied by using genomic DNA from 197 primary tumors and 27 cell lines by single-strand conformation polymorphism analysis and by direct sequencing of PCR-amplified fragments. Mutations were

Gianluca Gaidano; Paola Ballerini; Jerry Z. Gong; Giorgio Inghirami; Antonino Neri; Elizabeth W. Newcomb; Ian T. Magrath; Daniel M. Knowles; Riccardo dalla-Favera

1991-01-01

110

Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies  

Microsoft Academic Search

Mutations of receptor tyrosine kinases are implicated in the constitutive activation and development of human malignancy.An inter- nal tandem duplication (ITD) of the jux- tamembrane (JM) domain-coding sequence of the FLT3 gene (FLT3\\/ITD) is found in 20% of patients with acute myeloid leukemia (AML) and is strongly associated with leuko- cytosis and a poor prognosis. On the other hand, mutations

Yukiya Yamamoto; Hitoshi Kiyoi; Yasuyuki Nakano; Ritsuro Suzuki; Yoshihisa Kodera; Shuichi Miyawaki; Norio Asou; Kazutaka Kuriyama; Fumiharu Yagasaki; Chihiro Shimazaki; Hideki Akiyama; Kenji Saito; Miki Nishimura; Toshiko Motoji; Katsuji Shinagawa; Akihiro Takeshita; Hidehiko Saito; Ryuzo Ueda; Ryuzo Ohno; Tomoki Naoe

2010-01-01

111

Fas-mediated apoptosis and expression of related genes in human malignant hematopoietic cells  

Microsoft Academic Search

Fas transduces apoptotic signals upon cross-linking with the Fas ligand (FasL), which is experimentally replaced by agonistic anti-Fas monoclonal antibodies (mAb). Of eight human malignant hematopoietic cell lines (HL-60, KG-1, THP-1, K562, U937, Jurkat, IM-9, RPMI-8226) examined by flow cytometric analysis, all, except K562, were found to be positive for surface Fas antigen. How- ever, despite surface Fas expression, the

Kyung-Mi Kim; Keehyun Lee; Young-Sook Hong; Hae-Young Park

2000-01-01

112

Prostate cancer radiosensitization through PARP-1 hyperactivation  

PubMed Central

The clinical experimental agent, ?-lapachone (Arq 501), can act as a potent radiosensitizer in vitro through an unknown mechanism. In this study, we analyzed the mechanism to determine whether ?-lapachone may warrant clinical evaluation as a radiosensitizer. ?-lapachone killed prostate cancer cells by NAD(P)H:quinone oxidoreductase 1 (NQO1) metabolic bioactivation, triggering a massive induction of reactive oxygen species (ROS), irreversible DNA single strand breaks (SSBs), PARP-1 hyperactivation, NAD+/ATP depletion, and ?-calpain-induced programmed necrosis. In combination with ionizing radiation (IR), ?-lapachone radiosensitized NQO1+ prostate cancer cells, under conditions where nontoxic doses of either agent alone achieved threshold levels of SSBs required for hyperactivation of PARP-1. Combination therapy significantly elevated SSBs, ?-H2AX foci formation, and poly(ADP-ribosylation) of PARP-1, which were associated with ATP loss and induction of ?-calpain-induced programmed cell death. Radiosensitization by ?-lapachone was blocked by the NQO1 inhibitor, dicoumarol, or the PARP-1 inhibitor, DPQ. In a mouse xenograft model of prostate cancer, ?-lapachone synergized with IR to promote antitumor efficacy. NQO1 levels were elevated in ~60% of human prostate tumors evaluated relative to adjacent normal tissue, where ?-lapachone might be efficacious alone or in combination with radiation. Our findings offer a rationale for clinical assessment of ?-lapachone (Arq501) as a radiosensitizer in prostate cancers that overexpress NQO1, offering a potentially synergistic targeting strategy to exploit PARP-1 hyperactivation. PMID:20940411

Dong, Ying; Bey, Erik A.; Li, Long-Shan; Kabbani, Wareef; Yan, Jingsheng; Xie, Xian-Jin; Hsieh, Jer-Tsong; Gao, Jinming; Boothman, David A.

2010-01-01

113

Critical analysis of the potential for targeting STAT3 in human malignancy  

PubMed Central

The signal transducer and activator of transcription (STAT) family of proteins was originally discovered in the context of normal cell biology where they function to transduce intracellular and extracellular signals to the nucleus, ultimately leading to transcription of specific target genes and downstream phenotypic effects. It was quickly appreciated that the STATs, especially STAT3, play a fundamental role in human malignancy. In contrast to normal biology in which transient STAT3 signaling is strictly regulated by a tightly coordinated network of activators and deactivators, STAT3 is constitutively activated in human malignancies. Constitutive STAT3 signaling has been associated with many cancerous phenotypes across nearly all human cancers, including the upregulation of cell growth, proliferation, survival, and motility, among others. Studies involving candidate preclinical STAT3 inhibitors have further demonstrated that the reversal of these phenotypes results from pharmacologic or genetic inhibition of STAT3, suggesting that STAT3 may be a promising target for clinical interventions. Indeed, a Phase 0 clinical trial involving a STAT3 decoy oligonucleotide demonstrated that STAT3 is a drug-gable target in human tumors. Because of the ubiquity of overactive STAT3 in cancer, its role in promoting a wide variety of cancerous phenotypes, and the strong clinical and preclinical studies performed to date, STAT3 represents a promising target for the development of inhibitors for the treatment of human cancers. PMID:23935373

Peyser, Noah D; Grandis, Jennifer R

2013-01-01

114

Classification of normal and malignant human gastric mucosa tissue with confocal Raman microspectroscopy and wavelet analysis  

NASA Astrophysics Data System (ADS)

Thirty-two samples from the human gastric mucosa tissue, including 13 normal and 19 malignant tissue samples were measured by confocal Raman microspectroscopy. The low signal-to-background ratio spectra from human gastric mucosa tissues were obtained by this technique without any sample preparation. Raman spectral interferences include a broad featureless sloping background due to fluorescence and noise. They mask most Raman spectral feature and lead to problems with precision and quantitation of the original spectral information. A preprocessed algorithm based on wavelet analysis was used to reduce noise and eliminate background/baseline of Raman spectra. Comparing preprocessed spectra of malignant gastric mucosa tissues with those of counterpart normal ones, there were obvious spectral changes, including intensity increase at ˜1156 cm -1 and intensity decrease at ˜1587 cm -1. The quantitative criterion based upon the intensity ratio of the ˜1156 and ˜1587 cm -1 was extracted for classification of the normal and malignant gastric mucosa tissue samples. This could result in a new diagnostic method, which would assist the early diagnosis of gastric cancer.

Hu, Yaogai; Shen, Aiguo; Jiang, Tao; Ai, Yong; Hu, Jiming

2008-02-01

115

Drug Metabolism and Homologous Recombination Repair in Radiosensitization with Gemcitabine  

PubMed Central

Gemcitabine (difluorodeoxycytidine; dFdCyd) is a potent radiosensitizer, noted for its ability to enhance cytotoxicity with radiation at noncytotoxic concentrations in vitro and subchemotherapeutic doses in patients. Radiosensitization in human tumor cells requires dFdCyd-mediated accumulation of cells in S phase with inhibition of ribonucleotide reductase, resulting in ?80% deoxyadenosine triphosphate (dATP) depletion and errors of replication in DNA. Less is known of the role of specific DNA replication and repair pathways in the radiosensitization mechanism. Here the role of homologous recombination (HR) in relationship to the metabolic and cell cycle effects of dFdCyd was investigated using a matched pair of CHO cell lines that are either proficient (AA8 cells) or deficient (irs1SF cells) in HR based on expression of the HR protein XRCC3. The results demonstrated that the characteristics of radiosensitization in the rodent AA8 cells differed significantly from those in human tumor cells. In the AA8 cells, radiosensitization was achieved only under short (?4 h) cytotoxic incubations, and S-phase accumulation did not appear to be required for radiosensitization. In contrast, human tumor cell lines were radiosensitized using noncytotoxic concentrations of dFdCyd and required early S-phase accumulation. Studies of the metabolic effects of dFdCyd demonstrated low dFdCyd concentrations did not deplete dATP by ?80% in AA8 and irs1SF cells. However, at higher concentrations of dFdCyd, failure to radiosensitize the HR-deficient irs1SF cells could not be explained by a lack of dATP depletion or lack of S-phase accumulation. Thus, these parameters did not correspond to dFdCyd radiosensitization in the CHO cells. To evaluate directly the role of HR in radiosensitization, XRCC3 expression was suppressed in the AA8 cells with a lentiviral-delivered shRNA. Partial XRCC3 suppression significantly decreased radiosensitization [radiation enhancement ratio (RER) = 1.6 ± 0.15], compared to nontransduced (RER = 2.7 ± 0.27; P = 0.012), and a substantial decrease compared to nonspecific shRNA-transduced (RER =2.5 ± 0.42; P =0.056) AA8 cells. Although the results support a role for HR in radiosensitization with dFdCyd in CHO cells, the differences in the underlying metabolic and cell cycle characteristics suggest that dFdCyd radiosensitization in the nontumor-derived CHO cells is mechanistically distinct from that in human tumor cells. PMID:25564718

Im, Michael M.; Flanagan, Sheryl A.; Ackroyd, Jeffrey J.; Shewach, Donna S.

2015-01-01

116

Drug metabolism and homologous recombination repair in radiosensitization with gemcitabine.  

PubMed

Gemcitabine (difluorodeoxycytidine; dFdCyd) is a potent radiosensitizer, noted for its ability to enhance cytotoxicity with radiation at noncytotoxic concentrations in vitro and subchemotherapeutic doses in patients. Radiosensitization in human tumor cells requires dFdCyd-mediated accumulation of cells in S phase with inhibition of ribonucleotide reductase, resulting in ?80% deoxyadenosine triphosphate (dATP) depletion and errors of replication in DNA. Less is known of the role of specific DNA replication and repair pathways in the radiosensitization mechanism. Here the role of homologous recombination (HR) in relationship to the metabolic and cell cycle effects of dFdCyd was investigated using a matched pair of CHO cell lines that are either proficient (AA8 cells) or deficient (irs1SF cells) in HR based on expression of the HR protein XRCC3. The results demonstrated that the characteristics of radiosensitization in the rodent AA8 cells differed significantly from those in human tumor cells. In the AA8 cells, radiosensitization was achieved only under short (?4 h) cytotoxic incubations, and S-phase accumulation did not appear to be required for radiosensitization. In contrast, human tumor cell lines were radiosensitized using noncytotoxic concentrations of dFdCyd and required early S-phase accumulation. Studies of the metabolic effects of dFdCyd demonstrated low dFdCyd concentrations did not deplete dATP by ?80% in AA8 and irs1SF cells. However, at higher concentrations of dFdCyd, failure to radiosensitize the HR-deficient irs1SF cells could not be explained by a lack of dATP depletion or lack of S-phase accumulation. Thus, these parameters did not correspond to dFdCyd radiosensitization in the CHO cells. To evaluate directly the role of HR in radiosensitization, XRCC3 expression was suppressed in the AA8 cells with a lentiviral-delivered shRNA. Partial XRCC3 suppression significantly decreased radiosensitization [radiation enhancement ratio (RER) = 1.6 ± 0.15], compared to nontransduced (RER = 2.7 ± 0.27; P = 0.012), and a substantial decrease compared to nonspecific shRNA-transduced (RER = 2.5 ± 0.42; P = 0.056) AA8 cells. Although the results support a role for HR in radiosensitization with dFdCyd in CHO cells, the differences in the underlying metabolic and cell cycle characteristics suggest that dFdCyd radiosensitization in the nontumor-derived CHO cells is mechanistically distinct from that in human tumor cells. PMID:25564718

Im, Michael M; Flanagan, Sheryl A; Ackroyd, Jeffrey J; Shewach, Donna S

2015-01-01

117

Imidazoline I2 receptor density increases with the malignancy of human gliomas  

PubMed Central

Objective: To investigate the feasibility of using the measurement of imidazoline I2 receptor expression to differentiate glial tumours from other types of brain tumours and for grading the different gliomas. Methods: The specific binding of [3H]idazoxan to imidazoline I2 receptors was measured in homogenates from human gliomas of different grades. Results: The density of imidazoline I2 receptors was significantly greater in the three types of malignant glial tumours than in postmortem control brain or non-glial tumours. The increase in density correlated with the malignancy grade of the gliomas. No significant differences in affinity values were observed. Conclusion: These results suggest that the density of imidazoline I2 receptors may be a useful radioligand parameter for the differentiation of glial tumours from other types of brain tumours and for grading the different gliomas. PMID:15090584

Callado, L; Martin-Gomez, J; Ruiz, J; Garibi, J; Meana, J

2004-01-01

118

The Sodium Iodide Symporter (NIS) and Potential Regulators in Normal, Benign and Malignant Human Breast Tissue  

PubMed Central

Introduction The presence, relevance and regulation of the Sodium Iodide Symporter (NIS) in human mammary tissue remains poorly understood. This study aimed to quantify relative expression of NIS and putative regulators in human breast tissue, with relationships observed further investigated in vitro. Methods Human breast tissue specimens (malignant n?=?75, normal n?=?15, fibroadenoma n?=?10) were analysed by RQ-PCR targeting NIS, receptors for retinoic acid (RAR?, RAR?), oestrogen (ER?), thyroid hormones (THR?, THR?), and also phosphoinositide-3-kinase (PI3K). Breast cancer cells were treated with Retinoic acid (ATRA), Estradiol and Thyroxine individually and in combination followed by analysis of changes in NIS expression. Results The lowest levels of NIS were detected in normal tissue (Mean(SEM) 0.70(0.12) Log10 Relative Quantity (RQ)) with significantly higher levels observed in fibroadenoma (1.69(0.21) Log10RQ, p<0.005) and malignant breast tissue (1.18(0.07) Log10RQ, p<0.05). Significant positive correlations were observed between human NIS and ER? (r?=?0.22, p<0.05) and RAR? (r?=?0.29, p<0.005), with the strongest relationship observed between NIS and RAR? (r?=?0.38, p<0.0001). An inverse relationship between NIS and PI3K expression was also observed (r?=??0.21, p<0.05). In vitro, ATRA, Estradiol and Thyroxine individually stimulated significant increases in NIS expression (range 6–16 fold), while ATRA and Thyroxine combined caused the greatest increase (range 16–26 fold). Conclusion Although NIS expression is significantly higher in malignant compared to normal breast tissue, the highest level was detected in fibroadenoma. The data presented supports a role for retinoic acid and estradiol in mammary NIS regulation in vivo, and also highlights potential thyroidal regulation of mammary NIS mediated by thyroid hormones. PMID:21283523

Ryan, James; Curran, Catherine E.; Hennessy, Emer; Newell, John; Morris, John C.; Kerin, Michael J.; Dwyer, Roisin M.

2011-01-01

119

The human immunodeficiency virus protease inhibitor ritonavir is potentially active against urological malignancies  

PubMed Central

The human immunodeficiency virus protease inhibitor ritonavir has recently been shown to have antineoplastic activity, and its use in urological malignancies is under investigation with an eye toward drug repositioning. Ritonavir is thought to exert its antineoplastic activity by inhibiting multiple signaling pathways, including the Akt and nuclear factor-kappaB pathways. It can increase the amount of unfolded proteins in the cell by inhibiting both the proteasome and heat shock protein 90. Combinations of ritonavir with agents that increase the amount of unfolded proteins, such as proteasome inhibitors, histone deacetylase inhibitors, or heat shock protein 90 inhibitors, therefore, induce endoplasmic reticulum stress cooperatively and thereby kill cancer cells effectively. Ritonavir is also a potent cytochrome P450 3A4 and P-glycoprotein inhibitor, increasing the intracellular concentration of combined drugs by inhibiting their degradation and efflux from cancer cells and thereby enhancing their antineoplastic activity. Furthermore, riotnavir’s antineoplastic activity includes modulation of immune system activity. Therapies using ritonavir are thus an attractive new approach to cancer treatment and, due to their novel mechanisms of action, are expected to be effective against malignancies that are refractory to current treatment strategies. Further investigations using ritonavir are expected to find new uses for clinically available drugs in the treatment of urological malignancies as well as many other types of cancer.

Sato, Akinori

2015-01-01

120

Expression of cyclin D1 correlates with malignancy in human ovarian tumours.  

PubMed Central

Cyclin D1 is a cell cycle regulator of G1 progression that has been suggested to play a relevant role in the pathogenesis of several human cancer types. In the current study, the expression of cyclin D1 has been investigated in a series of 33 patients, with benign (10 patients), borderline (five patients) and malignant (18 patients) ovarian disease. Cyclin D1 protein and mRNA content were analysed by Western blotting and reverse transcriptase polymerase chain reaction respectively. The levels of cyclin D1 protein were undetectable in patients with benign disease, detectable in the majority of patients with borderline disease and elevated in those with ovarian carcinomas, being significantly related to the degree of malignancy (carcinoma vs benign, P = 0.0001; benign vs borderline, P = 0.0238). A significant relationship between cyclin D1 expression and tumour proliferative activity was also found (P = 0.000001). Moreover, eight benign lesions, two borderline tumours and 11 carcinomas proved to be suitable for the analysis of cyclin D1 transcript, and emerging data demonstrated significant agreement between protein abundance and mRNA expression. Results from the current study suggest that cyclin D1 expression is associated with the degree of transformation and most probably plays a role in the early development of ovarian malignancy. Images Figure 3 Figure 4 Figure 5 Figure 6 PMID:9155044

Barbieri, F.; Cagnoli, M.; Ragni, N.; Pedullà, F.; Foglia, G.; Alama, A.

1997-01-01

121

A molecular targeting against nuclear factor-?B, as a chemotherapeutic approach for human malignant mesothelioma.  

PubMed

Chronic inflammation due to the absorption of asbestos is an important cause of mesothelioma. Although the increased prevalence of mesothelioma is a serious problem, the development of effective chemotherapeutic agents remains incomplete. As the nuclear factor-?B (NF-?B) pathway contributes to malignant transformation of various types of cells, we explored NF-?B activity in three different pathological types of malignant mesothelioma cells, and evaluated the therapeutic potential of a recently reported NF-?B inhibitor, IMD-0354. NF-?B was constantly activated in MSTO-211H, NCI-H28, and NCI-H2052 cells, and the proliferation of these cell lines was inhibited by IMD-0354. D-type cyclins were effectively suppressed in mixed tissue type MSTO-211H, leading to cell cycle arrest at sub G1 /G1 phase. IMD-0354 reduced cyclin D3 in both epithelial tissue type NCI-H28 and sarcomatoid tissue type NCI-H2052. In a sphere formation assay, IMD-0354 effectively decreased the number and diameter of MSTO-211H spheres. Preincubation of MSTO-211H cells with IMD-0354 delayed tumor formation in transplanted immunodeficient mice. Furthermore, administration of IMD-0354 markedly rescued the survival rate of mice that received intrathoracic injections of MSTO-211H cells. These results indicate that a targeted drug against NF-?B might have therapeutic efficacy in the treatment of human malignant mesothelioma. PMID:24510578

Nishikawa, Sho; Tanaka, Akane; Matsuda, Akira; Oida, Kumiko; Jang, Hyosun; Jung, Kyungsook; Amagai, Yosuke; Ahn, Ginae; Okamoto, Noriko; Ishizaka, Saori; Matsuda, Hiroshi

2014-04-01

122

Raloxifene and Desmethylarzoxifene Block Estrogen-Induced Malignant Transformation of Human Breast Epithelial Cells  

PubMed Central

There is association between exposure to estrogens and the development and progression of hormone-dependent gynecological cancers. Chemical carcinogenesis by catechol estrogens derived from oxidative metabolism is thought to contribute to breast cancer, yet exact mechanisms remain elusive. Malignant transformation was studied in MCF-10A human mammary epithelial cells, since estrogens are not proliferative in this cell line. The human and equine estrogen components of estrogen replacement therapy (ERT) and their catechol metabolites were studied, along with the influence of co-administration of selective estrogen receptor modulators (SERMs), raloxifene and desmethyl-arzoxifene (DMA), and histone deacetylase inhibitors. Transformation was induced by human estrogens, and selectively by the 4-OH catechol metabolite, and to a lesser extent by an equine estrogen metabolite. The observed estrogen-induced upregulation of CYP450 1B1 in estrogen receptor negative MCF-10A cells, was compatible with a causal role for 4-OH catechol estrogens, as was attenuated transformation by CYP450 inhibitors. Estrogen-induced malignant transformation was blocked by SERMs correlating with a reduction in formation of nucleobase catechol estrogen (NCE) adducts and formation of 8-oxo-dG. NCE adducts can be formed consequent to DNA abasic site formation, but NCE adducts were also observed on incubation of estrogen quinones with free nucleotides. These results suggest that NCE adducts may be a biomarker for cellular electrophilic stress, which together with 8-oxo-dG as a biomarker of oxidative stress correlate with malignant transformation induced by estrogen oxidative metabolites. The observed attenuation of transformation by SERMs correlated with these biomarkers and may also be of clinical significance in breast cancer chemoprevention. PMID:22140478

Kastrati, Irida; Edirisinghe, Praneeth D.; Hemachandra, L-P-Madhubani P.; Chandrasena, Esala R.; Choi, Jaewoo; Wang, Yue-Ting; Bolton, Judy L.; Thatcher, Gregory R. J.

2011-01-01

123

Radiosensitization by 2-deoxy-D-glucose and 6-aminonicotinamide involves activation of redox sensitive ASK1-JNK/p38MAPK signaling in head and neck cancer cells.  

PubMed

Our previous studies on simultaneous inhibition of glycolysis by 2-deoxy-D-glucose (2-DG) and pentose phosphate activity by 6-aminonicotinamide (6-AN) have been shown to induce oxidative stress mediated selective radiosensitization in wide range of human malignant cells. However, the mechanism of radiosensitization induced by this combination (2-DG+6-AN) is not completely understood. Since activation of apoptotic signal regulating kinase (ASK1) and subsequent apoptosis are implicated in oxidative stress response, the role of ASK1 activation in radiosensitization by this combination was investigated in the present study. Our results demonstrated that redox alterations induced by this combination activated ASK1 and subsequent apoptosis during radiosensitization of head and neck carcinoma cells (KB). In addition, mRNA and protein expression of thioredoxin and thioredoxin reductase decreased significantly under similar treatment conditions. Further, the downstream targets such as JNK and p38MAPK were also activated by this combination, and their pharmacological inhibition by SP600125 and SB201291 respectively resulted in suppression of 2-DG+6-AN mediated apoptosis in irradiated KB cells. Interestingly, the activation of ASK1 was mediated by hydrogen peroxide rather than superoxide anions as PEG-catalase but not PEG-SOD suppressed its activation. Our observations clearly suggest that redox alterations by inhibition of glucose metabolism serves as a molecular switch that activate ASK1-JNK/p38MAPK signaling in malignant cells during radiosensitization by 2-DG+6-AN. The present study emphasizes the importance of redox alterations in determining radiosensitivity of tumor cells that may greatly influence the outcome of radiation therapy. PMID:22824861

Sharma, Pradeep Kumar; Dwarakanath, Bilikere Srinivasa; Varshney, Rajeev

2012-10-01

124

Inflammation precedes the development of human malignant mesotheliomas in a SCID mouse xenograft model  

PubMed Central

Asbestos fibers cause chronic inflammation that may be critical to the development of malignant mesothelioma (MM). Two human MM cell lines (Hmeso, PPM Mill) were used in a SCID mouse xenograft model to assess time-dependent patterns of inflammation and tumor formation. After intraperitoneal (IP) injection of MM cells, mice were euthanized at 7, 14, and 30 days, and peritoneal lavage fluid (PLF) was examined for immune cell profiles and human and mouse cytokines. Increases in human MM-derived IL-6, IL-8, bFGF, and VEGF were observed in mice at 7 days postinjection of either MM line, and a striking neutrophilia was observed at all time points. Free-floating tumor spheroids developed in mice at 14 days, and both spheroids and adherent MM tumor masses occurred in all mice at 30 days. Results suggest that inflammation and cytokine production precede and may be critical to the development of MMs. PMID:20716277

Hillegass, Jedd M.; Shukla, Arti; Lathrop, Sherrill A.; MacPherson, Maximilian B.; Beuschel, Stacie L.; Butnor, Kelly J.; Testa, Joseph R.; Pass, Harvey I.; Carbone, Michele; Steele, Chad; Mossman, Brooke T.

2010-01-01

125

Growth and Spread of Human Malignant T Lymphoblasts in Immunosuppressed Nude Mice: A Model for Meningeal Leukemia  

Microsoft Academic Search

Previous work has shown that nude (nu\\/nu) mice addition- ally immunosuppressed by splenectomy, sublethal irradia- tion, and treatment with antiasialo GMI antiserum (SIA- nu\\/nu mice) have no detectable natural killer activity and allow the growth of human malignant lymphoblasts. We show here that all SIA-nulnu mice engrafted intravenously with 5 x 108 malignant lymphoblasts originally derived from a child with

Federica Cavallo; Marco Forni; Carlo Riccardi; Antonio Soleti; Francesco Di Pierro; Guido Forni

1992-01-01

126

Selective growth inhibition of human malignant melanoma cells by syringic acid-derived proteasome inhibitors  

PubMed Central

Background It has been shown that proteasome inhibition leads to growth arrest in the G1 phase of the cell cycle and/or induction of apoptosis. However, it was found that some of these inhibitors do not induce apoptosis in several human normal cell lines. This selective activity makes proteasome inhibition a promising target for new generation of anticancer drugs. Clinical validation of the proteasome, as a therapeutic target in oncology, has been provided by the dipeptide boronic acid derivative; bortezomib. Bortezomib has proven to be effective as a single agent in multiple myeloma and some forms of non-Hodgkin’s lymphoma. Syringic acid (4-hydroxy-3,5-dimethoxybenzoic acid, 1), a known phenolic acid, was isolated from the methanol extract of Tamarix aucheriana and was shown to possess proteasome inhibitory activity. Methods Using Surflex-Dock program interfaced with SYBYL, the docking affinities of syringic acid and its proposed derivatives to 20S proteasome were studied. Several derivatives were virtually proposed, however, five derivatives: benzyl 4-hydroxy-3,5-dimethoxybenzoate (2), benzyl 4-(benzyloxy)-3,5-dimethoxybenzoate (3), 3'-methoxybenzyl 3,5-dimethoxy-4-(3'-methoxybenzyloxy)benzoate (4), 3'-methoxybenzyl 4-hydroxy-3,5-dimethoxybenzoate (5) and 3',5'-dimethoxybenzyl 4-hydroxy-3,5-dimethoxybenzoate (6), were selected based on high docking scores, synthesized, and tested for their anti-mitogenic activity against human colorectal, breast and malignant melanoma cells as well as normal human fibroblast cells. Results Derivatives 2, 5, and 6 showed selective dose-dependent anti-mitogenic effect against human malignant melanoma cell lines HTB66 and HTB68 with minimal cytotoxicity on colorectal and breast cancer cells as well as normal human fibroblast cells. Derivatives 2, 5 and 6 significantly (p???0.0001) inhibited the various proteasomal chymotrypsin, PGPH, and trypsin like activities. They growth arrested the growth of HTB66 cells at G1 and G2-phases. They also arrested the growth of HTB68 cells at S- and G2-phase, respectively. Moreover, derivatives 2, 5, and 6 markedly induced apoptosis (? 90%) in both HTB66 and HTB68. Conclusions Computer-derived syringic acid derivatives possess selective anti-mitogenic activity on human malignant melanoma cells that may be attributed to perturbation of cell cycle, induction of apoptosis and inhibition of various 26S proteasomal activities. PMID:23958424

2013-01-01

127

Acquisition of Androgen Independence by Human Prostate Epithelial Cells during Arsenic-Induced Malignant Transformation  

PubMed Central

Lethal phenotypes of human prostate cancer are characterized by progression to androgen independence, although the mechanisms behind this progression remain unclear. Arsenic is a potential human prostate carcinogen that may affect tumor progression. In this study, we used a prostate cancer cell model in which an immortalized, nontumorigenic human prostate epithelial cell line (RWPE-1) had been malignantly transformed by chronic low-level arsenic to help determine whether arsenic affects prostate tumor progression. Control and CAsE-PE (chronic-arsenic–exposed human prostate epithelial) cells were continuously maintained in a complete medium [keratinocyte serum-free medium (K-SFM) with bovine pituitary extract and epidermal growth factor] or in a steroid-depleted medium (K-SFM alone). The arsenic-transformed cells showed a more rapid proliferation rate in complete medium than did control cells and also showed sustained proliferation in steroid-reduced medium. Although both control and CAsE-PE cells showed similar levels of androgen receptor (AR), androgens were less effective in stimulating cell proliferation and AR-related gene expression in CAsE-PE cells. For instance, dihydrotestosterone caused a 4.5-fold increase in prostate-specific antigen transcript in control cells but only a 1.5-fold increase in CAsE-PE cells. CAsE-PE cells also showed relatively low levels of growth stimulation by nonandrogen steroids, such as estradiol. Thus, arsenic-induced malignant transformation is associated with acquired androgen independence in human prostate cells. This acquired androgen independence was apparently not due to AR up-regulation, increased activity, or altered ligand specificity. The precise manner in which arsenic altered CAsE-PE growth and progression is undefined but may involve a bypass of AR involving direct stimulation of downstream signaling pathways. PMID:16140617

Benbrahim-Tallaa, Lamia; Webber, Mukta M.; Waalkes, Michael P.

2005-01-01

128

Discrimination analysis of human lung cancer cells associated with histological type and malignancy using Raman spectroscopy  

NASA Astrophysics Data System (ADS)

The Raman spectroscopic technique enables the observation of intracellular molecules without fixation or labeling procedures in situ. Raman spectroscopy is a promising technology for diagnosing cancers-especially lung cancer, one of the most common cancers in humans-and other diseases. The purpose of this study was to find an effective marker for the identification of cancer cells and their malignancy using Raman spectroscopy. We demonstrate a classification of cultured human lung cancer cells using Raman spectroscopy, principal component analysis (PCA), and linear discrimination analysis (LDA). Raman spectra of single, normal lung cells, along with four cancer cells with different pathological types, were successfully obtained with an excitation laser at 532 nm. The strong appearance of bands due to cytochrome c (cyt-c) indicates that spectra are resonant and enhanced via the Q-band near 550 nm with excitation light. The PCA loading plot suggests a large contribution of cyt-c in discriminating normal cells from cancer cells. The PCA results reflect the nature of the original cancer, such as its histological type and malignancy. The five cells were successfully discriminated by the LDA.

Oshima, Yusuke; Shinzawa, Hideyuki; Takenaka, Tatsuji; Furihata, Chie; Sato, Hidetoshi

2010-01-01

129

Epigenetic Regulation of Inflammatory Cytokines and Associated Genes in Human Malignancies  

PubMed Central

Inflammation is a multifaceted defense response of immune system against infection. Chronic inflammation has been implicated as an imminent threat for major human malignancies and is directly linked to various steps involved in tumorigenesis. Inflammatory cytokines, interleukins, interferons, transforming growth factors, chemokines, and adhesion molecules have been associated with chronic inflammation. Numerous cytokines are reported to be aberrantly regulated by different epigenetic mechanisms like DNA methylation and histone modifications in tumor tissues, contributing to pathogenesis of tumor in multiple ways. Some of these cytokines also work as epigenetic regulators of other crucial genes in tumor biology, either directly or indirectly. Such regulations are reported in lung, breast, cervical, gastric, colorectal, pancreatic, prostate, and head and neck cancers. Epigenetics of inflammatory mediators in cancer is currently subject of extensive research. These investigations may help in understanding cancer biology and to develop effective therapeutic strategies. The purpose of this paper is to have a brief view of the aberrant regulation of inflammatory cytokines in human malignancies.

Yasmin, Rehana; Hassan, Amjad; Khan, Abdul Rehman; Abbasi, Rashda; Ahmad, Nafees

2015-01-01

130

Insulin-Like Growth Factor-Type 1 Receptor Inhibitor NVP-AEW541 Enhances Radiosensitivity of PTEN Wild-Type but Not PTEN-Deficient Human Prostate Cancer Cells  

SciTech Connect

Purpose: During the past decade, many clinical trials with both monoclonal antibodies and small molecules that target the insulin-like growth factor-type 1 receptor (IGF-1R) have been launched. Despite the important role of IGF-1R signaling in radioresistance, studies of such agents in combination with radiotherapy are lagging behind. Therefore, the aim of this study was to investigate the effect of the small molecule IGF-1R kinase inhibitor NVP-AEW541 on the intrinsic radioresistance of prostate cancer cells. Methods and Materials: The effect of NVP-AEW541 on cell proliferation, cell viability, IGF-1R signaling, radiosensitivity, cell cycle distribution, and double strand break repair was determined in three human prostate cancer cell lines (PC3, DU145, 22Rv1). Moreover, the importance of the PTEN pathway status was explored by means of transfection experiments with constitutively active Akt or inactive kinase-dead Akt. Results: NVP-AEW541 inhibited cell proliferation and decreased cell viability in a time-and dose-dependent manner in all three cell lines. Radiosensitization was observed in the PTEN wild-type cell lines DU145 and 22Rv1 but not in the PTEN-deficient PC3 cell line. NVP-AEW541-induced radiosensitization coincided with downregulation of phospho-Akt levels and high levels of residual double strand breaks. The importance of PTEN status in the radiosensitization effect was confirmed by transfection experiments with constitutively active Akt or inactive kinase-dead Akt. Conclusions: NVP-AEW541 enhances the effect of ionizing radiation in PTEN wild-type, but not in PTEN-deficient, prostate cancer cells. Proper patient selection based on the PTEN status of the tumor will be critical to the achievement of optimal results in clinical trials in which the combination of radiotherapy and this IGF-1R inhibitor is being explored.

Isebaert, Sofie F., E-mail: sofie.isebaert@med.kuleuven.be [Department of Radiation Oncology, University Hospitals Leuven Campus Gasthuisberg, Leuven (Belgium); Swinnen, Johannes V. [Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven (Belgium); McBride, William H. [Department of Radiation Oncology, University of California at Los Angeles, CA (United States); Haustermans, Karin M. [Department of Radiation Oncology, University Hospitals Leuven Campus Gasthuisberg, Leuven (Belgium)

2011-09-01

131

Expression of p21/sup ras/ in normal and malignant human tissues: lack of association with proliferation and malignancy  

SciTech Connect

Proteins encoded by cellular ras oncogenes (p21/sup ras) are expressed in a wide variety of malignant tumors, including carcinomas, lymphomas, and neuroectodermal tumors. The function of p21/sup ras/ in these tumors and the distribution and role of p21/sup ras/ in corresponding normal tissues are unclear. This immunohistochemical study examined the relationship between p21/sup ras/ expression and malignant transformation, cellular differentiation, and proliferative activity in vivo. p21/sup ras/ was found to be widely expressed in normal tissues, but within those tissues expression was often sharply restricted to cells at specific stages of differentiation; terminally differentiated cells generally showed stronger reactivity with antibodies to p21/sup ras/ than did rapidly proliferating cells. Fetal and adult tissues had corresponding patterns of p21/sup ras/ expression, and the distribution of p21/sup ras/ in neoplasms paralleled the pattern in normal tissue from which they were derived. Thus, p21/ras/ seems to play a role in many fully differentiated cell types, and levels of p21/sup ras/ expression do not correlate with proliferative activity in normal cells or, in contrast to past reports, with the transformed phenotype.

Chesa, P.G.; Rettig, W.J.; Melamed, M.R.; Old, L.J.; Niman, H.L.

1987-05-01

132

DNA of human papillomavirus type 16 in dysplastic and malignant lesions of the conjunctiva and cornea.  

PubMed

Human papillomaviruses are receiving attention for their role in the pathogenesis of cancer, especially cancer of the anogenital tract. Although strains of human papillomavirus are associated with benign lesions of the conjunctiva, their association with conjunctival dysplastic lesions and carcinomas has remained unclear. We examined a group of neoplastic lesions of the conjunctiva for the presence of DNA sequences for human papillomavirus types 16 and 18, using in vitro gene amplification with the polymerase chain reaction. Tissue specimens of five conjunctival dysplastic lesions and one invasive carcinoma and swab specimens of the mucosa of both corneas of a patient with unilateral corneal dysplasia contained DNA sequences related to human papillomavirus type 16. All dysplastic specimens examined were positive for DNA sequences. Viral DNA was not detected in six control specimens from patients with conjunctival melanoma, papilloma, nevus, or pterygium. We conclude that DNA from human papillomavirus type 16 is present in a substantial percentage of conjunctival premalignant and malignant lesions. It may play a part in the development of conjunctival dysplasia and carcinoma, as it does in cancers of certain other body sites. PMID:2541337

McDonnell, J M; Mayr, A J; Martin, W J

1989-06-01

133

Role of Mitochondrial Network Stabilisation by a Human Small Heat Shock Protein in Tumour Malignancy  

PubMed Central

Previously, we found that the unconventional small human heat-shock protein HSPB11 inhibits cell death by HSP90 mediated cholesterol-rich membrane microdomain dependent activation of phosphatidylinositol-3 kinase/protein kinase B pathway and by stabilising the mitochondrial membrane systems. Also, progressive cytoplasmic expression of HSPB11 correlated with brain tumor malignancy. In the present study we investigated how cytoplasmic abundance of HSPB11 augments tumor malignancy. We up- and downregulated the cytoplasmic level of HSPB11 before paclitaxel exposure in NIH3T3 and HeLa cells, which normally express low and high levels, respectively, of the HSPB11 protein. We examined the paclitaxel-mediated induction of cell death, mitochondrial fission, HSPB11 mitochondrial translocation and inhibitory phosphorylation of dynamin-like protein-1 (DLP1). We found that increasing cytoplasmic abundance of HSPB11 in NIH3T3 cells protected against paclitaxel-induced apoptosis, while suppressing HSPB11 in HeLa cells sensitised the cells toward paclitaxel. Also, paclitaxel enhanced mitochondrial translocation of HSPB11 in wild type HeLa but not in NIH3T3 cells. More importantly, increased cytoplasmic level of HSPB11 in NIH3T3 cells enhanced the inhibitory phosphorylation of DLP1 and attenuated paclitaxel-induced mitochondrial fission. All these results suggest that increased cytoplasmic abundance of HSPB11 augments inhibitory phosphorylation of DLP1 thereby reduces mitochondrial fission that eventually leads to decreased apoptosis. This novel mechanism may explain the resistance to apoptosis and increased malignancy of HSPB11-overexpressing tumours. The clinical significance of this mechanism has already been highlighted by the finding that the kinase inhibitor tyrphostin A9 induces cancer cell death by DLP1-mediated mitochondrial fragmentation. PMID:25874011

Turi, Zsuzsanna; Hocsak, Eniko; Racz, Boglarka; Szabo, Aliz; Balogh, Andras; Sumegi, Balazs; Gallyas, Ferenc

2015-01-01

134

Combination effect of photodynamic therapy using NPe6 with pemetrexed for human malignant pleural mesothelioma cells.  

PubMed

To identify a possible new treatment modality for malignant pleural mesothelioma (MPM), we examined whether combination treatment consisting of pemetrexed chemotherapy and photodynamic therapy (PDT) using the photosensitizer NPe6, enhanced the antitumor effect in both in vitro and in vivo models. We also investigated preclinical treatment schedules. Four human malignant mesothelioma cell lines (MSTO?211H, H2052, H2452 and H28) were assayed using the WST assay after treatment with pemetrexed and NPe6?PDT. The treatment schedule for the combination treatment was examined using nude mice. Pemetrexed pre?treatment enhanced the lethal effect of NPe6?PDT in the four malignant mesothelioma cell lines, but NPe6?PDT followed by pemetrexed treatment did not enhance cell lethality in the in vitro assay. Pemetrexed pre?treatment did not enhance the intracellular accumulation of NPe6, which is one of the determinants of the antitumor effect of PDT. In nude mice injected with MSTO?211H cells and then treated using a combination of pemetrexed and NPe6?PDT (10 mg/kg NPe6, 10 J/cm(2) laser irradiation), the tumor volume decreased by 50% but subsequently increased, reaching the pre?treatment value after 14 days. Pemetrexed treatment followed by NPe6?PDT resulted in an 80% reduction in the tumor size and inhibited re?growth. NPe6?PDT followed by pemetrexed treatment resulted in a 60% reduction in tumor size but did not inhibit re?growth. NPe6?PDT induced the expression of thymidylate synthase (TS), which confers resistance to pemetrexed, and NPe6?PDT followed by pemetrexed treatment did not enhance the treatment outcome in vivo. In conclusion, combination treatment, consisting of pemetrexed followed by NPe6?PDT, should be further investigated as a new treatment modality for MPM. In the future, this combination treatment may contribute to a reduction in local recurrence and a prolonged survival period in patients with MPM. PMID:25385189

Maehara, Sachio; Usuda, Jitsuo; Ishizumi, Taichiro; Ichinose, Shuji; Ohtani, Keishi; Inoue, Tatsuya; Imai, Kentaro; Furumoto, Hideyuki; Kudo, Yujin; Kajiwara, Naohiro; Ohira, Tatsuya; Ikeda, Norihiko

2015-02-01

135

Overexpression of CD99 Increases the Migration and Invasiveness of Human Malignant Glioma Cells  

PubMed Central

The malignant glioma is the most common primary human brain tumor, and its migration and invasiveness away from the primary tumor mass are considered a leading cause of tumor recurrence and treatment failure. Recently, gene expression profiling revealed that the transmembrane glycoprotein CD99 is more highly expressed in malignant glioma than in normal brain. Although its function is not completely understood, CD99 is implicated in cell adhesion and migration in a variety of different cell types. CD99 has wild-type and splice variant isoforms. Previous studies have shown that wild-type CD99 may be an oncosuppressor in some tumors, distinct from the role of the splice variant isoform. In this study, our data reveal that only wild-type CD99 is expressed in human glioma cells and tissues. Using a tissue microarray, we validated that gliomas demonstrate higher expression of CD99 compared with nonneoplastic brain. To assess the role of CD99 in glioma migration and invasion, we inhibited CD99 expression by siRNA and demonstrated decreased glioma migration and invasion. In contrast, when CD99 was overexpressed in glioma cells, we observed enhancement of cell migration and invasiveness. An orthotopic brain tumor model demonstrates that CD99 overexpression significantly increases invasiveness and decreases survival rate. Interestingly, Rac activity was decreased and Rho activity was increased in CD99 overexpressing glioma cells, and the proportion of amoeboid cells to mesenchymal cells was significantly increased. Taken together, our findings suggest that CD99 may play an important role in the migration and invasion of human gliomas independent of Akt, ERK, or JNK signaling pathways. Moreover, CD99 might be involved in amoeboid-mesenchymal transition in glioma migration. CD99 may be an important future target to inhibit migration and invasion, especially in CD99-expressing gliomas. PMID:23486730

Seol, Ho Jun; Chang, Jong Hee; Yamamoto, Junkoh; Romagnuolo, Rocco; Suh, Youngchul; Weeks, Adrienne; Agnihotri, Sameer; Smith, Christian A.

2012-01-01

136

Seroprevalence of human T-lymphotropic virus antibodies among patients with lymphoid malignancies at a tertiary center in Lagos, Nigeria  

PubMed Central

Background There is a significant association of human T-lymphotropic viruses (HTLV) with lymphoid malignancies. HTLV causes a lymphoproliferative malignancy of CD4-activated cells called adult T-cell leukemia/lymphoma (ATL) and a chronic myelopathy called tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). This study aims to determine the prevalence of HTLV among patients with lymphoid malignancies at a tertiary center in Lagos. Methods A cross-sectional study was carried out at the hematology clinic of the Lagos State University Teaching Hospital. After obtaining consent, approximately 5 mL of venous blood was collected from each subject. The serum was separated and stored at ?20°C. Sera were assayed for HTLV by an enzyme-linked immunoassay (ELISA) for the determination of antibodies to HTLV-1 and -2. Western blot confirmatory testing was done on reactive samples. All patients were also screened for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) by rapid kits. Results A total of 39 patients with lymphoid malignancies were enrolled, consisting of 24 (61.5%) with solid malignancies, while 15 (38.5%) had leukemia. Only two patients (5.1%) with lymphoid malignancies were reactive on the ELISA test. On confirmatory testing with Western blot, two patients (5.1%) with lymphoid malignancies were also positive for HTLV. All patients were HIV negative, but four were positive to HBsAg and HCV. There was no association between history of previous blood transfusion and positivity to HTLV (P=0.544). Conclusion A prevalence of 5.1% of HTLV among patients with lymphoid malignancies was found in this study, and previous history of blood transfusion was not found to be a significant cause of HTLV infection. PMID:25228827

Akinbami, Akinsegun; Durojaiye, Idris; Dosunmu, Adedoyin; John-Olabode, Sarah; Adediran, Adewumi; Oshinaike, Olajumoke; Uche, Ebele; Dada, Akinola; Odesanya, Mojeed; Okunoye, Olaitan

2014-01-01

137

Radiosensitizing Properties of Bortezomib Depend on Therapeutic Schedule  

SciTech Connect

Purpose: To investigate the influence of the bortezomib (BTZ) on malignant glioma radiosensitivity in two xenograft models. Methods and Materials: For TCG3 and U87 models, we evaluated the antitumor activity of BTZ, radiotherapy, and BTZ plus radiothearapy according to two therapeutic schedules: a 'nonfractionated' schedule corresponding to a single dose of treatment per week, and a 'fractionated' schedule corresponding to the same weekly dose divided into 5 fractions. Treatments influence on proliferation and apoptosis indexes, cell cycle distribution, and nuclear factor-{kappa}B pathway were explored. Results: The radiosensitizing properties of BTZ observed with the nonfractionated schedule were lost with the fractionated schedule. Bortezomib-mediated radiosensitization was associated with an increased apoptosis response and major changes in cell proliferation, but the nuclear factor-{kappa}B pathway was not involved. Most of the cellular effects induced by BTZ when tumors received a single irradiation were cancelled out if radiotherapy was fractionated. Conclusion: The influence of BTZ on glioma radiosensitivity seems to depend on the treatment fractionation schedule, emphasizing the need to clarify the mechanisms underlying BTZ's radiosensitizing effects before further clinical trials are initiated.

Labussiere, Marianne [EA 4421 SiGReTO, UHP Nancy-University (France); Pinel, Sophie, E-mail: Sophie.Pinel@medecine.uhp-nancy.f [EA 4421 SiGReTO, UHP Nancy-University (France); Vandamme, Marc [EA 4421 SiGReTO, UHP Nancy-University (France); Plenat, Francois [EA 4421 SiGReTO, UHP Nancy-University (France); Service d'Anatomie et Cytologie Pathologiques, Hopital de Brabois CHU Nancy (France); Chastagner, Pascal [EA 4421 SiGReTO, UHP Nancy-University (France); Service d'Onco-Hematologie Pediatrique, Hopital d'Enfants CHU Nancy F-54500 Vandoeuvre-les-Nancy (France)

2011-03-01

138

Genetic modification of human T lymphocytes for the treatment of hematologic malignancies  

PubMed Central

Modern chemotherapy regimens and supportive care have produced remarkable improvements in the overall survival of patients with hematologic malignancies. However, the development of targeted small molecules, monoclonal antibodies, and biological therapies that demonstrate greater efficacy and lower toxicity remains highly desirable in hematology, and oncology in general. In the context of biological therapies, T-lymphocyte based treatments have enormous potential. Donor lymphocyte infusion in patients relapsed after allogeneic hematopoietic stem cell transplant pioneered the concept that T lymphocytes can effectively control tumor growth, and this was then followed by the development of cell culture strategies to generate T lymphocytes with selective activity against tumor cells. Over the past decade, it has become clear that the adoptive transfer of ex vivo expanded antigen-specific cytotoxic T lymphocytes promotes sustained antitumor effects in patients with virus-associated lymphomas, such as Epstein-Barr virus related post-transplant lymphomas and Hodgkin's lymphomas. Because of this compelling clinical evidence and the concomitant development of methodologies for robust gene transfer to human T lymphocytes, the field has rapidly evolved, offering new opportunities to extend T-cell based therapies. This review summarizes the most recent biological and clinical developments using genetically manipulated T cells for the treatment of hematologic malignancies. PMID:22929977

Hoyos, Valentina; Savoldo, Barbara; Dotti, Gianpietro

2012-01-01

139

Expression of metalloprotease insulin-degrading enzyme insulysin in normal and malignant human tissues.  

PubMed

Insulin-degrading enzyme (IDE, insulysin, insulinase; EC 3.4.22.11), a thiol metalloendopeptidase, is involved in intracellular degradation of insulin, thereby inhibiting its translocation and accumulation to the nucleus. Recently, protein expression of IDE has been demonstrated in the epithelial ducts of normal breast and breast cancer tissue. Utilizing four different antibodies generated against different epitopes of the IDE molecule, we performed Western blot analysis and immunohistochemical staining on several normal human tissues, on a plethora of tumor cell lines of different tissue origin, and on malignant breast and ovarian tissue. Applying the four IDE-directed antibodies, we demonstrated IDE expression at the protein level, by means of immunoblotting and immunocytochemistry, in each of the tumor cell lines analyzed. Insulin-degrading enzyme protein expression was found in normal tissues of the kidney, liver, lung, brain, breast and skeletal muscle, as well as in breast and ovarian cancer tissues. Immunohistochemical visualization of IDE indicated cytoplasmic localization of IDE in each of the cell lines and tissues assessed. In conclusion, we performed for the first time a wide-ranging survey on IDE protein expression in normal and malignant tissues and cells thus extending our knowledge on the cellular and tissue distribution of IDE, an enzyme which to date has mainly been studied in connection with Alzheimer's disease and diabetes but not in cancer. PMID:18813847

Yfanti, Christina; Mengele, Karin; Gkazepis, Apostolos; Weirich, Gregor; Giersig, Cecylia; Kuo, Wen-Liang; Tang, Wei-Jen; Rosner, Marsha; Schmitt, Manfred

2008-10-01

140

Expression of metalloprotease insulin-degrading enzyme (insulysin) in normal and malignant human tissues  

PubMed Central

Background Insulin-degrading enzyme (IDE, insulysin, insulinase; EC 3.4.22.11), a thiol metalloendopeptidase, is involved in intracellular degradation of insulin, thereby inhibiting its translocation and accumulation to the nucleus. Recently, protein expression of IDE has been demonstrated in the epithelial ducts of normal breast and in breast cancer tissue (Radulescu et al., Int J Oncol 30:73; 2007). Materials and Methods Utilizing four different antibodies generated against different epitopes of the IDE molecule, we performed western blot analysis and immunohistochemical staining on several normal human tissues, on a plethora of tumor cell lines of different tissue origin, and on malignant breast and ovarian tissue. Results Applying the four IDE-directed antibodies, we demonstrate IDE expression at the protein level, both by means of immunoblotting and immunocytochemistry, in all of the tumor cell lines analyzed. Besides, IDE protein expression was found in normal tissues of the kidney, liver, lung, brain, breast and skeletal muscle, as well as in breast and ovarian cancer tissues. Immunohistochemical visualization of IDE indicated cytoplasmic localization of IDE in all of the cell lines and tissues assessed. Conclusions We performed for the first time a wide-ranging survey on IDE protein expression in normal and malignant tissues and cells and thus extend knowledge about cellular and tissue distribution of IDE, an enzyme which so far has mainly been studied in connection with Alzheimer’s disease and diabetes but not in cancer. PMID:18813847

Yfanti, Christina; Mengele, Karin; Gkazepis, Apostolos; Weirich, Gregor; Giersig, Cecylia; Kuo, Wen-Liang; Tang, Wei-Jen; Rosner, Marsha; Schmitt, Manfred

2013-01-01

141

Circadian rhythmometry of mammalian radiosensitivity  

NASA Technical Reports Server (NTRS)

In the case of human bone marrow, the largest number of mitoses is seen in the evening in diurnally active men, mitotic activity being at a minimum in the morning. The opposite pattern is observed for nocturnal animals such as rats and mice on a regimen of light during the daytime alternating with darkness during the night hours. The entirety of these rhythms plays an important role in the organism's responses to environmental stimuli, including its resistance to potentially harmful agents. Conditions under which circadian rhythms can be observed and validated by inferential statistical means are discussed while emphasizing how artifacts of the laboratory environment can be shown to obscure circadian periodic variations in radiosensitivity.

Haus, E.; Halberg, F.; Loken, M. K.; Kim, Y. S.

1974-01-01

142

Frequency analysis of multispectral photoacoustic images for differentiating malignant region from normal region in excised human prostate  

NASA Astrophysics Data System (ADS)

Frequency domain analysis of the photoacoustic (PA) radio frequency signals can potentially be used as a tool for characterizing microstructure of absorbers in tissue. This study investigates the feasibility of analyzing the spectrum of multiwavelength PA signals generated by excised human prostate tissue samples to differentiate between malignant and normal prostate regions. Photoacoustic imaging at five different wavelengths, corresponding to peak absorption coefficients of deoxyhemoglobin, whole blood, oxyhemoglobin, water and lipid in the near infrared (NIR) (700 nm - 1000 nm) region, was performed on freshly excised prostate specimens taken from patients undergoing prostatectomy for biopsy confirmed prostate cancer. The PA images were co-registered with the histopathology images of the prostate specimens to determine the region of interest (ROI) corresponding to malignant and normal tissue. The calibrated power spectrum of each PA signal from a selected ROI was fit to a linear model to extract the corresponding slope, midband fit and intercept parameters. The mean value of each parameter corresponding to malignant and adjacent normal prostate ROI was calculated for each of the five wavelengths. The results obtained for 9 different human prostate specimens, show that the mean values of midband fit and intercept are significantly different between malignant and normal regions. In addition, the average midband fit and intercept values show a decreasing trend with increasing wavelength. These preliminary results suggest that frequency analysis of multispectral PA signals can be used to differentiate malignant region from the adjacent normal region in human prostate tissue.

Sinha, Saugata; Rao, Navalgund A.; Valluru, Keerthi S.; Chinni, Bhargava K.; Dogra, Vikram S.; Helguera, Maria

2014-03-01

143

Understanding the role of NRF2-regulated miRNAs in human malignancies  

PubMed Central

Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a key transcription factor that regulates the expression of over a hundred cytoprotective and antioxidant genes that provide cellular protection from reactive oxygen species. Chemotherapy resistance in several cancers has been linked to dysregulation of the NRF2 signalling pathway, moreover there is growing evidence that NRF2 may contribute to tumorigenesis. MicroRNA (miRNA) are small non-coding RNA sequences that post-transcriptionally regulate mRNA sequences. In cancer pathogenesis, aberrantly expressed miRNAs can act as either tumor suppressor or oncogenic miRNA. Recent evidence has been described that identifies a number of miRNA that can be regulated by NRF2. This review outlines the importance of NRF2 in regulating miRNA, and the functional role this may have in the tumorigenesis of human malignancies and their chemotherapy resistance. PMID:24029073

Shah, Niraj M; Rushworth, Stuart A; Murray, Megan Y; Bowles, Kristian M; MacEwan, David J

2013-01-01

144

Accelerated malignant conversion of human HBL-100 cells by the v-Ki-ras oncogene  

SciTech Connect

The human epithelial HBL-100 cell line harbors SV{sub 40} genetic information and has an unlimited growth potential. Despite displaying properties characteristic of transformation since its early in vitro passages, it is capable of producing progressively growing tumors in nude mice only after long-term culture. This a reproducible phenomenon and apparently not the consequence of a selection of preexisting malignant cells. Superinfection of early passage nontumorigenic HBL-100 cells with Kirsten murine sarcoma virus, which contains a Ki-ras oncogene having undergone multiple activating events, induces morphologic alterations and rapidly converts the cells to neoplastic cells, further supporting the hypothesis of multistep carcinogenesis. The HBL-100 cell line might be useful in defining the oncogenes representative of different families, which are able to complement SV{sub 40} in this system.

Saint-Ruf, C.; Nardeux, P.; Estrade, S.; Brouty-Boye, D.; Lavialle, C.; Cassingena, R. (Institut de Recherches Scientifiques sur le Cancer, Villejuif (France)); Rhim, J.S. (National Cancer Institute, Bethesda, MD (USA))

1988-05-01

145

Characterization of a human monoclonal antibody with broad reactivity to malignant tumor cells.  

PubMed

Lymphocytes from mediastinal lymph nodes of 9 patients with primary lung cancer were fused with murine myeloma cells (P3U1). One of the clones (4G12) was stable for secretion (10 micrograms/ml) of human IgM lambda for 24 months. The antigen detected by 4G12 was sensitive to both trypsin and periodic acid-Schiff treatment. It immunoprecipitated a glycoprotein with an Mr of 65,000 upon analysis in sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reduced conditions. Immunohistochemical staining demonstrated that 4G12 possessed a high reactivity to squamous cell carcinomas of the lung (29 of 29) and also reacted with other lung carcinomas [adenocarcinomas (14 of 20) and large cell carcinomas (3 of 8)] and with some nonpulmonary malignant tumors (15 of 56). However, it did not react with small cell carcinomas of the lung. No benign tumors (0 of 26) so far tested have been positive. 4G12 did not react with most of the normal tissues; an exception was that it was weakly reactive on the glandular cells of the trachea and bronchi and on the proximal tubular cells of the kidneys. Thus 4G12 showed a broad reactivity to malignant tumors (68% of lung carcinomas, 27% of nonpulmonary carcinomas, and 0% of benign tumors). The reactivity of 4G12 on tissues from squamous cell carcinomas of the lung indicated that the expression of the antigenic determinant was much more in the well-differentiated grade than in the poorly differentiated grade. Thus the antigen detected by 4G12 appears to be related to tumor differentiation. Moreover, fluorescence-activated cell sorter analysis demonstrated that the expression of the antigen epitope depended on the cell cycle (G2-M). These data suggest that the 4G12 monoclonal antibody detects a new tumor-associated antigen that is recognized by the human immune system. PMID:2455061

Saito, H; Uchiyama, K; Nakamura, I; Hiraoka, H; Yamaguchi, Y; Taniguchi, M

1988-07-20

146

Role of malignant ascites on human mesothelial cells and their gene expression profiles  

PubMed Central

Background Malignant ascites is often present at diagnostic in women with advanced ovarian cancer (OC) and its presence is associated with a worse outcome. Human peritoneal mesothelial cells (HPMCs) are key components of malignant ascites. Although the interplay between HPMCs and OC cells is believed to be critical for tumor progression, it has not been well characterized. The purpose of this study was to assess the effect of ascites on HPMCs and clarify the role of HPMCs in OC progression. Methods Human OC ascites and benign peritoneal fluids were assessed for their ability to stimulate HPMC proliferation. Conditioned medium from ascites- and benign fluid-stimulated HPMCs were compared for their ability to attenuate apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL). We conducted a comparative analysis of global expression changes in ascites-stimulated HPMCs using Agilent oligonucleotide microarrays. Results As compared to benign peritoneal fluids, malignant ascites stimulated the proliferation of HPMCs. TRAIL-induced apoptosis was attenuated in OC cells exposed to conditioned medium from ascites-stimulated HPMCs as compared to OC cells exposed to conditioned medium from benign fluid-stimulated HPMCs. A total of 649 genes were differentially expressed in ascites-stimulated HPMCs. Based on a ratio of more than 1.5-fold and a P?

2014-01-01

147

Radiosensitization of human breast cancer cells by a novel ErbB family receptor tyrosine kinase inhibitor  

Microsoft Academic Search

Purpose: Overexpression of the ErbB family of growth factor receptors is present in a wide variety of human tumors and is correlated with poor prognosis. The purpose of this study was to determine the effects of a novel small molecule ErbB tyrosine kinase inhibitor, CI-1033, in combination with ionizing radiation on breast cancer cell growth and survival.Materials & Methods: Growth

Geetha S Rao; Susan Murray; Stephen P Ethier

2000-01-01

148

Human Telomerase Reverse Transcriptase Promoter Regulation in Normal and Malignant Human Ovarian Epithelial Cells1  

Microsoft Academic Search

The telomerase RNA-protein complex responsible for maintenance of telomeric DNA at chromosome ends, is usually inactive in most primary somatic human cells, but is specifically activated with in vitro immortal- ization and during tumorigenesis. Although expression of the RNA com- ponent of telomerase appears to be constitutive, the expression pattern of human telomerase reverse transcriptase (hTERT), the catalytic subunit of

Ilana Braunstein; Orit Cohen-Barak; Catherine Shachaf; Yael Ravel; Michal Yalon-Hacohen; Gordon B. Mills; Maty Tzukerman; Karl L. Skorecki

149

Genetic polymorphisms in the human tissue kallikrein (KLK) locus and their implication in various malignant and non-malignant diseases.  

PubMed

The Kallikrein ( KLK ) gene locus encodes a family of serine proteases and is the largest contiguous cluster of protease-encoding genes attributed an evolutionary age of 330 million years. The KLK locus has been implicated asa high susceptibility risk loci in numerous cancer studies through the last decade. The KLK3 gene already has established clinical relevance as a biomarker in prostate cancer prognosis through its encoded protein, prostate-specific antigen. Data mined through genome-wide association studies (GWAS) and next-generation sequencing point to many important candidate single nucleotide polymorphisms(SNPs) in KLK3 and other KLK genes. SNPs in the KLK locus have been found to be associated with several diseases including cancer, hypertension, cardiovascular disease and atopic dermatitis. Moreover, introducing a model incorporating SNPs to improve the efficiency of prostate-specific antigen in detecting malignant states of prostate cancer has been recently suggested. Establishing the functional relevance of these newly-discovered SNPs, and their interactions with each other, through in silico investigations followed by experimental validation,can accelerate the discovery of diagnostic and prognostic biomarkers. In this review, we discuss the various genetic association studies on the KLK loci identified either through candidate gene association studies or at the GWAS and post-GWAS front to aid researchers in streamlining their search for the most significant, relevant and therapeutically promising candidate KLK gene and/or SNP for future investigations. PMID:23667899

Batra, Jyotsna; O'Mara, Tracy; Patnala, Radhika; Lose, Felicity; Clements, Judith A

2012-12-01

150

Radiosensitization of human cervical cancer cells by inhibiting ribonucleotide reductase: Enhanced radiation response at low-dose-rates  

PubMed Central

Purpose To test whether pharmacologic inhibition of ribonucleotide reductase (RNR) by 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) enhances radiation sensitivity during low-dose-rate ionizing radiation provided by a novel purpose-built iridium-192 cell irradiator. Methods and Materials Cells were exposed to low (11, 23, 37, 67 cGy/hour) dose-rate radiation using a custom-fabricated cell irradiator or to high (330 cGy/min) dose-rate radiation using a conventional cell irradiator. Radiation sensitivity of human cervical (CaSki, C33-a) cancer cells with or without RNR inhibition by 3-AP was evaluated by clonogenic survival and RNR activity assay. Alteration in cell cycle distribution was monitored by flow cytometry. Results Increasing radiation sensitivity of both CaSki and C33-a cells was observed with incremental rise in radiation dose-rates. 3-AP treatment led to enhanced radiation sensitivity in both cell lines, eliminating differences in cell cytotoxicity due to radiation dose rate. RNR blockade by 3-AP during low-dose-rate irradiation was associated with low RNR activity and an extended G1-phase cell cycle arrest. Conclusions We conclude that RNR inhibition by 3-AP impedes DNA damage repair mechanisms that rely on deoxyribonucleotide production, and thereby increases radiation sensitivity of human cervical cancers to low-dose-rate radiation. PMID:21470790

Kunos, Charles A.; Colussi, Valdir C.; Pink, John; Radivoyevitch, Tomas; Oleinick, Nancy L.

2011-01-01

151

Radiosensitization of Human Cervical Cancer Cells by Inhibiting Ribonucleotide Reductase: Enhanced Radiation Response at Low-Dose Rates  

SciTech Connect

Purpose: To test whether pharmacologic inhibition of ribonucleotide reductase (RNR) by 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC no. 663249) enhances radiation sensitivity during low-dose-rate ionizing radiation provided by a novel purpose-built iridium-192 cell irradiator. Methods and Materials: The cells were exposed to low-dose-rate radiation (11, 23, 37, 67 cGy/h) using a custom-fabricated cell irradiator or to high-dose-rate radiation (330 cGy/min) using a conventional cell irradiator. The radiation sensitivity of human cervical (CaSki, C33-a) cancer cells with or without RNR inhibition by 3-AP was evaluated using a clonogenic survival and an RNR activity assay. Alteration in the cell cycle distribution was monitored using flow cytometry. Results: Increasing radiation sensitivity of both CaSki and C33-a cells was observed with the incremental increase in radiation dose rates. 3-AP treatment led to enhanced radiation sensitivity in both cell lines, eliminating differences in cell cytotoxicity from the radiation dose rate. RNR blockade by 3-AP during low-dose-rate irradiation was associated with low RNR activity and extended G{sub 1}-phase cell cycle arrest. Conclusions: We conclude that RNR inhibition by 3-AP impedes DNA damage repair mechanisms that rely on deoxyribonucleotide production and thereby increases radiation sensitivity of human cervical cancers to low-dose-rate radiation.

Kunos, Charles A., E-mail: charles.kunos@UHhospitals.org [Department of Radiation Oncology, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH (United States); Colussi, Valdir C. [Department of Radiation Oncology, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH (United States); Pink, John [Department of General Medical Sciences, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH (United States); Radivoyevitch, Tomas [Department of Epidemiology and Biostatistics, Case Comprehensive Cancer Center, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH (United States); Oleinick, Nancy L. [Department of Radiation Oncology, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH (United States)

2011-07-15

152

Expression of targeting protein for Xenopus kinesin-like protein 2 is associated with progression of human malignant astrocytoma  

Microsoft Academic Search

In humans, the targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a cell cycle-associated protein, and altered TPX2 expression has been found in various malignancies. However, the contribution of TPX2 expression to astrocytoma progression is unclear. The aim of this study was to investigate TPX2 expression in human astrocytoma samples and cell lines. TPX2 protein expression was detected in

Bin Li; Xiang-Qian Qi; Xin Chen; Xin Huang; Guo-Ying Liu; Huai-Rui Chen; Cheng-Guang Huang; Chun Luo; Yi-Cheng Lu

2010-01-01

153

Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma  

PubMed Central

The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth. PMID:22289125

Favoni, Roberto E; Daga, Antonio; Malatesta, Paolo; Florio, Tullio

2012-01-01

154

Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma.  

PubMed

The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth. PMID:22289125

Favoni, Roberto E; Daga, Antonio; Malatesta, Paolo; Florio, Tullio

2012-05-01

155

Aberrant Expression of Interleukin-1? and Inflammasome Activation in Human Malignant Gliomas  

PubMed Central

Objective Glioblastoma is the most frequent and malignant form of primary brain tumor with grave prognosis. Mounting evidence supports that chronic inflammation (such as chronic overactivation of IL-1 system) is a crucial event in carcinogenesis and tumor progression. IL-1 also is an important cytokine with species-dependent regulations and roles in CNS cell activation. While much attention is paid to specific anti-tumor immunity, little is known about the role of chronic inflammation/innate immunity in glioma pathogenesis. In this study, we examined whether human astrocytic cells (including malignant gliomas) can produce IL-1 and its role in glioma progression. Methods We used a combination of cell culture, real-time PCR, ELISA, western blot, immunocytochemistry, siRNA and plasmid transfection, micro-RNA analysis, angiogenesis (tube formation) assay, and neurotoxicity assay. Results Glioblastoma cells produced large quantities of IL-1 when activated, resembling macrophages/microglia. The activation signal was provided by IL-1 but not the pathogenic components LPS or poly IC. Glioblastoma cells were highly sensitive to IL-1 stimulation, suggesting its relevance in vivo. In human astrocytes, IL-1? mRNA was not translated to protein. Plasmid transfection also failed to produce IL-1 protein, suggesting active repression. Suppression of microRNAs that can target IL-1?/? did not induce IL-1 protein. Glioblastoma IL-1? processing occurred by the NLRP3 inflammasome, and ATP and nigericin increased IL-1? processing by upregulating NLRP3 expression, similar to macrophages. RNAi of annexin A2, a protein strongly implicated in glioma progression, prevented IL-1 induction, demonstrating its new role in innate immune activation. IL-1 also activated Stat3, a transcription factor crucial in glioma progression. IL-1 activated glioblastoma-conditioned media enhanced angiogenesis and neurotoxicity. Conclusions Our results demonstrate unique, species-dependent immune activation mechanisms involving human astrocytes and astrogliomas. Specifically, the ability to produce IL-1 by glioblastoma cells may confer them a mesenchymal phenotype including increased migratory capacity, unique gene signature and proinflammatory signaling. PMID:25054228

Tarassishin, Leonid; Casper, Diana; Lee, Sunhee C.

2014-01-01

156

Radioprotection of Human Cell Nuclear DNA by Polyamines: Radiosensitivity of Chromatin is Influenced by Tightly Bound Spermine  

NASA Technical Reports Server (NTRS)

The polyamines putrescine (PUT) and spermine (SPM) were examined for their ability to protect human cell Deoxyribonucleic Acid (DNA) against the formation of radiation-induced double-strand breaks (DSBs). As observed previously, under conditions where polyamines were shown to be almost completely absent, association with nuclear matrix protein into a nucleoid, and organization into chromatin structure, protected DNA from induction of DSBs by factors of 4.5 and 95, respectively. At concentrations below 1 mM, PUT or SPM provided equivalent levels of protection to deproteinized nuclear DNA, consistent with their capacity to scavenge radiation-induced radicals. At constant ionic strength, 5 mM SPM protected deproteinized DNA and nucleoid DNA and DNA in nuclear chromatin by factors of 100 and 26, respectively. At 5 mM, SPM provided 15 times greater protection of deproteinized DNA than did PUT. Under physiologically relevant conditions, 5 mM SPM protected DNA in the intact nucleus from the induction of DSBs by a factor of 2 relative to DNA in the absence of SPM. Studies of SPM binding during cellular fractionation revealed that a significant fraction of the cellular SPM is tightly bound in the nucleus but can be removed by extended washing. Thus the association of SPM with nuclear chromatin appears to be a significant contributor to the resistance of the cell's DNA to the induction of DSBs.

Warters, Raymond L.; Newton, Gerald L.; Olive, Peggy L.; Fahey, Robert C.

1999-01-01

157

Prognostic value and biological role of the kallikrein-related peptidases in human malignancies.  

PubMed

Cancer is a substantial health problem for the populations of the Western world. The discovery of new molecular biomarkers for diagnosis, prognosis and monitoring patients' response to therapy can aid in combating this complicated disease. The human kallikrein-related peptidases (human tissue kallikreins [KLKs]) are encoded by a continuous multigene family, located on chromosomal region 19q13.3-4. KLK3 (prostate-specific antigen) is the most efficient cancer biomarker ever employed. KLK genes are expressed abnormally in various malignancies, where they affect cancer-cell growth and metastasis. Their deregulated expression pattern, often associated with various clinicopathological characteristics of cancer patients, can be exploited, solely or within multiparametric panels, as a prognostic biomarker. Recent data illustrate that discernible molecular modulations of KLKs, occurring as a result of cancer cells' treatment with antitumor agents, may serve as new potential biomarkers, possibly predicting patients' treatment response. It is believed that KLKs might be employed in future clinical practice as novel and effective tumor markers. PMID:20146586

Mavridis, Konstantinos; Scorilas, Andreas

2010-02-01

158

Loss of canonical Smad4 signaling promotes KRAS driven malignant transformation of human pancreatic duct epithelial cells and metastasis.  

PubMed

Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer death in North America. Activating KRAS mutations and Smad4 loss occur in approximately 90% and 55% of PDAC, respectively. While their roles in the early stages of PDAC development have been confirmed in genetically modified mouse models, their roles in the multistep malignant transformation of human pancreatic duct cells have not been directly demonstrated. Here, we report that Smad4 represents a barrier in KRAS-mediated malignant transformation of the near normal immortalized human pancreatic duct epithelial (HPDE) cell line model. Marked Smad4 downregulation by shRNA in KRAS (G12V) expressing HPDE cells failed to cause tumorigenic transformation. However, KRAS-mediated malignant transformation occurred in a new HPDE-TGF-? resistant (T?R) cell line that completely lacks Smad4 protein expression and is resistant to the mito-inhibitory activity of TGF-?. This transformation resulted in tumor formation and development of metastatic phenotype when the cells were implanted orthotopically into the mouse pancreas. Smad4 restoration re-established TGF-? sensitivity, markedly increased tumor latency by promoting apoptosis, and decreased metastatic potential. These results directly establish the critical combination of the KRAS oncogene and complete Smad4 inactivation in the multi-stage malignant transformation and metastatic progression of normal human HPDE cells. PMID:24386371

Leung, Lisa; Radulovich, Nikolina; Zhu, Chang-Qi; Wang, Dennis; To, Christine; Ibrahimov, Emin; Tsao, Ming-Sound

2013-01-01

159

Loss of Canonical Smad4 Signaling Promotes KRAS Driven Malignant Transformation of Human Pancreatic Duct Epithelial Cells and Metastasis  

PubMed Central

Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer death in North America. Activating KRAS mutations and Smad4 loss occur in approximately 90% and 55% of PDAC, respectively. While their roles in the early stages of PDAC development have been confirmed in genetically modified mouse models, their roles in the multistep malignant transformation of human pancreatic duct cells have not been directly demonstrated. Here, we report that Smad4 represents a barrier in KRAS-mediated malignant transformation of the near normal immortalized human pancreatic duct epithelial (HPDE) cell line model. Marked Smad4 downregulation by shRNA in KRASG12V expressing HPDE cells failed to cause tumorigenic transformation. However, KRAS-mediated malignant transformation occurred in a new HPDE-TGF-? resistant (T?R) cell line that completely lacks Smad4 protein expression and is resistant to the mito-inhibitory activity of TGF-?. This transformation resulted in tumor formation and development of metastatic phenotype when the cells were implanted orthotopically into the mouse pancreas. Smad4 restoration re-established TGF-? sensitivity, markedly increased tumor latency by promoting apoptosis, and decreased metastatic potential. These results directly establish the critical combination of the KRAS oncogene and complete Smad4 inactivation in the multi-stage malignant transformation and metastatic progression of normal human HPDE cells. PMID:24386371

Leung, Lisa; Radulovich, Nikolina; Zhu, Chang-Qi; Wang, Dennis; To, Christine; Ibrahimov, Emin; Tsao, Ming-Sound

2013-01-01

160

The prevalence of opportunistic infections and malignancies in autopsied patients with human immunodeficiency virus infection in Japan  

PubMed Central

Background Opportunistic infections and malignancies such as malignant lymphoma and Kaposi sarcoma are significant complications of human immunodeficiency virus (HIV) infection. However, following the introduction of antiretroviral therapy in Japan in 1997, the incidence of clinical complications has decreased. In the present study, autopsy cases of HIV infection in Japan were retrospectively investigated to reveal the prevalence of opportunistic infections and malignancies. Methods A total of 225 autopsy cases of HIV infection identified at 4 Japanese hospitals from 1985–2012 were retrospectively reviewed. Clinical data were collected from patient medical records. Results Mean CD4 counts of patients were 77.0 cells/?L in patients who received any antiretroviral therapy during their lives (ART (+) patients) and 39.6 cells/?L in naïve patients (ART (?) patients). Cytomegalovirus infection (142 cases, 63.1%) and pneumocystis pneumonia (66 cases, 29.3%) were the most frequent opportunistic infections, and their prevalence was significantly lower in ART (+) patients than ART (?) patients. Non-Hodgkin lymphoma and Kaposi sarcoma were observed in 30.1% and 16.2% of ART (?) patients, and 37.9% and 15.2% of ART (+) patients, respectively. Malignant lymphoma was the most frequent cause of death, followed by cytomegalovirus infection regardless of ART. Non-acquired immunodeficiency syndrome (AIDS)-defining cancers such as liver and lung cancer caused death more frequently in ART (+) patients (9.1%) than in ART (?) patients (1.5%; P?=?0.026). Conclusions The prevalence of infectious diseases and malignancies were revealed in autopsy cases of HIV infection in Japan. The prevalence of cytomegalovirus infection and pneumocystis pneumonia at autopsy were lower in ART (+) patients than ART (?) patients. Higher prevalence of non-AIDS defining malignancies among ART (+) patients than ART (?) patients suggests that onsets of various opportunistic infections and malignancies should be carefully monitored regardless of whether the patient is receiving ART. PMID:24775713

2014-01-01

161

Human papillomavirus-associated subsequent malignancies among long-term survivors of pediatric and young adult cancers.  

PubMed

Long-term survivors of pediatric and young adult (PAYA) cancers have a high incidence of subsequent neoplasms, but few risk factors other than cancer treatment have been identified. We aimed to describe the burden of human papillomavirus (HPV)-associated malignancies among survivors of PAYA cancers to assess whether HPV infections might be a reasonable area of future etiologic research on subsequent malignancies in this population. We used longitudinal data from 9 population-based registries of the Surveillance, Epidemiology, and End Results program collected between 1973 and 2010 to assemble a cohort of individuals who were diagnosed with any cancer between the ages of 0 and 29 years and survived at least 5 years post-diagnosis. We estimated sex-specific standardized incidence ratios (SIRs) with corresponding 95% confidence limits (CL) of HPV-associated subsequent malignancies (cervical, vaginal, vulvar, penile, anal, tongue, tonsillar, and oropharyngeal). Our study population comprised 64,547 long-term survivors of PAYA cancers diagnosed between 1973 and 2010. Compared with females in the general US population, female PAYA cancer survivors had a 40% relative excess of HPV-associated malignancies overall (SIR?=?1.4, 95% CL: 1.2, 1.8). Compared with males in the general US population, male PAYA cancer survivors had a 150% relative excess of HPV-associated malignancies overall (SIR?=?2.5, 95% CL: 1.9, 3.4). Our findings suggest an excess of HPV-associated malignancies among PAYA cancer survivors compared with the general US population. We hypothesize that a portion of subsequent malignancies among PAYA cancer survivors may be directly attributable to HPV infection. This hypothesis warrants exploration in future studies. PMID:23940566

Ojha, Rohit P; Tota, Joseph E; Offutt-Powell, Tabatha N; Klosky, James L; Minniear, Timothy D; Jackson, Bradford E; Gurney, James G

2013-01-01

162

Expression of peroxiredoxin 1 and 4 promotes human lung cancer malignancy  

PubMed Central

Members of the Peroxiredoxin (Prx) family are major cellular antioxidants that scavenge hydrogen peroxide and play essential roles in oxidative stress and cell signaling. 2-Cys Prxs, including Prx1, 2, 3 and 4, have been indicated in multiple oncogenic signaling pathways and thus may contribute to various processes of cancer development. The significance of 2-Cys Prxs in lung cancer development and their biological function in signal transduction have not been fully investigated. In this study we analyzed the expression of 2-Cys Prxs in lung cancer, and examined their levels of expression in a variety of cell lines established from human lung normal or cancer tissues. We found that 2-Cys Prxs, in particular, Prx1 and Prx4, were preferentially expressed in cell lines derived from human lung cancer. Through isoform specific knockdown of individual Prx, we demonstrated that Prx1 and Prx4 (but not Prx3) were required for human lung cancer A549 cells to form soft agar colony and to invade through matrigel in culture. Knockdown of Prx1 or Prx4 significantly reduced the activation of c-Jun and repressed the AP-1 mediated promoter activity. In mouse xenograft models, knockdown of Prx4 in A549 cells reduced subcutaneous tumor growth and blocked metastasis formation initiated through tail vein injection. Moreover, overexpression of Prx1 or Prx4 further enhanced the malignancy of A549 cells both in culture and in mouse xenografts in vivo. These data provide an in-depth understanding of the contribution of Prx1 and Prx4 to lung cancer development and are of importance for future development of therapeutic methods that targeting 2-Cys Prxs. PMID:25232487

Jiang, Hong; Wu, Lisha; Mishra, Murli; Chawsheen, Hedy A; Wei, Qiou

2014-01-01

163

Malignant Transformation Potentials of Human Umbilical Cord Mesenchymal Stem Cells Both Spontaneously and via 3-Methycholanthrene Induction  

PubMed Central

Human umbilical cord mesenchymal stem cells (HUMSCs) are highly proliferative and can be induced to differentiate into advanced derivatives of all three germ layers. Thus, HUMSCs are considered to be a promising source for cell-targeted therapies and tissue engineering. However there are reports on spontaneous transformation of mesenchymal stem cells (MSCs) derived from human bone marrows. The capacity for HUMSCs to undergo malignant transform spontaneously or via induction by chemical carcinogens is presently unknown. Therefore, we isolated HUMSCs from 10 donors and assessed their transformation potential either spontaneously or by treating them with 3-methycholanthrene (3-MCA), a DNA-damaging carcinogen. The malignant transformation of HUMSCs in vitro was evaluated by morphological changes, proliferation rates, ability to enter cell senescence, the telomerase activity, chromosomal abnormality, and the ability to form tumors in vivo. Our studies showed that HUMSCs from all 10 donors ultimately entered senescence and did not undergo spontaneous malignant transformation. However, HUMSCs from two of the 10 donors treated with 3-MCA displayed an increased proliferation rate, failed to enter senescence, and exhibited an altered cell morphology. When these cells (tHUMSCs) were injected into immunodeficient mice, they gave rise to sarcoma-like or poorly differentiated tumors. Moreover, in contrast to HUMSCs, tHUMSCs showed a positive expression of human telomerase reverse transcriptase (hTERT) and did not exhibit a shortening of the relative telomere length during the long-term culture in vitro. Our studies demonstrate that HUMSCs are not susceptible to spontaneous malignant transformation. However, the malignant transformation could be induced by chemical carcinogen 3-MCA. PMID:24339974

Lai, Xiulan; Liu, Sizheng; Chen, Yezeng; Zheng, Zexin; Xie, Qingdong; Maldonado, Martin; Cai, Zhiwei; Qin, Shan; Ho, Guyu; Ma, Lian

2013-01-01

164

Activity of Glutathione-Metabolizing and Antioxidant Enzymes in Malignant and Benign Tumors of Human Lungs  

Microsoft Academic Search

We measured the content of glutathione and activity of glutathione-metabolizing and antioxidant enzymes superoxide dismutase and catalase in samples obtained from 52 patients with malignant lung tumors and 20 patients with benign lung tumors. The content of glutathione and activity of glutathione-metabolizing enzymes underwent similar changes, but these changes were most pronounced in malignant tumors. Antioxidant enzyme activity changed insignificantly

R. N. Korotkina; G. N. Matskevich; A. Sh. Devlikanova; A. A. Vishnevskii; A. G. Kunitsyn; A. A. Karelin

2002-01-01

165

Comparative analysis of cell death induction by Taurolidine in different malignant human cancer cell lines  

Microsoft Academic Search

BACKGROUND: Taurolidine (TRD) represents an anti-infective substance with anti-neoplastic activity in many malignant cell lines. So far, the knowledge about the cell death inducing mechanisms and pathways activated by TRD is limited. The aim of this study was therefore, to perform a comparative analysis of cell death induction by TRD simultaneously in different malignant cell lines. MATERIALS AND METHODS: Five

Ansgar M Chromik; Adrien Daigeler; Daniel Bulut; Annegret Flier; Christina May; Kamran Harati; Jan Roschinsky; Dominique Sülberg; Peter R Ritter; Ulrich Mittelkötter; Stephan A Hahn; Waldemar Uhl

2010-01-01

166

Serological analysis of cell surface antigens of malignant human brain tumors  

PubMed Central

Sera from 30 patients with astrocytoma were tested for antibody reacting with cell surface antigens of cultured autologous astrocytoma cells. Ten percent of the patients had antibody detectable by mixed hemadsorption assays, ?50% by immune adherence and protein A assays, and 100% by anti-C3-mixed hemadsorption assays. Absorption analysis of reactive sera with autologous, allogeneic, and xenogeneic cells permitted the definition of three classes of astrocytoma cell surface antigens. Class I antigens showed an absolute restriction to autologous astrocytoma cells. Class II antigens were shared by all astrocytomas tested and could be detected also on neuroblastoma, sarcoma, and some (but not all) melanoma cell lines; these antigens were not found on cell lines derived from carcinomas or normal tissues. Class III antigens were widely distributed on cultured normal and malignant cells of human and animal origin. In this series, sera from 2 patients recognized class I antigens, 4 patients' serum recognized class II antigens, and 13 patients' sera recognized class III antigens. Absorption tests have shown that the AJ (class II) antigen of astrocytoma is serologically related to the previously described AH (class II) antigen of melanoma; in tests of nine melanoma cell lines, there was a correspondence between the AJ and AH phenotypes. This method of autologous typing provides a way to classify the cell surface antigens of astrocytomas and to assess the clinical significance of humoral immunity to these antigens. PMID:283420

Pfreundschuh, Michael; Shiku, Hiroshi; Takahashi, Toshitada; Ueda, Ryuzo; Ransohoff, Joseph; Oettgen, Herbert F.; Old, Lloyd J.

1978-01-01

167

Biochemical signatures of doppel protein in human astrocytomas to support prediction in tumor malignancy.  

PubMed

Doppel (Dpl) is a membrane-bound glycoprotein mainly expressed in the testis of adult healthy people. It is generally absent in the central nervous system, but its coding gene sequence is ectopically expressed in astrocytoma specimens and in derived cell lines. In this paper, we investigated the expression and the biochemical features of Dpl in a panel of 49 astrocytoma specimens of different WHO malignancy grades. As a result, Dpl was expressed in the majority of the investigated specimens (86%), also including low grade samples. Importantly, Dpl exhibited different cellular localizations and altered glycan moieties composition, depending on the tumor grade. Most low-grade astrocytomas (83%) showed a membrane-bound Dpl, like human healthy testis tissue, whereas the majority of high-grade astrocytomas (75%) displayed a cytosolic Dpl. Deglycosylation studies with N-glycosidase F and/or neuraminidase highlighted defective glycan moieties and an unexpected loss of sialic acid. To find associations between glial tumor progression and Dpl biochemical features, predictive bioinformatics approaches were produced. In particular, Decision tree and Nomogram analysis showed well-defined Dpl-based criteria that separately clustered low-and high-grade astrocytomas. Taken together, these findings show that in astrocytomas, Dpl undergoes different molecular processes that might constitute additional helpful tools to characterize the glial tumor progression. PMID:20981146

Rognoni, Paola; Chiarelli, Laurent R; Comincini, Sergio; Azzalin, Alberto; Miracco, Clelia; Valentini, Giovanna

2010-01-01

168

Curcumin inhibits AP-2?-induced apoptosis in the human malignant testicular germ cells in vitro  

PubMed Central

Aim: To investigate the effects of curcumin on proliferation and apoptosis in testicular cancer cells in vitro and to investigate its molecular mechanisms of action. Methods: NTera-2 human malignant testicular germ cell line and F9 mouse teratocarcinoma stem cell line were used. The anti-proliferative effect was examined using MTT and colony formation assays. Hoechst 33258 staining, TUNEL and Annexin V-FITC/PI staining assays were used to analyze cell apoptosis. Protein expression was examined with Western blot analysis and immunocytochemical staining. Results: Curcumin (5, 10 and 15 ?mol/L) inhibited the viability of NTera-2 cells in dose- and time-dependent manners. Curcumin significantly inhibited the colony formation in both NTera-2 and F9 cells. Curcumin dose-dependently induced apoptosis of NTera-2 cells by reducing FasL expression and Bcl-2-to-Bax ratio, and activating caspase-9, -8 and -3. Furthermore, curcumin dose-dependently reduced the expression of AP transcription factor AP-2? in NTera-2 cells, whereas the pretreatment with the proteasome inhibitor MG132 blocked both the curcumin-induced reduction of AP-2? and antiproliferative effect. Curcumin inhibited ErbB2 expression, and decreased the phosphorylation of Akt and ERK in NTera-2 cells. Conclusion: Curcumin induces apoptosis and inhibits proliferation in NTera-2 cells via the inhibition of AP-2?-mediated downstream cell survival signaling pathways. PMID:23685957

Zhou, Chang; Zhao, Xiao-meng; Li, Xiao-feng; Wang, Cheng; Zhang, Xiao-ting; Liu, Xi-zhi; Ding, Xiao-feng; Xiang, Shuang-lin; Zhang, Jian

2013-01-01

169

Immunophenotype of human ovarian malignancies (cystadenocarcinomata and mixed müllerian tumor) established in SCID mice.  

PubMed

Human ovarian malignancies from three different patients (histology: two serous cystadenocarcinomata and one mixed Müllerian tumor, homologous type) were successfully serially transplanted intraperitoneally into severe combined immunodeficient (SCID) mice where the tumor cells spread around the peritoneal cavity. If the ascites derived from cystadenocarcinoma cells engrafted in the female genital tract of the SCID mice, they formed cystic tumors resembling remarkably well the original tumors in the patients. Immunohistochemical analysis revealed that the immunophenotype of the patients' original tumor and those grown in SCID mice were similar in the case of the two cystadenocarcinomata; in addition, the marker expression in general was stable during serial transplantation. If distant metastases occurred in the lungs, they immunophenotypically resembled those grown intraperitoneally. In contrast, the cells derived from the mixed Müllerian tumor shifted during serial transplantation from a spindle cell morphology toward a morphology characterized by cuboidal cells. The transition toward a more epithelial phenotype was accompanied by a changed immunophenotype of the tumor cells which became positive for epithelial cell markers such as carcinoembryonic antigens, CA 19-9 and CA 125. Concurrently with this differentiation, the p53 immunophenotype changed from positive to negative, indicating a further mutation in the p53 gene during serial passages. PMID:9316588

Schumacher, U; Adam, E; Dietl, J; Horny, H P

1997-04-01

170

Hydrogen peroxide promotes epithelial to mesenchymal transition and stemness in human malignant mesothelioma cells.  

PubMed

Reactive oxygen species (ROS) are known to promote mesothelial carcinogenesis that is closely associated with asbestos fibers and inflammation. Epithelial to mesenchymal cell transition (EMT) is an important process involved in the progression of tumors, providing cancer cells with aggressiveness. The present study was performed to determine if EMT is induced by H2O2 in human malignant mesothelioma (HMM) cells. Cultured HMM cells were treated with H2O2, followed by measuring expression levels of EMT-related genes and proteins. Immunohistochemically, TWIST1 expression was confined to sarcomatous cells in HMM tissues, but not in epithelioid cells. Treatment of HMM cells with H2O2 promoted EMT, as indicated by increased expression levels of vimentin, SLUG and TWIST1, and decreased E-cadherin expression. Expression of stemness genes such as OCT4, SOX2 and NANOG was also significantly increased by treatment of HMM cells with H2O2. Alteration of these genes was mediated via activation of hypoxia inducible factor 1 alpha (HIF-1?) and transforming growth factor beta 1 (TGF-?1). Considering that treatment with H2O2 results in excess ROS, the present study suggests that oxidative stress may play a critical role in HMM carcinogenesis by promoting EMT processes and enhancing the expression of stemness genes. PMID:23886156

Kim, Myung-Chul; Cui, Feng-Ji; Kim, Yongbaek

2013-01-01

171

Sequential transcriptome analysis of human liver cancer indicates late stage acquisition of malignant traits  

PubMed Central

Background & Aims Human hepatocarcinogenesis is as a multi-step process starting from dysplastic lesions to early carcinomas (eHCC) that ultimately progress to HCC (pHCC). However, the sequential molecular alterations driving malignant transformation of the pre-neoplastic lesions are not clearly defined. This lack of information represents a major challenge in the clinical management of patients at risk. Methods We applied next-generation transcriptome sequencing to tumor-free surrounding liver (n=7), low- (n=4) and high-grade (n=9) dysplastic lesions, eHCC (n=5) and pHCC (n=3) from 8 HCC patients with hepatitis B infection. Integrative analyses of genetic and transcriptomic changes were performed to characterize the genomic alterations during hepatocarcinogenesis. Results We report that changes in transcriptomes of early lesions including eHCC were modest and surprisingly homogenous. Extensive genetic alterations and subsequent activation of prognostic adverse signaling pathways occurred only late during hepatocarcinogenesis and were centered on TGF?, WNT, NOTCH and EMT-related genes highlighting the molecular diversity of pHCC. We further identify IGFALS as a key genetic determinant preferentially down-regulated in pHCC. Conclusions Our results define new hallmarks in molecular stratification and therapy options for patients at risk for HCC, and merit larger prospective investigations to develop a modified clinical-decision making algorithm based on the individualized next-generation sequencing analyses. PMID:24512821

Gillen, Matthew C.; Kim, Myoung Soo; Conner, Elizabeth A.; Galle, Peter R.; Factor, Valentina M.; Park, Young Nyun; Thorgeirsson, Snorri S.

2013-01-01

172

Malignant mesothelioma  

PubMed Central

Malignant mesothelioma is a fatal asbestos-associated malignancy originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis. The exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10–20 years. Pleural malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are those of chest pain and dyspnoea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. Mesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational "environmental" exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million. A combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. Distinguishing malignant from benign pleural disease can be challenging. The most helpful CT findings suggesting malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 4) mediastinal pleural involvement. Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with end of life care. Compensation issues must also be considered. Life expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis. PMID:19099560

Moore, Alastair J; Parker, Robert J; Wiggins, John

2008-01-01

173

The urokinase receptor supports tumorigenesis of human malignant pleural mesothelioma cells.  

PubMed

Malignant pleural mesothelioma (MPM) is a lethal neoplasm for which current therapy is unsatisfactory. The urokinase plasminogen activator receptor (uPAR) is associated with increased virulence of many solid neoplasms, but its role in the pathogenesis of MPM is currently unclear. We found that REN human pleural MPM cells expressed 4- to 10-fold more uPAR than MS-1 or M9K MPM cells or MeT5A human pleural mesothelial cells. In a new orthotopic murine model of MPM, we found that the kinetics of REN cell tumorigenesis is accelerated versus MS-1 or M9K cells, and that REN instillates generated larger tumors expressing increased uPAR, were more invasive, and caused earlier mortality. While REN, MS-1, and M9K tumors were all associated with prominent extravascular fibrin deposition, excised REN tumor homogenates were characterized by markedly increased uPAR at both the mRNA and protein levels. REN cells exhibited increased thymidine incorporation, which was attenuated in uPAR-silenced cells (P < 0.01). REN cells traversed three-dimensional fibrin gels while MS-1, M9K, and MeT5A cells did not. uPAR siRNA or uPAR blocking antibodies decreased REN cell migration and invasion, while uPA and fetal bovine serum augmented the effects. Transfection of relatively low uPAR expressing MS-1 cells with uPAR cDNA increased proliferation and migration in vitro and tumor formation in vivo. These observations link overexpression of uPAR to the pathogenesis of MPM, demonstrate that this receptor contributes to accelerated tumor growth in part through interactions with uPA, and suggest that uPAR may be a promising target for therapeutic intervention. PMID:19635932

Tucker, Torry A; Dean, Candice; Komissarov, Andrey A; Koenig, Kathy; Mazar, Andrew P; Pendurthi, Usha; Allen, Timothy; Idell, Steven

2010-06-01

174

Mechanisms of Acquired Androgen Independence during Arsenic-Induced Malignant Transformation of Human Prostate Epithelial Cells  

PubMed Central

Background Prostate cancer progression often occurs with overexpression of growth factors and receptors, many of which engage the Ras/mitogen-activated protein MAP kinase (MAPK) pathway. Objectives In this study we used arsenic-transformed human prostate epithelial cells, which also show androgen-independent growth, to study the possibility that chronic activation of Ras/MAPK signaling may contribute to arsenic-induced prostate cancer progression. Methods Control and chronic arsenic–transformed prostate epithelial cells (CAsE-PE) were compared for Ras/MAPK signaling capacities using reverse transcription–polymerase chain reaction and Western blot analyses. Results We found activation of HER-2/neu oncogene in transformed CAsE-PE cells, providing molecular evidence of androgen independence in the transformed cells. CAsE-PE cells displayed constitutively increased expression of unmutated K-Ras (6-fold), and the downstream MAP kinases A-Raf and B-Raf (2.2-fold and 3.2-fold, respectively). There was also increased expression of phosphorylated MEK1/2 and Elk1 in the transformant cells. The MEK1/2 inhibitor, U0126, blocked PSA overexpression in CAsE-PE cells. Conclusion Thus, arsenic-induced malignant transformation and acquired androgen independence are linked to Ras signaling activation in human prostate epithelial cells. Chronic activation of this pathway can sensitize the androgen receptor to subphysiologic levels of androgen. This may be important in arsenic carcinogenesis and provide a mechanism that may be common for prostate cancer progression driven by diverse agents. PMID:17384772

Benbrahim-Tallaa, Lamia; Webber, Mukta M.; Waalkes, Michael P.

2007-01-01

175

A three-dimensional tissue culture model to study primary human bone marrow and its malignancies.  

PubMed

Tissue culture has been an invaluable tool to study many aspects of cell function, from normal development to disease. Conventional cell culture methods rely on the ability of cells either to attach to a solid substratum of a tissue culture dish or to grow in suspension in liquid medium. Multiple immortal cell lines have been created and grown using such approaches, however, these methods frequently fail when primary cells need to be grown ex vivo. Such failure has been attributed to the absence of the appropriate extracellular matrix components of the tissue microenvironment from the standard systems where tissue culture plastic is used as a surface for cell growth. Extracellular matrix is an integral component of the tissue microenvironment and its presence is crucial for the maintenance of physiological functions such as cell polarization, survival, and proliferation. Here we present a 3-dimensional tissue culture method where primary bone marrow cells are grown in extracellular matrix formulated to recapitulate the microenvironment of the human bone (rBM system). Embedded in the extracellular matrix, cells are supplied with nutrients through the medium supplemented with human plasma, thus providing a comprehensive system where cell survival and proliferation can be sustained for up to 30 days while maintaining the cellular composition of the primary tissue. Using the rBM system we have successfully grown primary bone marrow cells from normal donors and patients with amyloidosis, and various hematological malignancies. The rBM system allows for direct, in-matrix real time visualization of the cell behavior and evaluation of preclinical efficacy of novel therapeutics. Moreover, cells can be isolated from the rBM and subsequently used for in vivo transplantation, cell sorting, flow cytometry, and nucleic acid and protein analysis. Taken together, the rBM method provides a reliable system for the growth of primary bone marrow cells under physiological conditions. PMID:24637629

Parikh, Mukti R; Belch, Andrew R; Pilarski, Linda M; Kirshner, Julia

2014-01-01

176

Increased betulinic acid induced cytotoxicity and radiosensitivity in glioma cells under hypoxic conditions  

PubMed Central

Background Betulinic acid (BA) is a novel antineoplastic agent under evaluation for tumor therapy. Because of the selective cytotoxic effects of BA in tumor cells (including gliomas), the combination of this agent with conservative therapies (such as radiotherapy and chemotherapy) may be useful. Previously, the combination of BA with irradiation under hypoxic conditions had never been studied. Methods In this study, the effects of 3 to 30 ?M BA on cytotoxicity, migration, the protein expression of PARP, survivin and HIF-1?, as well as radiosensitivity under normoxic and hypoxic conditions were analyzed in the human malignant glioma cell lines U251MG and U343MG. Cytotoxicity and radiosensitivity were analyzed with clonogenic survival assays, migration was analyzed with Boyden chamber assays (or scratch assays) and protein expression was examined with Western blot analyses. Results Under normoxic conditions, a half maximal inhibitory concentration (IC50) of 23 ?M was observed in U251MG cells and 24 ?M was observed in U343MG cells. Under hypoxic conditions, 10 ?M or 15 ?M of BA showed a significantly increased cytotoxicity in U251MG cells (p = 0.004 and p = 0.01, respectively) and U343MG cells (p < 0.05 and p = 0.01, respectively). The combination of BA with radiotherapy resulted in an additive effect in the U343MG cell line under normoxic and hypoxic conditions. Weak radiation enhancement was observed in U251MG cell line after treatment with BA under normoxic conditions. Furthermore, under hypoxic conditions, the incubation with BA resulted in increased radiation enhancement. The enhancement factor, at an irradiation dose of 15 Gy after treatment with 10 or 15 ?M BA, was 2.20 (p = 0.02) and 4.50 (p = 0.03), respectively. Incubation with BA led to decreased cell migration, cleavage of PARP and decreased expression levels of survivin in both cell lines. Additionally, BA treatment resulted in a reduction of HIF-1? protein under hypoxic conditions. Conclusion Our results suggest that BA is capable of improving the effects of tumor therapy in human malignant glioma cells, particularly under hypoxic conditions. Further investigations are necessary to characterize its potential as a radiosensitizer. PMID:21906280

2011-01-01

177

Radioimmunoassay for human pancreatic ribonuclease and measurement of serum immunoreactive pancreatic ribonuclease in patients with malignant tumors  

SciTech Connect

A method for radioimmunoassay of human pancreatic RNase was developed. The method is sensitive, reproducible, and specific. Almost no cross-reactivity exists between human pancreatic and liver RNases. A good correlation was observed between the serum concentration of pancreatic RNase as measured by radioimmunoassay and its enzymatic activity using polycytidylic acid as substrate. The concentration of serum pancreatic RNase correlates well with age, blood urea nitrogen, and albumin contents but does not correlate with serum amylase activity. Using the data of 52 patients with malignant tumors except pancreatic cancer, serum RNase level could be expressed by a multiple regression equation: Immunoreactive RNase content in pancreatic cancer was elevated in patients with complications from renal failure. Serum pancreatic RNase contents in patients with pancreatic cancer measured by radioimmunoassay agreed well with the values calculated using the equation derived from the data of patients with other malignant tumors.

Kurihara, M.; Ogawa, M.; Ohta, T.; Kurokawa, E.; Kitahara, T.; Murata, A.; Matsuda, K.; Kosaki, G.; Watanabe, T.; Wada, H.

1984-05-01

178

ZINGIPAIN, A CYSTEINE PROTEASE FROM Zingiber ottensii VALETON RHIZOMES WITH ANTIPROLIFERATIVE ACTIVITIES AGAINST FUNGI AND HUMAN MALIGNANT CELL LINES  

Microsoft Academic Search

The objective of this study was to investigate the activity of a protein identified as cysteine protease, purified from Zingiber ottensii Valeton rhizomes, in terms of antiproliferation against fungi, bacteria, and human malignant cell lines. By means of buffer extraction followed by (NH4)2SO4 precipitation and ion-exchange chromatography, the obtained dominant protein (designated F50) was submitted to non-denaturing and reducing sodium

Aphichart Karnchanatat; Nathachai Tiengburanatam; Apaporn Boonmee; Songchan Puthong; Polkit Sangvanich

2011-01-01

179

300. Adenoviral Delivery of the Gene Encoding Secretable Trimeric TRAIL Induces Apoptosis and Suppresses Human Malignant Glioma In Vivo  

Microsoft Academic Search

Malignant gliomas are most common human primary brain tumors. Despite of intensive research, current treatments have not significantly improved patient survival over last three decades. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a wide range of tumor cells without fatal effect on normal cells. In previous study, we designed a replication deficient adenovirus (Ad) to encode secretable trimeric TRAIL (stTRAIL).

Moonsup Jeong; In-Ho Kwon; Chae-Young Kim; Dai-Wu Seol; Paul D. Robbins; Byong-Moon Kim

2005-01-01

180

Radiosensitization by gold nanoparticles.  

PubMed

Recent years brought increasing use of gold nano particles (GNP) as a model platform for interaction of irradiation and GNPs aiming radiosensitization. Endocytosis seems to be one of the major pathways for cellular uptake of GNPs. Internalization mechanism of GNPs is likely receptor-mediated endocytosis, influenced by GNP size, shape, its coating and surface charging. Many showed that DNA damage can occur as a consequence of metal-enhanced production of low energy electrons, Auger electrons and alike. Kilovoltage radiotherapy (RT) carries significantly higher dose enhancement factor (DEF) that is observed with megavoltage irradiations, the latter usually been at the order of 1.1-1.2. Higher gold concentrations seem to carry higher risk of toxicity, while with lower concentrations the DEF can be reduced. Adding a chemotherapeutic agent could increase level of enhancement. Clinical trials are eagerly awaited with a promise of gaining more knowledge deemed necessary for more successful transition to widespread clinical practice. PMID:23359187

Jeremic, B; Aguerri, A R; Filipovic, N

2013-08-01

181

The Guanine Nucleotide Exchange Factor SWAP-70 Modulates the Migration and Invasiveness of Human Malignant Glioma Cells12  

PubMed Central

The malignant glioma is the most common primary human brain tumor. Its tendency to invade away from the primary tumor mass is considered a leading cause of tumor recurrence and treatment failure. Accordingly, the molecular pathogenesis of glioma invasion is currently under investigation. Previously, we examined a gene expression array database comparing human gliomas to nonneoplastic controls and identified several Rac guanine nucleotide exchange factors with differential expression. Here, we report that the guanine nucleotide exchange factor SWAP-70 has increased expression in malignant gliomas and strongly correlates with lowered patient survival. SWAP-70 is a multifunctional signaling protein involved in membrane ruffling that works cooperatively with activated Rac. Using a glioma tissue microarray, we validated that SWAP-70 demonstrates higher expression in malignant gliomas compared with low-grade gliomas or nonneoplastic brain tissue. Through immunofluorescence, SWAP-70 localizes to membrane ruffles in response to the growth factor, epidermal growth factor. To assess the role of SWAP-70 in glioma migration and invasion, we inhibited its expression withsmall interfering RNAs and observed decreased glioma cell migration and invasion. SWAP-70 overexpression led to increased levels of active Rac even in low-serum conditions. In addition, when SWAP-70 was overexpressed in glioma cells, we observed enhanced membrane ruffle formation followed by increased cellmigration and invasiveness. Taken together, our findings suggest that the guanine nucleotide exchange factor SWAP-70 plays an important role in the migration and invasion of human gliomas into the surrounding tissue. PMID:19956392

Seol, Ho Jun; Smith, Christian A; Salhia, Bodour; Rutka, James T

2009-01-01

182

Role of human chromosome 11 in determining surface antigenic phenotype of normal and malignant cells. Somatic cell genetic analysis of eight antigens, including putative human Thy-1  

PubMed Central

The expression of eight serologically and biochemically distinct human cell surface antigens defined by monoclonal antibodies was examined on a panel of rodent-human somatic cell hybrids. Cosegregation was observed for human chromosome 11, and surface expression of all eight antigens was studied. Serological analysis of hybrids containing defined segments of human chromosome 11 permitted the regional assignment of genes controlling antigens JF23 (90 kD glycoprotein), G344 (25 kD), T43 (85 kD), A124, and NP13 to chromosome 11pter-q13, and of genes controlling Q14 (130 kD), MC139 (35 kD), and K117 (25 kD) to chromosome 11q13-qter. K117, the putative human Thy-1 antigen, was expressed at high levels in chromosome 11-containing hybrids constructed with mouse neuroblastoma cells, but showed little or no expression in hybrids constructed with mouse L cells. A similar pattern of expression in hybrids was found for MC139, an antigen shared by neuroectoderm-derived cells and normal and malignant T lymphocytes. T43 is a marker of malignant tumors (but not benign tumors) derived from a number of T43- epithelia, and the regional assignment of the T43 locus on chromosome 11 raises questions about its possible involvement in the specific rearrangements of this chromosome seen in human malignancies. PMID:2865325

1985-01-01

183

HSF1 Drives a Transcriptional Program Distinct from Heat Shock to Support Highly Malignant Human Cancers  

E-print Network

Heat-Shock Factor 1 (HSF1), master regulator of the heat-shock response, facilitates malignant transformation, cancer cell survival, and proliferation in model systems. The common assumption is that these effects are ...

Mendillo, Marc L.

184

A novel preclinical model of human malignant melanoma utilizing bioreactor rotating-wall vessels  

Microsoft Academic Search

Summary  Malignant melanoma poses a serious health risk which is becoming more crucial as the incidence of this disease steadily increases.\\u000a The development of appropriate in vitro models that reflect the in vivo tumor environment is a key factor for the study of\\u000a this malignancy. The local tumor microenvironment plays a critical role in the ability of tumor cells to proliferate

L. L. Licato; V. G. Prieto; E. A. Grimm

2001-01-01

185

Virus-like particles for the prevention of human papillomavirus-associated malignancies  

PubMed Central

As compared to peptide/protein-based vaccines, naked DNA vectors and even traditional attenuated or inactived virus vaccines, virus-like particles (VLPs) are an attractive vaccine platform because they offer a combination of safety, ease of production, and both high density B cell epitope display and intracellular presentation of T cell epitopes that induce potent humoral and cellular immune responses respectively. Indeed, human papillomavirus (HPV) vaccines based on VLP production by recombinant expression of major capsid antigen L1 in yeast (Gardasil®, Merck & Co.) or insect cells (Cervarix®, GlaxoSmithKline) have been licensed for the prevention of cervical and anogenital infection and disease associated with the genotypes targeted by each vaccine. These HPV vaccines however have not been demonstrated as effective to treat existing infections, and efforts to develop a therapeutic HPV vaccine continue. Furthermore, current HPV L1-VLP vaccines provide type-restricted protection, requiring highly multivalent formulations to broaden coverage to the dozen or more oncogenic HPV genotypes. This raises the complexity and cost of vaccine production. The lack of access to screening and high disease burden in developing countries has spurred efforts to develop second generation HPV vaccines that are more affordable, induce wider protective coverage and offer therapeutic coverage against HPV-associated malignancies. Given the previous success with L1 VLP-based vaccines against HPV, VLPs have been also adopted as platforms for many second generation HPV and non-HPV vaccine candidates with both prophylactic and therapeutic intent. Here we examine the progress and challenges of these efforts, with a focus on how they inform VLP vaccine design. PMID:23414405

Wang, Joshua W.; Roden, Richard B.S.

2013-01-01

186

p53 mutations in human lymphoid malignancies: Association with Burkitt lymphoma and chronic lymphocytic leukemia  

SciTech Connect

The authors have investigated the frequency of p53 mutations in B- and T-cell human lymphoid malignancies, including acute lymphoblastic leukemia, the major subtypes of non-Hodgkin lymphoma, and chronic lymphocytic leukemia. p53 exons 5-9 were studied by using genomic DNA from 197 primary tumors and 27 cell lines by single-strand conformation polymorphism analysis and by direst sequencing of PCR-amplified fragments. Mutations were found associated with (i) Burkitt lymphoma (9/27 biopsoes; 17/27 cell lines) and its leukemic counterpart L{sub 3}-type B-cell acute lymphoblastic leukemia (5/9), both of which also carry activated c-myc oncogenes, and (ii) B-cell chronic lymphocytic leukemia (6/40) and, in particular, its stage of progression known as Richter's transformation (3/7). Mutations were not found at any significant frequency in other types of non-Hodgkin lymphoma or acute lymphoblastic leukemia. In many cases, only the mutated allele was detectable, implying loss of the normal allele. These results suggest that (1) significant differences in the frequency of p53 mutations are present among subtypes of neoplasms derived from the same tissue; (2) p53 may play a role in tumor progression in B-cell chronic lymphocytic leukemia; (3) the presence of both p53 loss/inactivation and c-myc oncogene activation may be important in the pathogenesis of Burkitt lymphoma and its leukemia form L{sub 3}-type B-cell acute lymphoblastic leukemia.

Gaidano, G.; Ballerini, P.; Gong, J.Z.; Inghirami, G.; Knowles, D.M.; Dalla-Favera, R. (Columbia Univ., New York, NY (United States)); Neri, A, (Columbia Univ., New York, NY (United States) Centro Malattie del Sangue G. Marcora, Milan (Italy)); Newcomb, E.W. (New York Univ. School of Medicine, New York (United States)); Magrath, I.T. (National Cancer Institute, Bethesda, MD (United States))

1991-06-15

187

Loss of receptors for transforming growth factor beta in human T-cell malignancies.  

PubMed Central

Ki-1 (CD30)+ cutaneous T-cell lymphomas CTCLs) are slowly progressive lymphomas in which initial spontaneous regression is often observed. To better understand the mechanisms of spontaneous regression and eventual tumor progression in Ki-1+ CTCLs, type beta transforming growth factor (TGF-beta)-mediated growth inhibition of clonally related cell lines derived from two time points, before and after tumor progression, was studied. TGF-beta 1 inhibited colony-forming efficiency (CFE) of a cell line (Mac-1) derived from clinically indolent Ki-1+ CTCLs but failed to inhibit CFE of Mac-2A and -2B cell lines from advanced CTCLs. To determine the basis for TGF-beta 1 resistance in advanced CTCL cells, we looked for possible defects in the expression of cell surface TGF-beta receptors. Mac-1 cells were found to express TGF-beta receptors I and II, which mediate growth inhibition, and the TGF-beta-binding proteoglycan betaglycan. In contrast, receptors I and II were not detected in CTCL lines Mac-2A and -2B even though these cell lines did express betaglycan. Various treatments that unmask or induce TGF-beta receptors in other cells failed to show evidence for these receptors in advanced CTCL cells. Loss of TGF-beta receptor expression in these cells correlated with a marked decrease in TGF-beta receptor II mRNA levels. Loss of cell surface TGF-beta receptors was also found in two of five other patients with T-cell lymphomas including the Sezary syndrome and a noncutaneous T-cell lymphoma, suggesting that loss of TGF-beta receptor expression may be a recurrent feature of human T-cell malignancies. Images PMID:8016105

Kadin, M E; Cavaille-Coll, M W; Gertz, R; Massagué, J; Cheifetz, S; George, D

1994-01-01

188

Ganglioside expression on human malignant melanoma assessed by quantitative immune thin-layer chromatography.  

PubMed

The ganglioside composition of 20 human malignant melanomas and 5 normal tissues (muscle, spleen, kidney, liver and brain) was analyzed by high-performance thin-layer chromatography (HPTLC) and immune HPTLC using a panel of antiganglioside monoclonal antibodies, and quantified by photodensitometry. The most prominent gangliosides were GM3 and GD3, present in all 20 melanomas; however these were expressed in the 5 normal tissues as well. GD2, GM2, GT3 and 9-O-Ac-GD3 were each expressed in at least 17 of 20 melanomas, but distribution on the normal tissues examined was largely restricted to brain. The detection of several additional glycolipids was studied. GMI was highly expressed in normal brain tissue, but was not detected in any melanoma biopsies, and SGPG was detected in neither. Fuc-GMI was identified in 3 melanoma specimens and a base-sensitive ganglioside, not previously identified in melanoma, was detected in 4 of 20 melanomas with the anti-GD2 MAb 3F8. This compound is most likely O-acetylated GD2. GD3 lactones were identified in 16 of 20 melanoma biopsies, however the proportion that are naturally occurring rather than artifacts of extraction is unclear. The total expression of the more restricted gangliosides (GM2, GD2, GT3 and 9-O-Ac-GD3) in these 20 melanomas ranged between 2.4 and 102.5 micrograms/g, representing 8 x 10(6) to 3 x 10(8) ganglioside molecules per cell. This number of tumor-surface antigens provides the rationale for a polyvalent anti-melanoma vaccine containing GM2, GD2, GT3 and 9-O-Ac-GD3. PMID:8436430

Hamilton, W B; Helling, F; Lloyd, K O; Livingston, P O

1993-02-20

189

The Involvement of Xanthohumol in the Expression of Annexin in Human Malignant Glioblastoma Cells  

PubMed Central

Glioblastoma multiforme (GBM) is the most common malignant and resistant tumor of the central nervous system in humans and new therapeutic strategies are urgently required. Recently, we have shown that the potential chemotherapeutic polyphenol xanthohumol (XH), isolated from Humulus Lupulus, induces apoptosis of human T98G glioblastoma cells by increasing reactive oxygen species and activating MAPK pathways. Then we have found, by western blotting and microscopic analysis, that XH up-regulates cytosolic levels of ANXA1 and induces translocation of the protein on the cell membrane of T98G cells in a time-dependent manner with significant effects observed after 24 h. On the basis of the above evidence, the aim of this work was to investigate the role of intracellular and cell membrane localized ANXA1 in GBM cells. RT-PCR analysis has shown that XH up-regulates mRNA levels of ANXA1 after 16 h treatment. To demonstrate the involvement of ANXA1 in apoptosis of GBM cells we down-regulated ANXA1 expression with small interfering RNA (siRNA) and then analysed apoptosis in the presence and absence of apoptotic stimuli. Importantly, apoptosis induced by XH was reduced in siRNA-ANXA1 transfected cells where western blot analysis shows a significant reduction of ANXA1 protein levels. To investigate the role of ANXA1 expression on the cell membrane of T98G cells as potential “eat-me” signal we studied phagocytosis of apoptotic cells by human macrophages. We incubated apoptotic T98G cells with human blood monocyte derived macrophages (M=). After co-incubation period we analysed the percentage of M= phagocytosing the apoptotic cells by cytofluorimetric FACS analysis and by confocal microscopy. Our results show that XH induces phagocytosis of apoptotic T98G cells by human M= in a concentration-effect manner, a processes that is dependent on caspase mediated apoptosis. ANXA1 acts as an “eat-me” signal on the cell membrane of T98G cells, and interestingly, apoptotic siRNA-ANXA1 transfected cells are not completely ingested by M=. These results were confirmed by incubating apoptotic cells with a neutralizing anti-ANXA1 antiboby and ANXA1 membrane depletion by EDTA washing. ANXA1 was also detected in supernatants of apoptotic cells and the incubation of enriched supernatants enhanced the percentage of phagocytosis by M=. These results demonstrated that ANXA1 is involved both in the apoptosis and phagocytosis of glioblastoma cells. This study shows a possible role of ANXA1 in maintenance of brain homeostasis and may lead to novel therapeutic approaches for neuro-inflammatory diseases and chemotherapy targets in the treatment of glioblastoma multiforme. PMID:23407460

Festa, M; Caputo, M; Cipolla, C; D'Acunto, CW; Rossi, AG; Tecce, MF; Capasso, A

2013-01-01

190

The involvement of xanthohumol in the expression of annexin in human malignant glioblastoma cells.  

PubMed

Glioblastoma multiforme (GBM) is the most common malignant and resistant tumor of the central nervous system in humans and new therapeutic strategies are urgently required. Recently, we have shown that the potential chemotherapeutic polyphenol xanthohumol (XH), isolated from Humulus Lupulus, induces apoptosis of human T98G glioblastoma cells by increasing reactive oxygen species and activating MAPK pathways. Then we have found, by western blotting and microscopic analysis, that XH up-regulates cytosolic levels of ANXA1 and induces translocation of the protein on the cell membrane of T98G cells in a time-dependent manner with significant effects observed after 24 h. On the basis of the above evidence, the aim of this work was to investigate the role of intracellular and cell membrane localized ANXA1 in GBM cells. RT-PCR analysis has shown that XH up-regulates mRNA levels of ANXA1 after 16 h treatment. To demonstrate the involvement of ANXA1 in apoptosis of GBM cells we down-regulated ANXA1 expression with small interfering RNA (siRNA) and then analysed apoptosis in the presence and absence of apoptotic stimuli. Importantly, apoptosis induced by XH was reduced in siRNA-ANXA1 transfected cells where western blot analysis shows a significant reduction of ANXA1 protein levels. To investigate the role of ANXA1 expression on the cell membrane of T98G cells as potential "eat-me" signal we studied phagocytosis of apoptotic cells by human macrophages. We incubated apoptotic T98G cells with human blood monocyte derived macrophages (M=). After co-incubation period we analysed the percentage of M= phagocytosing the apoptotic cells by cytofluorimetric FACS analysis and by confocal microscopy. Our results show that XH induces phagocytosis of apoptotic T98G cells by human M= in a concentration-effect manner, a processes that is dependent on caspase mediated apoptosis. ANXA1 acts as an "eat-me" signal on the cell membrane of T98G cells, and interestingly, apoptotic siRNA-ANXA1 transfected cells are not completely ingested by M=. These results were confirmed by incubating apoptotic cells with a neutralizing anti-ANXA1 antiboby and ANXA1 membrane depletion by EDTA washing. ANXA1 was also detected in supernatants of apoptotic cells and the incubation of enriched supernatants enhanced the percentage of phagocytosis by M=. These results demonstrated that ANXA1 is involved both in the apoptosis and phagocytosis of glioblastoma cells. This study shows a possible role of ANXA1 in maintenance of brain homeostasis and may lead to novel therapeutic approaches for neuro-inflammatory diseases and chemotherapy targets in the treatment of glioblastoma multiforme. PMID:23407460

Festa, M; Caputo, M; Cipolla, C; D'Acunto, Cw; Rossi, Ag; Tecce, Mf; Capasso, A

2013-01-01

191

The activation of human endogenous retrovirus K (HERV-K) is implicated in melanoma cell malignant transformation  

SciTech Connect

Melanoma development is a multi-step process arising from a series of genetic and epigenetic events. Although the sequential stages involved in progression from melanocytes to malignant melanoma are clearly defined, our current understanding of the mechanisms leading to melanoma onset is still incomplete. Growing evidence show that the activation of endogenous retroviral sequences might be involved in transformation of melanocytes as well as in the increased ability of melanoma cells to escape immune surveillance. Here we show that human melanoma cells in vitro undergo a transition from adherent to a more malignant, non-adherent phenotype when exposed to stress conditions. Melanoma-derived non-adherent cells are characterized by an increased proliferative potential and a decreased expression of both HLA class I molecules and Melan-A/MART-1 antigen, similarly to highly malignant cells. These phenotypic and functional modifications are accompanied by the activation of human endogenous retrovirus K expression (HERV-K) and massive production of viral-like particles. Down-regulation of HERV-K expression by RNA interference prevents the transition from the adherent to the non-adherent growth phenotype in low serum. These results implicate HERV-K in at least some critical steps of melanoma progression.

Serafino, A. [Institute of Neurobiology and Molecular Medicine - ARTOV, CNR via Fosso del Cavaliere 100, 00133 - Rome (Italy)], E-mail: annalucia.serafino@artov.inmm.cnr.it; Balestrieri, E. [Department of Experimental Medicine and Biochemical Science - University of Rome 'Tor Vergata', via Montpellier, 00133 - Rome (Italy); Pierimarchi, P. [Institute of Neurobiology and Molecular Medicine - ARTOV, CNR via Fosso del Cavaliere 100, 00133 - Rome (Italy); Matteucci, C.; Moroni, G. [Department of Experimental Medicine and Biochemical Science - University of Rome 'Tor Vergata', via Montpellier, 00133 - Rome (Italy); Oricchio, E. [Department of Experimental Medicine and Biochemical Science - University of Rome 'Tor Vergata', via Montpellier, 00133 - Rome (Italy); Istituto Superiore di Sanita, Viale Regina Elena, 299, 00161 - Rome (Italy); Rasi, G. [Institute of Neurobiology and Molecular Medicine - ARTOV, CNR via Fosso del Cavaliere 100, 00133 - Rome (Italy); Mastino, A. [Department of Life Sciences, University of Messina, Salita Sperone 31, 98166 - Messina (Italy); Spadafora, C. [Istituto Superiore di Sanita, Viale Regina Elena, 299, 00161 - Rome (Italy); Garaci, E.; Vallebona, P. Sinibaldi [Department of Experimental Medicine and Biochemical Science - University of Rome 'Tor Vergata', via Montpellier, 00133 - Rome (Italy)

2009-03-10

192

Increased age of transformed mouse neural progenitor/stem cells recapitulates age-dependent clinical features of human glioma malignancy.  

PubMed

Increasing age is the most robust predictor of greater malignancy and treatment resistance in human gliomas. However, the adverse association of clinical course with aging is rarely considered in animal glioma models, impeding delineation of the relative importance of organismal versus progenitor cell aging in the genesis of glioma malignancy. To address this limitation, we implanted transformed neural stem/progenitor cells (NSPCs), the presumed cells of glioma origin, from 3- and 18-month-old mice into 3- and 20-month host animals. Transplantation with progenitors from older animals resulted in significantly shorter (P ? 0.0001) median survival in both 3-month (37.5 vs. 83 days) and 20-month (38 vs. 67 days) hosts, indicating that age-dependent changes intrinsic to NSPCs rather than host animal age accounted for greater malignancy. Subsequent analyses revealed that increased invasiveness, genomic instability, resistance to therapeutic agents, and tolerance to hypoxic stress accompanied aging in transformed NSPCs. Greater tolerance to hypoxia in older progenitor cells, as evidenced by elevated HIF-1 promoter reporter activity and hypoxia response gene (HRG) expression, mirrors the upregulation of HRGs in cohorts of older vs. younger glioma patients revealed by analysis of gene expression databases, suggesting that differential response to hypoxic stress may underlie age-dependent differences in invasion, genomic instability, and treatment resistance. Our study provides strong evidence that progenitor cell aging is responsible for promoting the hallmarks of age-dependent glioma malignancy and that consideration of progenitor aging will facilitate development of physiologically and clinically relevant animal models of human gliomas. PMID:22958206

Mikheev, Andrei M; Ramakrishna, Rohan; Stoll, Elizabeth A; Mikheeva, Svetlana A; Beyer, Richard P; Plotnik, David A; Schwartz, Jeffrey L; Rockhill, Jason K; Silber, John R; Born, Donald E; Kosai, Yoshito; Horner, Philip J; Rostomily, Robert C

2012-12-01

193

Toll-like receptors in the pathogenesis of human B cell malignancies  

PubMed Central

Toll-like receptors (TLRs) are important players in B-cell activation, maturation and memory and may be involved in the pathogenesis of B-cell lymphomas. Accumulating studies show differential expression in this heterogeneous group of cancers. Stimulation with TLR specific ligands, or agonists of their ligands, leads to aberrant responses in the malignant B-cells. According to current data, TLRs can be implicated in malignant transformation, tumor progression and immune evasion processes. Most of the studies focused on multiple myeloma and chronic lymphocytic leukemia, but in the last decade the putative role of TLRs in other types of B-cell lymphomas has gained much interest. The aim of this review is to discuss recent findings on the role of TLRs in normal B cell functioning and their role in the pathogenesis of B-cell malignancies. PMID:25112836

2014-01-01

194

TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo.  

PubMed

STAT3 operates in both cancer cells and tumor-associated immune cells to promote cancer progression. As a transcription factor, it is a highly desirable but difficult target for pharmacologic inhibition. We have recently shown that the TLR9 agonists CpG oligonucleotides can be used for targeted siRNA delivery to mouse immune cells. In the present study, we demonstrate that a similar strategy allows for targeted gene silencing in both normal and malignant human TLR9(+) hematopoietic cells in vivo. We have developed new human cell-specific CpG(A)-STAT3 siRNA conjugates capable of inducing TLR9-dependent gene silencing and activation of primary immune cells such as myeloid dendritic cells, plasmacytoid dendritic cells, and B cells in vitro. TLR9 is also expressed by several human hematologic malignancies, including B-cell lymphoma, multiple myeloma, and acute myeloid leukemia. We further demonstrate that oncogenic proteins such as STAT3 or BCL-X(L) are effectively knocked down by specific CpG(A)-siRNAs in TLR9(+) hematologic tumor cells in vivo. Targeting survival signaling using CpG(A)-siRNAs inhibits the growth of several xenotransplanted multiple myeloma and acute myeloid leukemia tumors. CpG(A)-STAT3 siRNA is immunostimulatory and nontoxic for normal human leukocytes in vitro. The results of the present study show the potential of using tumoricidal/immunostimulatory CpG-siRNA oligonucleotides as a novel 2-pronged therapeutic strategy for hematologic malignancies. PMID:23287859

Zhang, Qifang; Hossain, Dewan Md Sakib; Nechaev, Sergey; Kozlowska, Anna; Zhang, Wang; Liu, Yong; Kowolik, Claudia M; Swiderski, Piotr; Rossi, John J; Forman, Stephen; Pal, Sumanta; Bhatia, Ravi; Raubitschek, Andrew; Yu, Hua; Kortylewski, Marcin

2013-02-21

195

TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo  

PubMed Central

STAT3 operates in both cancer cells and tumor-associated immune cells to promote cancer progression. As a transcription factor, it is a highly desirable but difficult target for pharmacologic inhibition. We have recently shown that the TLR9 agonists CpG oligonucleotides can be used for targeted siRNA delivery to mouse immune cells. In the present study, we demonstrate that a similar strategy allows for targeted gene silencing in both normal and malignant human TLR9+ hematopoietic cells in vivo. We have developed new human cell-specific CpG(A)-STAT3 siRNA conjugates capable of inducing TLR9-dependent gene silencing and activation of primary immune cells such as myeloid dendritic cells, plasmacytoid dendritic cells, and B cells in vitro. TLR9 is also expressed by several human hematologic malignancies, including B-cell lymphoma, multiple myeloma, and acute myeloid leukemia. We further demonstrate that oncogenic proteins such as STAT3 or BCL-XL are effectively knocked down by specific CpG(A)-siRNAs in TLR9+ hematologic tumor cells in vivo. Targeting survival signaling using CpG(A)-siRNAs inhibits the growth of several xenotransplanted multiple myeloma and acute myeloid leukemia tumors. CpG(A)-STAT3 siRNA is immunostimulatory and nontoxic for normal human leukocytes in vitro. The results of the present study show the potential of using tumoricidal/immunostimulatory CpG-siRNA oligonucleotides as a novel 2-pronged therapeutic strategy for hematologic malignancies. PMID:23287859

Zhang, Qifang; Hossain, Dewan Md Sakib; Nechaev, Sergey; Kozlowska, Anna; Zhang, Wang; Liu, Yong; Kowolik, Claudia M.; Swiderski, Piotr; Rossi, John J.; Forman, Stephen; Pal, Sumanta; Bhatia, Ravi; Raubitschek, Andrew

2013-01-01

196

PTHrP promotes malignancy of human oral cancer cell downstream of the EGFR signaling  

SciTech Connect

Parathyroid hormone-related protein (PTHrP) is detected in many aggressive tumors and involved in malignant conversion; however, the underlying mechanism remains obscure. Here, we identified PTHrP as a mediator of epidermal growth factor receptor (EGFR) signaling to promote the malignancies of oral cancers. PTHrP mRNA was abundantly expressed in most of the quiescent oral cancer cells, and was significantly upregulated by EGF stimulation via ERK and p38 MAPK. PTHrP silencing by RNA interference, as well as EGFR inhibitor AG1478 treatment, significantly suppressed cell proliferation, migration, and invasiveness. Furthermore, combined treatment of AG1478 and PTHrP knockdown achieved synergistic inhibition of malignant phenotypes. Recombinant PTHrP substantially promoted cell motility, and rescued the inhibition by PTHrP knockdown, suggesting the paracrine/autocrine function of PTHrP. These data indicate that PTHrP contributes to the malignancy of oral cancers downstream of EGFR signaling, and may thus provide a therapeutic target for oral cancer.

Yamada, Tamaki [Laboratory of Pathophysiology and Signal Transduction, Department of Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638 (Japan); Division of Oral Pathobiological Science, Hokkaido University Graduate School of Dental Medicine, N13W7, Kita-ku, Sapporo 060-8586 (Japan); Laboratory of Oral and Maxillofacial Surgery, Hokkaido University Graduate School of Dental Medicine, N13W7, Kita-ku, Sapporo 060-8586 (Japan); Tsuda, Masumi [Laboratory of Pathophysiology and Signal Transduction, Department of Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638 (Japan); Ohba, Yusuke [Laboratory of Pathophysiology and Signal Transduction, Department of Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638 (Japan)], E-mail: yohba@med.hokudai.ac.jp; Kawaguchi, Hideaki [Laboratory of Pathophysiology and Signal Transduction, Department of Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638 (Japan); Totsuka, Yasunori [Laboratory of Oral and Maxillofacial Surgery, Hokkaido University Graduate School of Dental Medicine, N13W7, Kita-ku, Sapporo 060-8586 (Japan); Shindoh, Masanobu [Division of Oral Pathobiological Science, Hokkaido University Graduate School of Dental Medicine, N13W7, Kita-ku, Sapporo 060-8586 (Japan)

2008-04-11

197

A Hypermutation Phenotype and Somatic MSH6 Mutations in Recurrent Human Malignant Gliomas after Alkylator Chemotherapy  

Microsoft Academic Search

Malignant gliomas have a very poor prognosis. The current standard of care for these cancers consists of extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy. Although a statis- tically significant increase in survival has been reported with this regimen, nearly all gliomas recur and become insensitive to further treatment with this class of agents. We

Chris Hunter; Raffaella Smith; Daniel P. Cahill; Philip Stephens; Claire Stevens; Jon Teague; Chris Greenman; Sarah Edkins; Graham Bignell; Helen Davies; Sarah O'Meara; Adrian Parker; Tim Avis; Syd Barthorpe; Lisa Brackenbury; Gemma Buck; Adam Butler; Jody Clements; Jennifer Cole; Ed Dicks; Simon Forbes; Matthew Gorton; Kristian Gray; Kelly Halliday; Rachel Harrison; Katy Hills; Jonathon Hinton; Andy Jenkinson; David Jones; Vivienne Kosmidou; Ross Laman; Richard Lugg; Andrew Menzies; Janet Perry; Robert Petty; Keiran Raine; David Richardson; Rebecca Shepherd; Alexandra Small; Helen Solomon; Calli Tofts; Jennifer Varian; Sofie West; Sara Widaa; Andy Yates; Douglas F. Easton; Gregory Riggins; Jennifer E. Roy; Kymberly K. Levine; Wolf Mueller; Tracy T. Batchelor; David N. Louis; Michael R. Stratton; P. Andrew Futreal; Richard Wooster

2006-01-01

198

The casein kinase 2 inhibitor, CX-4945, as an anti-cancer drug in treatment of human hematological malignancies  

PubMed Central

The casein kinase 2 (CK2) protein kinase is a pro-survival kinase and therapeutic target in treatment of various human cancers. CK2 overexpression has been demonstrated in hematological malignancies, including chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and multiple myeloma. CX-4945, also known as Silmitasertib, is an orally administered, highly specific, ATP-competitive inhibitor of CK2. CX-4945 induces cytotoxicity and apoptosis and is currently being evaluated in clinical trials for treatment of many cancer types. In the past 2 years, the focus on the therapeutic potential of CX-4945 has shifted from solid tumors to hematological malignancies. CX-4945 exerts anti-proliferative effects in hematological tumors by downregulating CK2 expression and suppressing activation of CK2-mediated PI3K/Akt/mTOR signaling pathways. Furthermore, combination of CX-4945 with other inhibitors yielded synergistic effects in cell death induction. These new findings demonstrate that CK2 overexpression contributes to blood cancer cell survival and resistance to chemotherapy. Combinatorial use of CX-4945 is a promising therapeutic tool for treatment of hematological malignancies.

Chon, Hae J.; Bae, Kyoung J.; Lee, Yura; Kim, Jiyeon

2015-01-01

199

The casein kinase 2 inhibitor, CX-4945, as an anti-cancer drug in treatment of human hematological malignancies.  

PubMed

The casein kinase 2 (CK2) protein kinase is a pro-survival kinase and therapeutic target in treatment of various human cancers. CK2 overexpression has been demonstrated in hematological malignancies, including chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and multiple myeloma. CX-4945, also known as Silmitasertib, is an orally administered, highly specific, ATP-competitive inhibitor of CK2. CX-4945 induces cytotoxicity and apoptosis and is currently being evaluated in clinical trials for treatment of many cancer types. In the past 2 years, the focus on the therapeutic potential of CX-4945 has shifted from solid tumors to hematological malignancies. CX-4945 exerts anti-proliferative effects in hematological tumors by downregulating CK2 expression and suppressing activation of CK2-mediated PI3K/Akt/mTOR signaling pathways. Furthermore, combination of CX-4945 with other inhibitors yielded synergistic effects in cell death induction. These new findings demonstrate that CK2 overexpression contributes to blood cancer cell survival and resistance to chemotherapy. Combinatorial use of CX-4945 is a promising therapeutic tool for treatment of hematological malignancies. PMID:25873900

Chon, Hae J; Bae, Kyoung J; Lee, Yura; Kim, Jiyeon

2015-01-01

200

Microspectroscopic Analysis Of HpD Fluorescence In Bioptic Samples From Human Pre-Malignant And Malignant Lesions Of The Skin  

NASA Astrophysics Data System (ADS)

Microfluorometric analysis was performed on bioptic samples of pre-malignant and malignant cutanous lesions present in the same patients, 48 h after i.v. injection of HpD. Data obtained indicate that actinic keratosis and squamous celle carcinoma show a preferential accumulation if compared to normal skin. The two lesions differ for both intensity and spectral shape of HpD fluorescence. This difference is correlated with a different clinical response to HpD laser phototherapy.

Bottiroli, G.; Dell'Acqua, R.; Jucci, A.; Ricevuti, G.; Sacchi, A. S.

1987-07-01

201

Comparative analysis of cell death induction by Taurolidine in different malignant human cancer cell lines  

PubMed Central

Background Taurolidine (TRD) represents an anti-infective substance with anti-neoplastic activity in many malignant cell lines. So far, the knowledge about the cell death inducing mechanisms and pathways activated by TRD is limited. The aim of this study was therefore, to perform a comparative analysis of cell death induction by TRD simultaneously in different malignant cell lines. Materials and methods Five different malignant cell lines (HT29/Colon, Chang Liver/Liver, HT1080/fibrosarcoma, AsPC-1/pancreas and BxPC-3/pancreas) were incubated with increasing concentrations of TRD (100 ?M, 250 ?M and 1000 ?M) for 6 h and 24 h. Cell viability, apoptosis and necrosis were analyzed by FACS analysis (Propidiumiodide/AnnexinV staining). Additionally, cells were co-incubated with the caspase Inhibitor z-VAD, the radical scavenger N-Acetylcystein (NAC) and the Gluthation depleting agent BSO to examine the contribution of caspase activation and reactive oxygen species in TRD induced cell death. Results All cell lines were susceptible to TRD induced cell death without resistance toward this anti-neoplastic agent. However, the dose response effects were varying largely between different cell lines. The effect of NAC and BSO co-treatment were highly different among cell lines - suggesting a cell line specific involvement of ROS in TRD induced cell death. Furthermore, impact of z-VAD mediated inhibition of caspases was differing strongly among the cell lines. Conclusion This is the first study providing a simultaneous evaluation of the anti-neoplastic action of TRD across several malignant cell lines. The involvement of ROS and caspase activation was highly variable among the five cell lines, although all were susceptible to TRD induced cell death. Our results indicate, that TRD is likely to provide multifaceted cell death mechanisms leading to a cell line specific diversity. PMID:20205945

2010-01-01

202

TRAIL triggers apoptosis in human malignant glioma cells through extrinsic and intrinsic pathways.  

PubMed

Many malignant glioma cells express death receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), yet some of these cells are resistant to TRAIL. Here, we examined signaling events in TRAIL-induced apoptosis and searched for therapeutic agents that could overcome TRAIL resistance in glioma cells. TRAIL induced apoptosis through death receptor 5 (DR5) and was mediated by caspase-8-initiated extrinsic and intrinsic mitochondrial pathways in sensitive glioma cell lines. TRAIL also triggered apoptosis in resistant glioma cell lines through the same pathways, but only if the cells were pretreated with chemotherapeutic agents, cisplatin, camptothecin and etoposide. Previous studies suggested that this was due to an increase in DR5 expression in wild-type TP53 cells, but this mechanism did not account for cells with mutant TP53. Here, we show that a more general effect of these agents is to downregulate caspase-8 inhibitor c-FLIP(S) (the short form of cellular Fas-associated death domain-fike interleukin-1-converting enzyme-inhibitory protein) and up-regulate Bak, a pro-apoptotic Bcl-2 family member, independently of cell's TP53 status. Furthermore, we showed that TRAIL alone or in combination with chemotherapeutic agents, induced apoptosis in primary tumor cultures from patients with malignant gliomas, reinforcing the potential of TRAIL as an effective therapeutic agent for malignant gliomas. PMID:14655759

Song, Jin H; Song, Doyoun K; Pyrzynska, Beata; Petruk, Kenneth C; Van Meir, Erwin G; Hao, Chunhai

2003-10-01

203

[Frontiers in Bioscience 11, 1508-1521, May 1, 2006] Posttranslational modifications of Bcl2 family members-a potential therapeutic target for human malignancy  

E-print Network

immunotherapy utilizes the body's immune system either directly or indirectly to boost body's cancer fighting family members-a potential therapeutic target for human malignancy Aruna Basu 1 Garrett DuBois 2 feature of all known human cancers-the ability to influence their onset, progression and outcome. Bcl2

204

Radiosensitization of tumours by porphyrins  

Microsoft Academic Search

Our previous data indicate, that hematoporphyrin dimethyl ether (HPde) can totally inhibit the growth of aggressive Ehrlich ascite tumour, when combined with low doses (2Gy) of ionizing radiation. Taking into account these findings, it appears of particular interest to evaluate the dependence of radiosensitizing efficiency of porphyrins on tumour aggressiveness. For this purpose two experimental tumour models (aggressive murine Ehrlich

Zivile Luksiene; Petras Juzenas; Johan Moan

2006-01-01

205

Radiosensitization of tumours by porphyrins.  

PubMed

Our previous data indicate, that hematoporphyrin dimethyl ether (HPde) can totally inhibit the growth of aggressive Ehrlich ascite tumour, when combined with low doses (2Gy) of ionizing radiation. Taking into account these findings, it appears of particular interest to evaluate the dependence of radiosensitizing efficiency of porphyrins on tumour aggressiveness. For this purpose two experimental tumour models (aggressive murine Ehrlich ascite carcinoma, (EAT), and not-aggressive hepatoma MH-22A) were used. Moreover, radiosensitizing properties of three porphyrin-type compounds of different chemical heterogeneity were evaluated (hematoporphyrin dimethyl ether (HPde), photofrin II (PII) and hematoporphyrin derivative (HPD)). Data obtained indicate, that HPde is the most effective one in this context (HPde>PII>HPD). It is important to note, that only the aggressive EAT tumours were radiosensitized by these dyes. No signs of radiosensitization (inhibition of tumour growth, injury of tumour tissue, evaluated by histological analysis) were observed in not-aggressive MH-22A hepatoma. Moreover, it was shown, that ligands of peripheral benzodiazepine receptors (PBR) might diminish the cell growth in aggressive EAT, but not in not-aggressive MH-22A hepatoma. The mechanism of radiosensitization by porphyrins, proposed in our previous studies, was strongly confirmed by these data. Actually, dicarboxylic porphyrins, being ligands of PBR, which are highly expressed in just aggressive tumours, can inhibit tumour cell proliferation and act in concert with ionizing radiation. Thus, combination of porphyrin and ionising radiation reflects the action of two antiproliferative factors, what eventually increases the response of aggressive tumours to the low doses of ionising radiation. PMID:15946797

Luksiene, Zivile; Juzenas, Petras; Moan, Johan

2006-04-01

206

Angiopoietin-like protein 2 induces androgen-independent and malignant behavior in human prostate cancer cells  

PubMed Central

Angiopoietin-like proteins (ANGPTLs), which comprise 7 members (ANGPTL1-ANGPTL7), structurally resemble angiopoietins. We investigated the roles of ANGPTLs in the acquisition of androgen independence and the malignant behavior of human prostate cancer cells. Expression of ANGPTL messenger RNA (mRNA) and proteins were ascertained using RT-qPCR and western blot analysis in human prostate cancer cell lines. Androgen-dependent LNCaP and androgen-independent LNCaP/AI cells, respectively, were cultured in fetal bovine and charcoal-stripped medium. Cell proliferation, androgen dependence, migration and invasion, respectively, were examined under the overexpression and knockdown of ANGPTL2 by transfection of ANGPTL2 cDNA and its small-interfering RNA (siRNA). The effects of exogenous ANGPTL2 and blocking of its receptor, integrin ?5?1, were also investigated. Human prostate cancer cell lines predominantly expressed ANGPTL2 among the members. Interrupting ANGPTL2 expression with siRNA suppressed the proliferation, migration and invasion of LNCaP cells. LNCaP/AI cells showed a higher ANGPTL2 expression than that of LNCaP cells. Furthermore, siRNA led to apoptosis of LNCaP/AI cells. The ANGPTL2-overexpressing LNCaP cells markedly increased proliferation, epithelial-to-mesenchymal transition (EMT) and malignant behavior in androgen-deprived medium. The migration rates were increased depending on the concentration of ANGPTL2 recombinant protein and were inhibited by anti-integrin ?5?1 antibodies. To the best of our knowledge, this is the first study to elucidate the expression of ANGPTL2 in human prostate cancer cells. ANGPTL2 may be important in the acquisition of androgen independency and tumor progression of prostate cancer in an autocrine and/or paracrine manner via the integrin ?5?1 receptor. Targeting ANGPTL2 may therefore be an efficacious therapeutic modality for prostate cancer. PMID:25370833

SATO, RYUTA; YAMASAKI, MUTSUSHI; HIRAI, KENICHI; MATSUBARA, TAKANORI; NOMURA, TAKEO; SATO, FUMINORI; MIMATA, HIROMITSU

2015-01-01

207

Angiopoietin-like protein 2 induces androgen-independent and malignant behavior in human prostate cancer cells.  

PubMed

Angiopoietin-like proteins (ANGPTLs), which comprise 7 members (ANGPTL1-ANGPTL7), structurally resemble angiopoietins. We investigated the roles of ANGPTLs in the acquisition of androgen independence and the malignant behavior of human prostate cancer cells. Expression of ANGPTL messenger RNA (mRNA) and proteins were ascertained using RT-qPCR and western blot analysis in human prostate cancer cell lines. Androgen?dependent LNCaP and androgen-independent LNCaP/AI cells, respectively, were cultured in fetal bovine and charcoal-stripped medium. Cell proliferation, androgen dependence, migration and invasion, respectively, were examined under the overexpression and knockdown of ANGPTL2 by transfection of ANGPTL2 cDNA and its small?interfering RNA (siRNA). The effects of exogenous ANGPTL2 and blocking of its receptor, integrin ?5?1, were also investigated. Human prostate cancer cell lines predominantly expressed ANGPTL2 among the members. Interrupting ANGPTL2 expression with siRNA suppressed the proliferation, migration and invasion of LNCaP cells. LNCaP/AI cells showed a higher ANGPTL2 expression than that of LNCaP cells. Furthermore, siRNA led to apoptosis of LNCaP/AI cells. The ANGPTL2-overexpressing LNCaP cells markedly increased proliferation, epithelial-to-mesenchymal transition (EMT) and malignant behavior in androgen?deprived medium. The migration rates were increased depending on the concentration of ANGPTL2 recombinant protein and were inhibited by anti-integrin ?5?1 antibodies. To the best of our knowledge, this is the first study to elucidate the expression of ANGPTL2 in human prostate cancer cells. ANGPTL2 may be important in the acquisition of androgen independency and tumor progression of prostate cancer in an autocrine and/or paracrine manner via the integrin ?5?1 receptor. Targeting ANGPTL2 may therefore be an efficacious therapeutic modality for prostate cancer. PMID:25370833

Sato, Ryuta; Yamasaki, Mutsushi; Hirai, Kenichi; Matsubara, Takanori; Nomura, Takeo; Sato, Fuminori; Mimata, Hiromitsu

2015-01-01

208

Repair of chromosome damage induced by X-irradiation during G2 phase in a line of normal human fibroblasts and its malignant derivative  

SciTech Connect

A line of normal human skin fibroblasts (KD) differed from its malignant derivative (HUT-14) in the extent of cytogenetic damage induced by X-irradiation during G2 phase. Malignant cells had significantly more chromatid breaks and gaps after exposure to 25, 50, or 100 rad. The gaps may represent single-strand breaks. Results from alkaline elution of cellular DNA immediately after irradiation showed that the normal and malignant cells in asynchronous population were equally sensitive to DNA single-strand breakage by X-irradiation. Caffeine or beta-cytosine arabinoside (ara-C), inhibitors of DNA repair, when added directly following G2 phase exposure, significantly increased the incidence of radiation-induced chromatid damage in the normal cells. In contrast, similar treatment of the malignant cells had little influence. Ara-C differed from caffeine in its effects; whereas both agents increased the frequency of chromatid breaks and gaps, only ara-C increased the frequency of gaps to the level observed in the irradiated malignant cells. Addition of catalase, a scavenger of the derivative free hydroxyl radical (.OH), to the cultures of malignant cells before, during, and following irradiation significantly reduced the chromatid damage; and catalase prevented formation of chromatid gaps. The DNA damage induced by X-ray during G2 phase in the normal KD cells was apparently repaired by a caffeine- and ara-C-sensitive mechanism(s) that was deficient or absent in their malignant derivatives.

Parshad, R.; Gantt, R.; Sanford, K.K.; Jones, G.M.; Tarone, R.E.

1982-08-01

209

Hedgehog Signaling and Bmi-1 Regulate Self-renewal of Normal and Malignant Human Mammary Stem Cells  

PubMed Central

The epithelial components of the mammary gland are thought to arise from stem cells with a capacity for self-renewal and multilineage differentiation. Furthermore, these cells and/or their immediate progeny may be targets for transformation. We have used both in vitro cultivation and a xenograft mouse model to examine the role of hedgehog signaling and Bmi-1 in regulating self-renewal of normal and malignant human mammary stem cells. We show that hedgehog signaling components PTCH1, Gli1, and Gli2 are highly expressed in normal human mammary stem/progenitor cells cultured as mammospheres and that these genes are down-regulated when cells are induced to differentiate. Activation of hedgehog signaling increases mammosphere-initiating cell number and mammosphere size, whereas inhibition of the pathway results in a reduction of these effects. These effects are mediated by the polycomb gene Bmi-1. Overexpression of Gli2 in mammosphere-initiating cells results in the production of ductal hyperplasia, and modulation of Bmi-1 expression in mammosphere-initiating cells alters mammary development in a humanized nonobese diabetic-severe combined immunodeficient mouse model. Furthermore, we show that the hedgehog signaling pathway is activated in human breast “cancer stem cells” characterized as CD44+CD24?/lowLin?. These studies support a cancer stem cell model in which the hedgehog pathway and Bmi-1 play important roles in regulating self-renewal of normal and tumorigenic human mammary stem cells. PMID:16778178

Liu, Suling; Dontu, Gabriela; Mantle, Ilia D.; Patel, Shivani; Ahn, Nam-shik; Jackson, Kyle W.; Suri, Prerna; Wicha, Max S.

2012-01-01

210

Revealing the inherent heterogeneity of human malignancies by variant consensus strategies coupled with cancer clonal analysis  

PubMed Central

Tumors are heterogeneous in composition. They are composed of cancer cells proper, along with stromal elements that collectively form a microenvironment, all of which are necessary to nurture the malignant process. In addition, many of the stromal cells are modified to support the unique needs of the malignant state. Tumors are composed of a variety of clones or subpopulations of cancer cells, which may differ in karyotype, growth rate, expression of cell surface markers, sensitivity to therapeutics, etc. New tools and methods to provide an improved understanding of tumor clonal architecture are needed to guide therapy. The subclonal structure and transcription status of underlying somatic mutations reveal the trajectory of tumor progression in patients with cancer. Approaching the analysis of tumors to reveal clonal complexity in a quantitative manner should facilitate better characterization and therapeutic assignments. The challenge is the interpretation of massive amounts of data from next generation sequencing (NGS) experiments to find what is truly meaningful for improving the understanding of basic cancer biology, as well as therapeutic assignments and outcomes. To meet this need, a methodology named CloneViz was developed and utilized for the identification of serial clonal mutations. Whole exome sequencing (WES) on an Illumina HiSeq 2500 was performed on paired tumor and normal samples from a Multiple Myeloma (MM) patient at presentation, then first and second relapse. Following alignment, a consensus strategy for variant selection was employed along with computational linkage to a formal tumor clonality analysis based on visualization and quantitative methods. PMID:25350589

2014-01-01

211

Alcohol metabolism by oral streptococci and interaction with human papillomavirus leads to malignant transformation of oral keratinocytes.  

PubMed

Poor oral hygiene, ethanol consumption, and human papillomavirus (HPV) are associated with oral and esophageal cancers. However, the mechanism is not fully known. This study examines alcohol metabolism in Streptococcus and its interaction with HPV-16 in the malignant transformation of oral keratinocytes. The acetaldehyde-producing strain Streptococcus gordonii V2016 was analyzed for adh genes and activities of alcohol and aldehyde dehydrogenases. Streptococcus attachment to immortalized HPV-16 infected human oral keratinocytes, HOK (HPV/HOK-16B), human oral buccal keratinocytes, and foreskin keratinocytes was studied. Acetaldehyde, malondialdehyde, DNA damage, and abnormal proliferation among keratinocytes were also quantified. We found that S. gordonii V2016 expressed three primary alcohol dehydrogenases, AdhA, AdhB, and AdhE, which all oxidize ethanol to acetaldehyde, but their preferred substrates were 1-propanol, 1-butanol, and ethanol, respectively. S. gordonii V2016 did not show a detectable aldehyde dehydrogenase. AdhE is the major alcohol dehydrogenase in S. gordonii. Acetaldehyde and malondialdehyde production from permissible Streptococcus species significantly increased the bacterial attachment to keratinocytes, which was associated with an enhanced expression of furin to facilitate HPV infection and several malignant phenotypes including acetaldehyde adduct formation, abnormal proliferation, and enhanced migration through integrin-coated basement membrane by HPV-infected oral keratinocytes. Therefore, expression of multiple alcohol dehydrogenases with no functional aldehyde dehydrogenase contributes to excessive production of acetaldehyde from ethanol by oral streptococci. Oral Streptococcus species and HPV may cooperate to transform oral keratinocytes after ethanol exposure. These results suggest a significant clinical interaction, but further validation is warranted. PMID:25427911

Tao, Lin; Pavlova, Sylvia I; Gasparovich, Stephen R; Jin, Ling; Schwartz, Joel

2015-01-01

212

Highly aneuploid zebrafish malignant peripheral nerve sheath tumors have genetic alterations similar to human cancers  

E-print Network

Aneuploidy is a hallmark of human cancers, but most mouse cancer models lack the extensive aneuploidy seen in many human tumors. The zebrafish is becoming an increasingly popular model for studying cancer. Here we report ...

Zhang, GuangJun

213

LIM Mineralization Protein-1 Inhibits the Malignant Phenotypes of Human Osteosarcoma Cells  

PubMed Central

Osteosarcoma (OS), also known as osteogenic sarcoma, is the most common primary malignancy of bone tumor in children and adolescents. However, its underlying molecular pathogenesis is still only vaguely understood. Recently, LIM mineralization protein-1 (LMP-1) was reported to be an essential positive regulator of osteoblast differentiation. In the present study, we found that the expression of LMP-1 is downregulated in OS tissues compared with adjacent normal tissues. Moreover, we restored the expression of LMP-1 through a recombinant adenovirus. Overexpression of LMP-1 inhibited cell proliferation and invasion, arrested cell cycle progression, and induced apoptosis in vitro. Finally, ectopic LMP-1 expression suppressed the expression of Runx2 and BMP-2 in OS cells. These data demonstrate that LMP-1 is an essential tumor suppressor in the OS pathological process, which will provide a new opportunity for discovering and identifying novel effective treatment strategies. PMID:24762763

Liu, Huiwen; Huang, Lu; Zhang, Zhongzu; Zhang, Zhanming; Yu, Zhiming; Chen, Xiang; Chen, Zhuo; Zen, Yongping; Yang, Dong; Han, Zhimin; Shu, Yong; Dai, Min; Cao, Kai

2014-01-01

214

Multipotent Cancer Stem Cells Derived from Human Malignant Peritoneal Mesothelioma Promote Tumorigenesis  

PubMed Central

During the progression of malignant peritoneal mesothelioma (MPeM), tumor nodules propagate diffusely within the abdomen and tumors are characterized by distinct phenotypic sub-types. Recent studies in solid organ cancers have shown that cancer stem cells (CSCs) play a pivotal role in the initiation and progression of tumors. However, it is not known whether tumorigenic stem cells exist and whether they promote tumor growth in MPeM. In this study, we developed and characterized a CSC model for MPeM using stably expandable tumorigenic stem cells derived from patient tumors. We found morphologically distinct populations of CSCs that divide asymmetrically or symmetrically in MPeM in vitro cell culture. The MPeM stem cells (MPeMSCs) express stem cell markers c-MYC, NES and VEGFR2 and in the presence of matrix components cells form colony spheres. MPeMSCs are multipotent, differentiate into neuronal, vascular and adipose progeny upon defined induction and the differentiating cells express lineage-specific markers such as TUBB3, an early neuronal marker; vWF, VEGFA, VEGFC and IL-8, endothelial markers; and PPAR? and FABP4, adipose markers. Xenotransplantation experiments using MPeMSCs demonstrated early tumor growth compared with parental cells. Limiting dilution experiments using MPeMSCs and endothelial lineage-induced cells derived from a single MPeMSC resulted in early tumor growth in the latter group indicating that endothelial differentiation of MPeMSCs is important for MPeM tumor initiation. Our observation that the MPeM tumors contain stem cells with tumorigenic potential has important implications for understanding the cells of origin and tumor progression in MPeM and hence targeting CSCs may be a useful strategy to inhibit malignant progression. PMID:23285196

Varghese, Sheelu; Whipple, Rebecca; Martin, Stuart S.; Alexander, H. Richard

2012-01-01

215

Identification of cancer stem cell markers in human malignant mesothelioma cells  

SciTech Connect

Research highlights: {yields} We performed serial transplantation of surgical samples and established new cell lines of malignant mesothelioma. {yields} SP cell and expressions of CD9/CD24/CD26 were often observed in mesothelioma cell lines. {yields} SP and CD24{sup +} cells proliferated by asymmetric cell division-like manner. CD9{sup +} and CD24{sup +} cells have higher potential to generate spheroid colony. {yields} The marker-positive cells have clear tendency to generate larger tumors in mice. -- Abstract: Malignant mesothelioma (MM) is an aggressive and therapy-resistant neoplasm arising from the pleural mesothelial cells and usually associated with long-term asbestos exposure. Recent studies suggest that tumors contain cancer stem cells (CSCs) and their stem cell characteristics are thought to confer therapy-resistance. However, whether MM cell has any stem cell characteristics is not known. To understand the molecular basis of MM, we first performed serial transplantation of surgical samples into NOD/SCID mice and established new cell lines. Next, we performed marker analysis of the MM cell lines and found that many of them contain SP cells and expressed several putative CSC markers such as CD9, CD24, and CD26. Interestingly, expression of CD26 closely correlated with that of CD24 in some cases. Sorting and culture assay revealed that SP and CD24{sup +} cells proliferated by asymmetric cell division-like manner. In addition, CD9{sup +} and CD24{sup +} cells have higher potential to generate spheroid colony than negative cells in the stem cell medium. Moreover, these marker-positive cells have clear tendency to generate larger tumors in mouse transplantation assay. Taken together, our data suggest that SP, CD9, CD24, and CD26 are CSC markers of MM and could be used as novel therapeutic targets.

Ghani, Farhana Ishrat; Yamazaki, Hiroto; Iwata, Satoshi; Okamoto, Toshihiro [Division of Clinical Immunology, Institute of Medical Science, University of Tokyo, Tokyo (Japan)] [Division of Clinical Immunology, Institute of Medical Science, University of Tokyo, Tokyo (Japan); Aoe, Keisuke; Okabe, Kazunori; Mimura, Yusuke [Departments of Medical Oncology, Yamaguchi-Ube Medical Center, Yamaguchi (Japan)] [Departments of Medical Oncology, Yamaguchi-Ube Medical Center, Yamaguchi (Japan); Fujimoto, Nobukazu; Kishimoto, Takumi [Department of Respiratory Medicine, Okayama Rosai Hospital, Okayama (Japan)] [Department of Respiratory Medicine, Okayama Rosai Hospital, Okayama (Japan); Yamada, Taketo [Department of Pathology, Keio University School of Medicine, Tokyo (Japan)] [Department of Pathology, Keio University School of Medicine, Tokyo (Japan); Xu, C. Wilson [Drug Development Program, Nevada Cancer Institute, Las Vegas, NV (United States)] [Drug Development Program, Nevada Cancer Institute, Las Vegas, NV (United States); Morimoto, Chikao, E-mail: morimoto@ims.u-tokyo.ac.jp [Division of Clinical Immunology, Institute of Medical Science, University of Tokyo, Tokyo (Japan) [Division of Clinical Immunology, Institute of Medical Science, University of Tokyo, Tokyo (Japan); Drug Development Program, Nevada Cancer Institute, Las Vegas, NV (United States)

2011-01-14

216

Down-regulation of malignant potential by alpha linolenic acid in human and mouse colon cancer cells.  

PubMed

Omega-3 fatty acids (also called ?-3 fatty acis or n-3 fatty acid) are polyunsaturated fatty acids (PUFAs) with a double bond (C=C) at the third carbon atom from the end of the carbon chain. Numerous test tube and animal studies have shown that omega-3 fatty acids may prevent or inhibit the growth of cancers, suggesting that omega-3 fatty acids are important in cancer physiology. Alpha-linolenic acid (ALA) is one of an essential omega-3 fatty acid and organic compound found in seeds (chia and flaxseed), nuts (notably walnuts), and many common vegetable oils. ALA has also been shown to down-regulate cell proliferation of prostate, breast, and bladder cancer cells. However, direct evidence that ALA suppresses to the development of colon cancer has not been studied. Also, no previous studies have evaluated whether ALA may regulate malignant potential (adhesion, invasion and colony formation) in colon cancer cells. In order to address the questions above, we conducted in vitro studies and evaluated whether ALA may down-regulate malignant potential in human (HT29 and HCT116) and mouse (MCA38) colon cancer cell lines. We observed that treatment with 1-5 mM of ALA inhibits cell proliferation, adhesion and invasion in both human and mouse colon cancer cell lines. Interestingly, we observed that ALA did not decrease total colony numbers when compared to control. By contrast, we found that size of colony was significantly changed by ALA treatment when compared to control in all colon cancer cell lines. We suggest that our data enhance our current knowledge of ALA's mechanism and provide crucial information to further the development of new therapies for the management or chemoprevention of colon cancer. PMID:25336096

Chamberland, John P; Moon, Hyun-Seuk

2015-03-01

217

Landscape of DNA virus associations across human malignant cancers: analysis of 3,775 cases using RNA-Seq.  

PubMed

Elucidation of tumor-DNA virus associations in many cancer types has enhanced our knowledge of fundamental oncogenesis mechanisms and provided a basis for cancer prevention initiatives. RNA-Seq is a novel tool to comprehensively assess such associations. We interrogated RNA-Seq data from 3,775 malignant neoplasms in The Cancer Genome Atlas database for the presence of viral sequences. Viral integration sites were also detected in expressed transcripts using a novel approach. The detection capacity of RNA-Seq was compared to available clinical laboratory data. Human papillomavirus (HPV) transcripts were detected using RNA-Seq analysis in head-and-neck squamous cell carcinoma, uterine endometrioid carcinoma, and squamous cell carcinoma of the lung. Detection of HPV by RNA-Seq correlated with detection by in situ hybridization and immunohistochemistry in squamous cell carcinoma tumors of the head and neck. Hepatitis B virus and Epstein-Barr virus (EBV) were detected using RNA-Seq in hepatocellular carcinoma and gastric carcinoma tumors, respectively. Integration sites of viral genes and oncogenes were detected in cancers harboring HPV or hepatitis B virus but not in EBV-positive gastric carcinoma. Integration sites of expressed viral transcripts frequently involved known coding areas of the host genome. No DNA virus transcripts were detected in acute myeloid leukemia, cutaneous melanoma, low- and high-grade gliomas of the brain, and adenocarcinomas of the breast, colon and rectum, lung, prostate, ovary, kidney, and thyroid. In conclusion, this study provides a large-scale overview of the landscape of DNA viruses in human malignant cancers. While further validation is necessary for specific cancer types, our findings highlight the utility of RNA-Seq in detecting tumor-associated DNA viruses and identifying viral integration sites that may unravel novel mechanisms of cancer pathogenesis. PMID:23740984

Khoury, Joseph D; Tannir, Nizar M; Williams, Michelle D; Chen, Yunxin; Yao, Hui; Zhang, Jianping; Thompson, Erika J; Meric-Bernstam, Funda; Medeiros, L Jeffrey; Weinstein, John N; Su, Xiaoping

2013-08-01

218

Targeted DNA vaccines eliciting crossreactive anti-idiotypic antibody responses against human B cell malignancies in mice  

PubMed Central

Background Therapeutic idiotypic (Id) vaccination is an experimental treatment for selected B cell malignancies. A broader use of Id-based vaccination, however, is hampered by the complexity and costs due to the individualized production of protein vaccines. These limitations may be overcome by targeted DNA vaccines encoding stereotyped immunoglobulin V regions of B cell malignancies. We have here investigated whether such vaccines might elicit cross-reactive immune responses thus offering the possibility to immunize subsets of patients with the same vaccine. Methods Fusion vaccines targeting patient Id to mouse Major Histocompatibility Complex (MHC) class II molecules (chimeric mouse/human) or chemokine receptors (fully human) on antigen-presenting cells (APC) were genetically constructed for two Chronic Lymphocytic Leukemia (CLL) patients and one prototypic stereotyped B-cell receptor (BCR) commonly expressed by Hepatitis C Virus (HCV)-associated Non Hodgkin Lymphoma (NHL). The A20 murine B lymphoma cells were engineered to express prototypic HCV-associated B cell lymphoma BCR. Anti-Id antibody responses were studied against stereotyped and non-stereotyped BCRs on CLL patients’ cells as well as transfected A20 cells. Results DNA vaccination of mice with Id vaccines that target APC elicited increased amounts of antibodies specific for the patient’s Id as compared with non targeted control vaccines. Anti–Id antibodies cross-reacted between CLL cells with closely related BCR. A20 cells engineered to express patients’ V regions were not tumorigenic in mice, preventing tumor challenge experiments. Conclusions These findings provide experimental support for use of APC-targeted fusion Id DNA vaccines for the treatment of B cell lymphoma and CLL that express stereotyped BCRs. PMID:25059102

2014-01-01

219

Mucosal Human Papillomaviruses Encode Four Different E5 Proteins Whose Chemistry and Phylogeny Correlate with Malignant or Benign Growth  

PubMed Central

We performed a phylogenetic study of the E2-L2 region of human mucosal papillomaviruses (PVs) and of the proteins therein encoded. Hitherto, proteins codified in this region were known as E5 proteins. We show that many of these proteins could be spurious translations, according to phylogenetic and chemical coherence criteria between similar protein sequences. We show that there are four separate families of E5 proteins, with different characteristics of phylogeny, chemistry, and rate of evolution. For the sake of clarity, we propose a change in the present nomenclature. E5? is present in groups A5, A6, A7, A9, and A11, PVs highly associated with malignant carcinomas of the cervix and penis. E5? is present in groups A2, A3, A4, and A12, i.e., viruses associated with certain warts. E5? is present in group A10, and E5? is encoded in groups A1, A8, and A10, which are associated with benign transformations. The phylogenetic relationships between mucosal human PVs are the same when considering the oncoproteins E6 and E7 and the E5 proteins and differ from the phylogeny estimated for the structural proteins L1 and L2. Besides, the protein divergence rate is higher in early proteins than in late proteins, increasing in the order L1 < L2 < E6 ? E7 < E5. Moreover, the same proteins have diverged more rapidly in viruses associated with malignant transformations than in viruses associated with benign transformations. The E5 proteins display, therefore, evolutionary characteristics similar to those of the E6 and E7 oncoproteins. This could reflect a differential involvement of the E5 types in the transformation processes. PMID:15564472

Bravo, Ignacio G.; Alonso, Ángel

2004-01-01

220

Low-Dose Radiation Cataract and Genetic Determinants of Radiosensitivity  

SciTech Connect

The lens of the eye is one of the most radiosensitive tissues in the body. Ocular ionizing radiation exposure results in characteristic, dose related, progressive lens changes leading to cataract formation. While initial, early stages of lens opacification may not cause visual disability, the severity of such changes progressively increases with dose until vision is impaired and cataract extraction surgery may be required. Because of the transparency of the eye, radiation induced lens changes can easily be followed non-invasively over time. Thus, the lens provides a unique model system in which to study the effects of low dose ionizing radiation exposure in a complex, highly organized tissue. Despite this observation, considerable uncertainties remain surrounding the relationship between dose and risk of developing radiation cataract. For example, a growing number of human epidemiological findings suggest significant risk among various groups of occupationally and accidentally exposed individuals and confidence intervals that include zero dose. Nevertheless, questions remain concerning the relationship between lens opacities, visual disability, clinical cataract, threshold dose and/or the role of genetics in determining radiosensitivity. Experimentally, the response of the rodent eye to radiation is quite similar to that in humans and thus animal studies are well suited to examine the relationship between radiation exposure, genetic determinants of radiosensitivity and cataractogenesis. The current work has expanded our knowledge of the low-dose effects of X-irradiation or high-LET heavy ion exposure on timing and progression of radiation cataract and has provided new information on the genetic, molecular, biochemical and cell biological features which contribute to this pathology. Furthermore, findings have indicated that single and/or multiple haploinsufficiency for various genes involved in DNA repair and cell cycle checkpoint control, such as Atm, Brca1 or Rad9, influence cataract development and thus radiosensitivity. These observations have direct applicability to various human populations including accidentally exposed individuals, interventional medical workers, astronauts and nuclear plant workers.

Kleiman, Norman Jay [Columbia University] [Columbia University

2013-11-30

221

Glutathione levels and chemosensitizing effects of buthionine sulfoximine in human malignant glioma cells.  

PubMed

Biopsy samples and cultured cells derived from them were obtained from 39 patients with malignant glioma and were analyzed for 1) glutathione (GSH) content; 2) sensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and/or nitrogen mustard (HN2) treatment and 3) the effect of buthionine sulfoximine (BSO) treatment on BCNU and/or HN2 cytotoxicity. The average GSH concentration of biopsy specimens was lower than those of cultured cells (2.36 +/- 0.44 vs. 11.42 +/- 2.32 nmol/10(6) cells). While some of the tumor specimens were sensitive to either BCNU or HN2, the majority were resistant to both. However, 8 of 23 tumors tested showed enhanced sensitivity to BCNU following treatment with BSO. Five of 17 tumors were similarly sensitized to HN2 by BSO. These results suggest that BSO chemosensitization may be of value for certain patients and that screening assays may help identify treatment-sensitive individuals. PMID:1744683

Allalunis-Turner, M J; Day, R S; McKean, J D; Petruk, K C; Allen, P B; Aronyk, K E; Weir, B K; Huyser-Wierenga, D; Fulton, D S; Urtasun, R C

1991-10-01

222

Ionizing radiation predisposes non-malignant human mammaryepithelial cells to undergo TGF beta-induced epithelial to mesenchymaltransition  

SciTech Connect

Transforming growth factor {beta}1 (TGF{beta}) is a tumor suppressor during the initial stage of tumorigenesis, but it can switch to a tumor promoter during neoplastic progression. Ionizing radiation (IR), both a carcinogen and a therapeutic agent, induces TGF{beta}, activation in vivo. We now show that IR sensitizes human mammary epithelial cells (HMEC) to undergo TGF{beta}-mediated epithelial to mesenchymal transition (EMT). Non-malignant HMEC (MCF10A, HMT3522 S1 and 184v) were irradiated with 2 Gy shortly after attachment in monolayer culture, or treated with a low concentration of TGF{beta} (0.4 ng/ml), or double-treated. All double-treated (IR+TGF{beta}) HMEC underwent a morphological shift from cuboidal to spindle-shaped. This phenotype was accompanied by decreased expression of epithelial markers E-cadherin, {beta}-catenin and ZO-1, remodeling of the actin cytoskeleton, and increased expression of mesenchymal markers N-cadherin, fibronectin and vimentin. Furthermore, double-treatment increased cell motility, promoted invasion and disrupted acinar morphogenesis of cells subsequently plated in Matrigel{trademark}. Neither radiation nor TGF{beta} alone elicited EMT, even though IR increased chronic TGF{beta} signaling and activity. Gene expression profiling revealed that double treated cells exhibit a specific 10-gene signature associated with Erk/MAPK signaling. We hypothesized that IR-induced MAPK activation primes non-malignant HMEC to undergo TGF{beta}-mediated EMT. Consistent with this, Erk phosphorylation were transiently induced by irradiation, persisted in irradiated cells treated with TGF{beta}, and treatment with U0126, a Mek inhibitor, blocked the EMT phenotype. Together, these data demonstrate that the interactions between radiation-induced signaling pathways elicit heritable phenotypes that could contribute to neoplastic progression.

Andarawewa, Kumari L.; Erickson, Anna C.; Chou, William S.; Costes, Sylvain; Gascard, Philippe; Mott, Joni D.; Bissell, Mina J.; Barcellos-Hoff, Mary Helen

2007-04-06

223

Malignant transformation of immortalized human bronchial epithelial cells by asbestos fibers.  

PubMed Central

Although asbestos is a well-established lung carcinogen, there currently is no suitable human cell model in which to examine the underlying cellular and molecular changes associated with fiber-mediated bronchial carcinogenesis. Using a recently established transformation model based on a human papillomavirus-immortalized human bronchial epithelial cell line, we successfully transformed these BEP2D cells after a single, 7-day treatment with a 20-microgram/ml (4 micrograms per cm2 area) dose of Union Internationale Contre le Cancer (UICC) Rhodesian chrysotile fibers. Asbestos treatment resulted in a surviving fraction of 0.18 compared to control cells. Transformed cells developed through a series of sequential steps, including altered growth kinetics, resistance to serum-induced terminal differentiation, and anchorage-independent growth, before becoming tumorigenic to form progressively growing tumors in nude mice. Seven tumorigenic cell lines were isolated and determined to be of human epithelial origin based on immunofluorescent staining of keratin and isozyme analysis. Analysis of tumor DNA revealed no mutations at either codon 12 or 13 in any the ras oncogenes. An independent role for K-ras mutation in fiber carcinogenesis, therefore, cannot be confirmed. This model provides a unique opportunity to study the cellular and molecular changes at the various stages in fiber-mediated neoplastic transformation of human bronchial epithelial cells. Images Figure 3. Figure 4. PMID:9400704

Hei, T K; Wu, L J; Piao, C Q

1997-01-01

224

Photoacoustic Tomography of Human Hepatic Malignancies Using Intraoperative Indocyanine Green Fluorescence Imaging  

PubMed Central

Recently, fluorescence imaging following the preoperative intravenous injection of indocyanine green has been used in clinical settings to identify hepatic malignancies during surgery. The aim of this study was to evaluate the ability of photoacoustic tomography using indocyanine green as a contrast agent to produce representative fluorescence images of hepatic tumors by visualizing the spatial distribution of indocyanine green on ultrasonographic images. Indocyanine green (0.5 mg/kg, intravenous) was preoperatively administered to 9 patients undergoing hepatectomy. Intraoperatively, photoacoustic tomography was performed on the surface of the resected hepatic specimens (n?=?10) under excitation with an 800 nm pulse laser. In 4 hepatocellular carcinoma nodules, photoacoustic imaging identified indocyanine green accumulation in the cancerous tissue. In contrast, in one hepatocellular carcinoma nodule and five adenocarcinoma foci (one intrahepatic cholangiocarcinoma and 4 colorectal liver metastases), photoacoustic imaging delineated indocyanine green accumulation not in the cancerous tissue but rather in the peri-cancerous hepatic parenchyma. Although photoacoustic tomography enabled to visualize spatial distribution of ICG on ultrasonographic images, which was consistent with fluorescence images on cut surfaces of the resected specimens, photoacoustic signals of ICG-containing tissues decreased approximately by 40% even at 4 mm depth from liver surfaces. Photoacoustic tomography using indocyanine green also failed to identify any hepatocellular carcinoma nodules from the body surface of model mice with non-alcoholic steatohepatitis. In conclusion, photoacoustic tomography has a potential to enhance cancer detectability and differential diagnosis by ultrasonographic examinations and intraoperative fluorescence imaging through visualization of stasis of bile-excreting imaging agents in and/or around hepatic tumors. However, further technical advances are needed to improve the visibility of photoacoustic signals emitted from deeply-located lesions. PMID:25379674

Miyata, Akinori; Ishizawa, Takeaki; Kamiya, Mako; Shimizu, Atsushi; Kaneko, Junichi; Ijichi, Hideaki; Shibahara, Junji; Fukayama, Masashi; Midorikawa, Yutaka; Urano, Yasuteru; Kokudo, Norihiro

2014-01-01

225

Wnt7A is a putative prognostic and chemosensitivity marker in human malignant pleural mesothelioma  

PubMed Central

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that has a poor prognosis, limited treatment options, and a worldwide incidence that is expected to increase in the next decade. We evaluated Wnt7A expression in 50 surgically resected tumor specimens using quantitative PCR. The expression values, were assessed by clinicopathological factors and K-M and Cox’s regression with OS. The mean level of Wnt7A expression had a significant correlation with International Mesothelioma Interest Group (IMIG) stage (P<0.034), gender, smoking history and ethnicity, respectively (P=0.020, P=0.014, P=0.039). In the univariate analysis, low Wnt7A expression was a significant negative factor for overall survival (P=0.043, HR=2.30). However, multivariate Cox’s regression revealed no significant factors for overall survival (low Wnt7A: P=0.051, HR=2.283; non-epithelioid subtype: P=0.050, HR=2.898). In patients with epithelioid tumors, those with low Wnt7A expression had significantly worse prognosis (P=0.019, HR=2.98). In patients with epithelioid tumors, females had significantly better prognosis than males (P=0.035). In patients who did not have neoadjuvant chemotherapy, prognosis was significantly more favorable for patients with high Wnt7A expression than for those with low Wnt7A expression (P=0.031). Among the patients with low Wnt7A-expressing tumors, those who received neoadjuvant chemotherapy had better prognosis than those who did not (P=0.024). The results of our study suggest that Wnt7A expression is a putative prognostic factor and a predictor of chemosensitivity. PMID:25632963

HIRATA, TOMOMI; ZHENG, QINGFENG; CHEN, ZHAO; KINOSHITA, HIROYASU; OKAMOTO, JUNICHI; KRATZ, JOHANNES; LI, HUI; LUI, NATALIE; DO, HANH; CHENG, TIFFANY; TSENG, HSIN-HUI KATTY; KOIZUMI, KIYOSHI; SHIMIZU, KAZUO; ZHOU, HAI-MENG; JABLONS, DAVID; HE, BIAO

2015-01-01

226

Role of androgen and vitamin D receptors in endothelial cells from benign and malignant human prostate  

PubMed Central

Forty years ago, Judah Folkman (Folkman. N Engl J Med 285: 1182–1186, 1971) proposed that tumor growth might be controlled by limiting formation of new blood vessels (angiogenesis) needed to supply a growing tumor with oxygen and nutrients. To this end, numerous “antiangiogenic” agents have been developed and tested for therapeutic efficacy in cancer patients, including prostate cancer (CaP) patients, with limited success. Despite the lack of clinical efficacy of lead anti-angiogenic therapeutics in CaP patients, recent published evidence continues to support the idea that prostate tumor vasculature provides a reasonable target for development of new therapeutics. Particularly relevant to antiangiogenic therapies targeted to the prostate is the observation that specific hormones can affect the survival and vascular function of prostate endothelial cells within normal and malignant prostate tissues. Here, we review the evidence demonstrating that both androgen(s) and vitamin D significantly impact the growth and survival of endothelial cells residing within prostate cancer and that systemic changes in circulating androgen or vitamin D drastically affect blood flow and vascularity of prostate tissue. Furthermore, recent evidence will be discussed about the expression of the receptors for both androgen and vitamin D in prostate endothelial cells that argues for direct effects of these hormone-activated receptors on the biology of endothelial cells. Based on this literature, we propose that prostate tumor vasculature represents an unexplored target for modulation of tumor growth. A better understanding of androgen and vitamin D effects on prostate endothelial cells will support development of more effective angiogenesis-targeting therapeutics for CaP patients. PMID:23548616

Chung, Ivy; Montecinos, Viviana P.; Buttyan, Ralph; Johnson, Candace S.; Smith, Gary J.

2013-01-01

227

Histone H2B monoubiquitination: roles to play in human malignancy.  

PubMed

Ubiquitination has traditionally been viewed in the context of polyubiquitination that is essential for marking proteins for degradation via the proteasome. Recent discoveries have shed light on key cellular roles for monoubiquitination, including as a post-translational modification (PTM) of histones such as histone H2B. Monoubiquitination plays a significant role as one of the largest histone PTMs, alongside smaller, better-studied modifications such as methylation, acetylation and phosphorylation. Monoubiquitination of histone H2B at lysine 120 (H2Bub1) has been shown to have key roles in transcription, the DNA damage response and stem cell differentiation. The H2Bub1 enzymatic cascade involves E3 RING finger ubiquitin ligases, with the main E3 generally accepted to be the RNF20-RNF40 complex, and deubiquitinases including ubiquitin-specific protease 7 (USP7), USP22 and USP44. H2Bub1 has been shown to physically disrupt chromatin strands, fostering a more open chromatin structure accessible to transcription factors and DNA repair proteins. It also acts as a recruiting signal, actively attracting proteins with roles in transcription and DNA damage. H2Bub1 also appears to play central roles in histone cross-talk, influencing methylation events on histone H3, including H3K4 and H3K79. Most significantly, global levels of H2Bub1 are low to absent in advanced cancers including breast, colorectal, lung and parathyroid, marking H2Bub1 and the enzymes that regulate it as key molecules of interest as possible new therapeutic targets for the treatment of cancer. This review offers an overview of current knowledge regarding H2Bub1 and highlights links between dysregulation of H2Bub1-associated enzymes, stem cells and malignancy. PMID:24891457

Cole, Alexander J; Clifton-Bligh, Roderick; Marsh, Deborah J

2015-02-01

228

Effects of curcumin on bleomycin-induced apoptosis in human malignant testicular germ cells.  

PubMed

Testicular cancer is the most common cancer among young men of reproductive age. Bleomycin is a frequently used drug for the treatment of several malignancies and is part of the chemotherapy protocols in testicular cancer. Bleomycin causes an increase in oxidative stress which has been shown to induce apoptosis in cancer cells. Curcumin (diferuloylmethane), an active component of the spice turmeric, has attracted interest because of its anti-inflammatory and chemopreventive activities. However, no study has been carried out so far to elucidate its interaction with bleomycin in testicular cancer cells. In this study, we investigated the effects of curcumin and bleomycin on apoptosis signalling pathways and compared the effects of bleomycin with H2O2 which directly produces reactive oxygen species. We measured apoptosis markers such as caspase-3, caspase-8, and caspase-9 activities and Bcl-2, Bax, and Cyt-c levels in NCCIT cells incubated with curcumin (5 ?M), bleomycin (120 ?g/ml), bleomycin + curcumin, H2O2 (35 ?M), and H2O2 + curcumin for 72 h. Curcumin, bleomycin, and H2O2 caused apoptosis indicated as increases in caspase-3, caspase-8, and caspase-9 activities and Bax and cytoplasmic Cyt-c levels and a decrease in Bcl-2 level. Concurrent use of curcumin with bleomycin decreased caspase activities and Bax and Cyt-c levels compared to their separate effects in NCCIT cells. Our findings suggest that concurrent use of curcumin during chemotherapy in testis cancer should be avoided due to the inhibitory effect of curcumin on bleomycin-induced apoptosis. PMID:23001851

Cort, Aysegul; Timur, Mujgan; Ozdemir, Evrim; Ozben, Tomris

2013-06-01

229

Virus-like particles for the prevention of human papillomavirus-associated malignancies.  

PubMed

As compared with peptide- or protein-based vaccines, naked DNA vectors and even traditional attenuated or inactivated virus vaccines, virus-like particles (VLPs) are an attractive vaccine platform, as they offer a combination of safety, ease of production and both high-density B-cell epitope display and intracellular presentation of T-cell epitopes that induce potent humoral and cellular immune responses, respectively. Indeed, HPV vaccines based on VLP production by recombinant expression of major capsid antigen L1 in yeast (Gardasil(®), Merck & Co., NJ, USA) or insect cells (Cervarix(®), GlaxoSmithKline, London, UK) have been licensed for the prevention of cervical and anogenital infection and disease associated with the genotypes targeted by each vaccine. However, these HPV vaccines have not been demonstrated as effective to treat existing infections, and efforts to develop a therapeutic HPV vaccine continue. Furthermore, current HPV L1-VLP vaccines provide type-restricted protection, requiring highly multivalent formulations to broaden coverage to the dozen or more oncogenic HPV genotypes. This raises the complexity and cost of vaccine production. The lack of access to screening and high disease burden in developing countries has spurred efforts to develop second-generation HPV vaccines that are more affordable, induce wider protective coverage and offer therapeutic coverage against HPV-associated malignancies. Given the previous success with L1-VLP-based vaccines against HPV, VLPs have been also adopted as platforms for many second-generation HPV and non-HPV vaccine candidates with both prophylactic and therapeutic intent. In this article, the authors examine the progress and challenges of these efforts, with a focus on how they inform VLP vaccine design. PMID:23414405

Wang, Joshua W; Roden, Richard B S

2013-02-01

230

Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology.  

PubMed Central

Hypervascularity, focal necrosis, persistent cerebral edema, and rapid cellular proliferation are key histopathologic features of glioblastoma multiforme (GBM), the most common and malignant of human brain tumors. By immunoperoxidase and immunofluorescence, we definitively have demonstrated the presence of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFr) in five out of five human glioma cell lines (U-251MG, U-105MG, D-65MG, D-54MG, and CH-235MG) and in eight human GBM tumor surgical specimens. In vitro experiments with glioma cell lines revealed a consistent and reliable relation between EGFr activation and VEGF production; namely, EGF (1-20 ng/ml) stimulation of glioma cells resulted in a 25-125% increase in secretion of bioactive VEGF. Conditioned media (CM) prepared from EGF-stimulated glioma cell lines produced significant increases in cytosolic free intracellular concentrations of Ca2+ ([Ca2+]i) in human umbilical vein endothelial cells (HUVECs). Neither EGF alone or CM from glioma cultures prepared in the absence of EGF induced [Ca2+]i increases in HUVECs. Preincubation of glioma CM with A4.6.1, a monoclonal antibody to VEGF, completely abolished VEGF-mediated [Ca2+]i transients in HUVECs. Likewise, induction by glioma-derived CM of von Willebrand factor release from HUVECs was completely blocked by A4.6.1 pretreatment. These observations provide a key link in understanding the basic cellular pathophysiology of GBM tumor angiogenesis, increased vascular permeability, and cellular proliferation. Specifically, EGF activation of EGFr expressed on glioma cells leads to enhanced secretion of VEGF by glioma cells. VEGF released by glioma cells in situ most likely accounts for pathognomonic histopathologic and clinical features of GBM tumors in patients, including striking tumor angiogenesis, increased cerebral edema and hypercoagulability manifesting as focal tumor necrosis, deep vein thrombosis, or pulmonary embolism. Images PMID:7680247

Goldman, C K; Kim, J; Wong, W L; King, V; Brock, T; Gillespie, G Y

1993-01-01

231

T24 human bladder carcinoma cells with activated Ha-ras protooncogene: Nontumorigenic cells susceptible to malignant transformation with carcinogen  

SciTech Connect

A comparative analysis of T24 human bladder carcinoma cells and N-methyl-N{prime}-nitro-N-nitrosoguanidine (MeNNG)-transformed derivatives (MeNNG-T24) revealed the following: (i) The presence of an activated c-Ha-ras gene (in the absence of the normal allele) is sufficient to confer upon T24 cells a tumor-associated phenotype. (ii) MeNNG-transformed T24 cells not only acquire tumor-associated (in vitro) traits (growth in soft agar and rhodamine retention) but, are highly tumorigenic in nude mice. (iii) It is possible to render T24 cells tumorigenic by chemical transformation; therefore, the reason that T24 cells lack tumorigenicity is not because of possible incompatibilities between these cells and nude mice but, in fact, because T24 cells are not malignant. (iv) The loss of expression of a transformation-related M{sub r} 67,000 phosphoprotein by MeNNG-T24 cells after explanation of these cells from nude mouse tumors to in vitro culture indicates that culture conditions can be responsible for rapid phenotypic conversion of human tumor cell lines.

Senger, D.R.; Perruzzi, C.A.; Ali, I.U. (Harvard Medical School, Boston, MA (USA))

1988-07-01

232

Loss of the malignant phenotype of human neuroblastoma cells by a catalytically inactive dominant-negative hTERT mutant.  

PubMed

Telomerase, a ribonucleoprotein complex mainly composed of the reverse transcriptase catalytic subunit (human telomerase reverse transcriptase, hTERT) and the RNA component (hTR), is a key enzyme of cancer progression. That aggressive stage 4-neuroblastoma expressed high levels of telomerase activity, whereas favorable tumors had no or little telomerase expression and activity, prompted us to investigate the role of this enzyme in this tumor model of altered proliferation, neuronal differentiation, and apoptosis. A human MYCN-amplified neuroblastoma cell line (IGR-N-91) was engineered to stably express either the normal hTERT protein (WT-hTERT) or a catalytically inactive dominant-negative mutant of this protein (DN-hTERT). We showed that DN-hTERT expression inhibited the endogenous hTERT in the malignant neuroblasts without telomere shortening nor loss of in vitro proliferative capacity. Importantly, DN-hTERT expression induced major changes in cell morphology of neuroblasts that switched them from a neuronal to a substrate adherent phenotype, which was more prone to apoptosis and lost their tumorigenic properties in nude mice. These biologic effects arose from modifications in the expression of genes involved in both apoptosis and neuroblastoma biology. Taken together these results highlighted the functional relevance of noncanonical functions of hTERT in the determination of neuroblast cell fate. Therefore, our results envision new therapeutic strategies for metastatic neuroblastoma therapeutic management. PMID:22933702

Samy, Mona; Gattolliat, Charles-Henry; Pendino, Frédéric; Hillion, Josette; Nguyen, Eric; Bombard, Sophie; Douc-Rasy, Sétha; Bénard, Jean; Ségal-Bendirdjian, Evelyne

2012-11-01

233

Role of the human papilloma virus in the development of cervical intraepithelial neoplasia and malignancy  

Microsoft Academic Search

Human papilloma virus (HPV) is a public health problem as a sexually transmitted disease and as a critical factor in the pathogenesis of various cancers. The clinical manifestations, epidemiology, and virology that are critical to understanding the process of cervical dysplasia and neoplasia are reviewed. A discussion of the cervical transformation zone and the classification of cervical dysplasia and neoplasia

A M Jastreboff; T Cymet

2002-01-01

234

Cytogenetic Abnormalities of Tumor-Associated Endothelial Cells in Human Malignant Tumors  

PubMed Central

Tumor blood vessels are thought to contain genetically normal and stable endothelial cells (ECs), unlike tumor cells, which typically display genetic instability. Yet, chromosomal aberration in human tumor-associated ECs (hTECs) in carcinoma has not yet been investigated. Here we isolated TECs from 20 human renal cell carcinomas and analyzed their cytogenetic abnormalities. The degree of aneuploidy was analyzed by fluorescence in situ hybridization using chromosome 7 and chromosome 8 DNA probes in isolated hTECs. In human renal cell carcinomas, 22–58% (median, 33%) of uncultured hTECs were aneuploid, whereas normal ECs were diploid. The mechanisms governing TEC aneuploidy were then studied using mouse TECs (mTECs) isolated from xenografts of human epithelial tumors. To investigate the contribution of progenitor cells to aneuploidy in mTECs, CD133+ and CD133? mTECs were compared for aneuploidy. CD133+ mTECs showed aneuploidy more frequently than CD133? mTECs. This is the first report showing cytogenetic abnormality of hTECs in carcinoma, contrary to traditional belief. Cytogenetic alterations in tumor vessels of carcinoma therefore can occur and may play a significant role in modifying tumor- stromal interactions. PMID:19875502

Akino, Tomoshige; Hida, Kyoko; Hida, Yasuhiro; Tsuchiya, Kunihiko; Freedman, Deborah; Muraki, Chikara; Ohga, Noritaka; Matsuda, Kouhei; Akiyama, Kousuke; Harabayashi, Toru; Shinohara, Nobuo; Nonomura, Katsuya; Klagsbrun, Michael; Shindoh, Masanobu

2009-01-01

235

Telomerase Activity Associated with Acquisition of Malignancy in Human Colorectal Cancer1  

Microsoft Academic Search

Shortening of telomeres may contribute to the control of the prolifer- ative capacity of normal cells, and telomerase, the enzyme that elongates telomeric DNA, may be essential for unlimited cell proliferation. We have shown previously that telomerase activity is present in human cells im mortalized in vitro and in metastatic ovarian carcinoma cells but is undetectable in normal cultured cells

Corinne Chadeneau; Kazy Hay; Hal W. Hirte; Steven Gallinger; Silvia Bacchetti

236

Repair of chromosome damage induced by X-irradiation during G/sub 2/ phase in a line of normal human fibroblasts and its malignant derivative  

SciTech Connect

A line of normal human skin fibroblasts (KD) differed from its malignant derivative (HUT-14) in the extent of cytogenetic damage induced by X-irradiation during G/sub 2/ phase. Malignant cells had significantly more chromatid breaks and gaps after exposure to 25, 50, or 100 rad. Results from alkaline elution of cellular DNA immediately after irradiation showed that the normal and malignant cells in asynchronous population were equally sensitive to DNA single-strand breakage by X-irradiation. Caffeine or ..beta..-cytosine arabinoside (ara-C), inhibitors of DNA repair, when added directly following G/sub 2/ phase exposure, significantly increased the incidence of radiation-induced chromatid damage in the normal cells. In contrast, similar treatment of the malignant cells had little influence. Ara-C differed from caffeine in its effects; whereas both agents increased the frequency of chromatid breaks and gaps, only ara-C increased the frequency of gaps to the level observed in the irradiated malignant cells. Addition of catalase, which destroys H/sub 2/O/sub 2/, or mannitol, a scavenger of the derivative free hydroxyl radical (.OH), to the cultures of malignant cells before, during, and following irradiation significantly reduced the chromatid damage; and catalase prevented formation of chromatid gaps. The DNA damage induced by X-ray during G/sub 2/ phase in the normal KD cells was apparently repaired by a caffeine- and ara-C-sensitive mechanism(s) that was deficient or absent in their malignant derivatives.

Parshad, R. (Howard Univ. College of Medicine, Washington, DC); Gantt, R.; Sanford, K.K.; Jones, G.M.; Tarone, R.E.

1982-08-01

237

The human Bosniak model applied to a cat with renal cystadenoma. A classification to differentiate benign and malignant cystic renal masses via computed tomography and ultrasound.  

PubMed

A 13-year-old domestic shorthair cat was presented with weight loss and azotemia. Abdominal ultrasound revealed a large cystic space- occupying lesion with multiple septae in the left kidney. A core needle biopsy yielded a renal cystadenoma originating from the epithelial cells. This report describes the clinical, ultrasonographic and computed tomographic features and the growth progression of a renal cystadenoma. We describe the first attempt to apply the human Bosniak classification to a cat with renal cystic neoplasia to differentiate between benign and malignant lesions. Cystadenoma should be a differential diagnosis in cases of renal cystic space-occupying lesions. Other differentials, imaging features to differentiate benign and malignant lesions and the risk of malignant transformation will be discussed. PMID:25599531

Baloi, P; Del Chicca, F; Ruetten, M; Gerber, B

2015-02-17

238

Immunohistochemical study on the expression of matrix metalloproteinase 2 and high-risk human papilloma virus in the malignant progression of papillomas  

PubMed Central

Objectives Papilloma frequently develops as a benign tumor of the head and neck area, but its potential for malignant transformation has yet to be studied. This study aims to provide basic information for papillomas using the immunohistochemical staining of matrix metalloproteinase 2 (MMP-2) and human papilloma virus (HPV) 16 and 18. Materials and Methods To evaluate the malignant transformation of papillomas, the selected tissue samples were serially diagnosed with pre-cancerous papilloma (with epithelial dysplasia, pseudo-epitheliomatous hyperplasia) or malignant lesion (squamous cell carcinoma, SCC) after the first diagnosis (squamous papilloma, inverted papilloma). The selected tissues were stained with an antibody to MMP-2 and HPV 16-E7, HPV 18-L1. A statistical analysis was performed according to each transformation step. Results The epithelial layer of papilloma and pre-cancerous papilloma lesions had a similar MMP-2 expression, but that of the malignant lesion had a significantly increased MMP-2 expression. HPV 16 and 18 infection rates were 28.6%, 33.3% and 63.6% in papillomas, pre-cancerous papilloma lesions, and SCC. Conclusions A relatively high MMP-2 expression and HPV 16 or 18 infection of papillomas may be associated with early events in the multistep processes of malignant transformation of papillomas. PMID:24471049

Lee, Ho-Jin

2013-01-01

239

Knowledge of human papillomavirus and its association with head and neck benign and malignant lesions in a group of dental patients in pakistan.  

PubMed

Human papillomaviruses (HPVs) remain a serious world health problem due to their association with cervical and head and neck cancers. While over 100 HPV types have been identified, only a few subtypes are associated with malignancies. HPV 16 and 18 are the most prevalent oncogenic types in head and neck cancers. Although it has been proven that some subsets of benign and malignant head and neck lesions are associated with HPV, the general population have very little awareness and knowledge of their association with HPV. Therefore, the purpose of this study was to determine the knowledge of HPV and its links with head and neck benign and malignant lesions in a group of Pakistani dental patients who attended the Dental Department of the Sandeman provincial hospital in Quetta, Pakistan. One hundred and ninety-two patients were recruited and requested to answer a questionnaire. It was revealed that there was a low level of knowledge about HPV and its association with head and neck benign and malignant lesions among the participants. This result suggested that more education regarding the relationship of HPV in inducing head and neck benign and malignant lesions is required in this group of patients. PMID:25743835

Gichki, Abdul Samad; Buajeeb, Waranun; Doungudomdacha, Sombhun; Khovidhunkit, Siribang-On Pibooniyom

2015-01-01

240

Gemcitabine uptake in glioblastoma multiforme: potential as a radiosensitizer.  

PubMed

Glioblastoma multiforme (GBM), the most frequent malignant brain tumor, has a poor prognosis, but is relatively sensitive to radiation. Both gemcitabine and its metabolite difluorodeoxyuridine (dFdU) are potent radiosensitizers. The aim of this phase 0 study was to investigate whether gemcitabine passes the blood-tumor barrier, and is phosphorylated in the tumor by deoxycytidine kinase (dCK) to gemcitabine nucleotides in order to enable radiosensitization, and whether it is deaminated by deoxycytidine deaminase (dCDA) to dFdU. Gemcitabine was administered at 500 or 1000 mg/m(2) just before surgery to 10 GBM patients, who were biopsied after 1-4 h. Plasma gemcitabine and dFdU levels varied between 0.9 and 9.2 microM and 24.9 and 72.6 microM, respectively. Tumor gemcitabine and dFdU levels varied from 60 to 3580 pmol/g tissue and from 29 to 72 nmol/g tissue, respectively. The gene expression of dCK (beta-actin ratio) varied between 0.44 and 2.56. The dCK and dCDA activities varied from 1.06 to 2.32 nmol/h/mg protein and from 1.51 to 5.50 nmol/h/mg protein, respectively. These enzyme levels were sufficient to enable gemcitabine phosphorylation, leading to 130-3083 pmol gemcitabine nucleotides/g tissue. These data demonstrate for the first time that gemcitabine passes the blood-tumor barrier in GBM patients. In tumor samples, both gemcitabine and dFdU concentrations are high enough to enable radiosensitization, which warrants clinical studies using gemcitabine in combination with radiation. PMID:18701427

Sigmond, J; Honeywell, R J; Postma, T J; Dirven, C M F; de Lange, S M; van der Born, K; Laan, A C; Baayen, J C A; Van Groeningen, C J; Bergman, A M; Giaccone, G; Peters, G J

2009-01-01

241

Impact of MACC1 on human malignant glioma progression and patients' unfavorable prognosis  

PubMed Central

Background Metastasis-associated in colon cancer 1 (MACC1) has been established as an independent prognostic indicator of metastasis formation and metastasis-free survival for patients with colon cancer and other solid tumors. However, no data are available concerning MACC1 expression in human astrocytic tumors. Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor of adulthood, and due to its invasive and rapid growth, patients have unfavorable prognoses. Although these tumors rarely metastasize, their invasive and migratory behavior is similar to those of metastatic cells of tumors of different origin. Thus, we hypothesized that MACC1 may be involved in progression of human gliomas. Methods We performed real-time measurements of proliferation and migration in MACC1-transfected GBM cell lines (U138, U251) and evaluated tumor formation in organotypic hippocampal slice cultures of mice. Semiquantitative and quantitative real-time reverse transcription PCR analyses were performed for MACC1 and for its transcriptional target c-Met in human astrocytoma of World Health Organization grade II (low-grade astrocytoma) and GBM biopsies. Data were validated by MACC1 immunohistochemistry in independent matched samples of low-grade astrocytoma and GBM. Results MACC1 increases the proliferative, migratory, and tumor-formation abilities of GBM cells. The c-Met inhibitor crizotinib reduced MACC1-induced migration and tumor formation in organotypic hippocampal slice cultures of mice. Analyzing patients’ biopsies, MACC1 expression increased concomitantly with increasing World Health Organization grade. Moreover, MACC1 expression levels allowed discrimination of dormant and recurrent low-grade astrocytomas and of primary and secondary GBM. Strong MACC1 expression correlated with reduced patient survival. Conclusions MACC1 may represent a promising biomarker for prognostication and a new target for treatment of human gliomas. PMID:24220141

Hagemann, Carsten; Fuchs, Steffen; Monoranu, Camelia M.; Herrmann, Pia; Smith, Janice; Hohmann, Tim; Grabiec, Urszula; Kessler, Almuth F.; Dehghani, Faramarz; Löhr, Mario; Ernestus, Ralf-Ingo; Vince, Giles H.; Stein, Ulrike

2013-01-01

242

Mechanism of radiosensitization by porphyrins.  

PubMed

According to our previous data, hematoporphyrin dimethyl ether (HPde) at concentrations useful for photodynamic therapy can radiosensitize aggressive Ehrlich ascite carcinoma (EAT) to 2Gy irradiation inducing total tumour growth inhibition. The aim of this study was to further investigate the possible mechanism of radiosensitization of EAT by dicarboxylic porphyrin-HPde. Our results reveal that HPde is inducing several rearrangements in the EAT cells: 1.2 x 10-6 M of the photosensitizer diminishes the number of cells in mitosis by a factor of 3, increases the number of cells in the S phase of the cell cycle, modifies the activities of antioxidant enzymes glutation S-transferase (GST) and DT-diaphorase (DTD), and eventually induces slight apoptosis. Moreover, it was shown that HPde is a ligand of peripheral benzodiazepine receptor (PBR). Named "house keeper," PBR is usually responsible for all these perturbations, which, in our case, act in concert with the following ionizing radiation, producing the interaction of two antiproliferative/destructive factors. PMID:16566725

Luksiene, Zivile; Labeikyte, Danute; Juodka, Benediktas; Moan, Johan

2006-01-01

243

Radiosensitization Effect of STI-571 on Pancreatic Cancer Cells In Vitro  

SciTech Connect

Purpose: To examine STI-571-induced radiosensitivity in human pancreatic cancer cells in vitro. Methods and Materials: Three human pancreatic cancer cell lines (Bxpc-3, Capan-1, and MiaPaCa-2) exhibiting different expression levels of c-Kit and platelet-derived growth factor receptor beta (PDGFRbeta) and showing different K-ras mutation types were used. For evaluation of the antitumor activity of STI-571 in combination with radiation, clonogenic survival assays, Western blot analysis, and the annexin V/propidium iodide assay with microscopic evaluation by 4',6-diamidino-2-phenylindole were conducted. Results: Dramatic phosphorylated (p)-c-Kit and p-PDGFRbeta attenuation, a modest dose- and time-dependent growth inhibition, and significant radiosensitization were observed after STI-571 treatment in view of apoptosis, although the levels of growth inhibition and increased radiosensitization were different according to cell lines. The grades of radiosensitivity corresponded to the attenuation levels of p-c-Kit and p-PDGFRbeta by STI-571, particularly to those of p-c-Kit, and the radiosensitivity was partially affected by K-ras mutation in pancreatic cancer cells. Among downstream pathways associated with c-Kit or PDGFRbeta, p-PLCgamma was more closely related to radiosensitivity compared with p-Akt1 or p-extracellular signal-regulated kinase 1. Conclusion: STI-571 enhances radiation response in pancreatic cancer cells. This effect is affected by the attenuation levels of p-c-Kit or p-PDGFRbeta, and K-ras mutation status. Among them, p-c-Kit plays more important roles in the radiosensitivity in pancreatic cancer compared with p-PDGFRbeta or K-ras mutation status.

Chung, Hye Won [Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of); Wen, Jing [Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul (Korea, Republic of); Lim, Jong-Baeck [Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of); Bang, Seung Min; Park, Seung Woo [Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of); Song, Si Young, E-mail: sysong@yuhs.a [Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of); Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul (Korea, Republic of)

2009-11-01

244

Expression of tropomyosin isoforms in benign and malignant human breast lesions.  

PubMed Central

High molecular weight tropomyosins (tms) are commonly down-regulated in fibroblasts transformed by oncogenes. Previous studies have also demonstrated that specific tm isoforms are down-regulated in human breast carcinoma cell lines. We examined tropomyosin isoforms in cells prepared from non-cancerous breast lesions and primary human breast carcinomas. The average level of expression of all three high molecular weight tm isoforms (tm 1-3) in carcinomas was generally found to be less than 25% of that observed in non-cancerous breast lesions. Interestingly, the expression of tm 1 was found to be 1.7-fold higher in primary tumours with metastatic spread to axillary lymph nodes compared with primary tumours with no evidence of metastasis (p<0.05). Similarly, tm 1 expression was higher in two 12V-H-ras transformed fibroblast cell lines capable of experimental metastasis compared with three weakly metastatic cell lines. We conclude from these studies that expression of high molecular weight tm isoforms is low in primary breast carcinomas, and that metastatic tumours express relatively high levels of tm 1. Images Figure 1 PMID:8611405

Franzén, B.; Linder, S.; Uryu, K.; Alaiya, A. A.; Hirano, T.; Kato, H.; Auer, G.

1996-01-01

245

Human Malignant Melanoma-Derived Progestagen-Associated Endometrial Protein Immunosuppresses T Lymphocytes In Vitro  

PubMed Central

Progestagen-associated endometrial protein (PAEP) is a glycoprotein of the lipocalin family that acts as a negative regulator of T cell receptor-mediated activation. However, the function of tumor-derived PAEP on the human immune system in the tumor microenvironment is unknown. PAEP is highly expressed in intermediate and thick primary melanomas (Breslow’s 2.5mm or greater) and metastatic melanomas, correlating with its expression in daughter cell lines established in vitro. The current study investigates the role of melanoma cell-secreted PAEP protein in regulating T cell function. Upon the enrichment of CD3+, CD4+ and CD8+ T cells from human peripheral blood mononuclear cells, each subset was then mixed with either melanoma-derived PAEP protein or PAEP-poor supernatant of gene-silenced tumor cells. IL-2 and IFN-? secretion of CD4+ T cells significantly decreased with the addition of PAEP-rich supernatant. And the addition of PAEP-positive cell supernatant to activated lymphocytes significantly inhibited lymphocyte proliferation and cytotoxic T cell activity, while increasing lymphocyte apoptosis. Our result suggests that melanoma cell-secreted PAEP protein immunosuppresses the activation, proliferation and cytotoxicity of T lymphocytes, which might partially explain the mechanism of immune tolerance induced by melanoma cells within the tumor microenvironment. PMID:25785839

Ren, Suping; Chai, Lina; Wang, Chunyan; Li, Changlan; Ren, Qiquan; Yang, Lihua; Wang, Fumei; Qiao, Zhixin; Li, Weijing; He, Min; Riker, Adam I.; Han, Ying; Yu, Qun

2015-01-01

246

Radiosensitizing Effects of Ectopic miR-101 on Non-Small-Cell Lung Cancer Cells Depend on the Endogenous miR-101 Level  

SciTech Connect

Purpose: Previously, we showed that ectopic miR-101 could sensitize human tumor cells to radiation by targeting ATM and DNA-PK catalytic subunit (DNA-PKcs) to inhibit DNA repair, as the endogenous miR-101 levels are low in tumors in general. However, the heterogeneity of human cancers may result in an exception. The purpose of this study was to test the hypothesis that a few tumor cell lines with a high level of endogenous miR-101 would prove less response to ectopic miR-101. Methods and Materials: Fourteeen non-small-cell lung cancer (NSCLC) cell lines and one immortalized non-malignant lung epithelial cell line (NL20) were used for comparing endogenous miR-101 levels by real-time reverse transcription-polymerase chain reaction. Based on the different miR-101 levels, four cell lines with different miR-101 levels were chosen for transfection with a green fluorescent protein-lentiviral plasmid encoding miR-101. The target protein levels were measured by using Western blotting. The radiosensitizing effects of ectopic miR-101 on these NSCLC cell lines were determined by a clonogenic assay and xenograft mouse model. Results: The endogenous miR-101 level was similar or lower in 13 NSCLC cell lines but was 11-fold higher in one cell line (H157) than in NL20 cells. Although ectopic miR-101 efficiently decreased the ATM and DNA-PKcs levels and increased the radiosensitization level in H1299, H1975, and A549 cells, it did not change the levels of the miR-101 targets or radiosensitivity in H157 cells. Similar results were observed in xenograft mice. Conclusions: A small number of NSCLC cell lines could have a high level of endogenous miR-101. The ectopic miR-101 was able to radiosensitize most NSCLC cells, except for the NSCLC cell lines that had a much higher endogenous miR-101 level. These results suggest that when we choose one miRNA as a therapeutic tool, the endogenous level of the miRNA in each tumor should be considered.

Chen, Susie; Wang Hongyan; Ng, Wooi Loon; Curran, Walter J. [Department of Radiation Oncology, School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, GA (United States); Wang Ya, E-mail: ywang94@emory.edu [Department of Radiation Oncology, School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, GA (United States)

2011-12-01

247

Estimation of the epidemiological burden of human papillomavirus-related cancers and non-malignant diseases in men in Europe: a review  

PubMed Central

Background The role of human papillomavirus (HPV) in malignant and non-malignant genital diseases in women is well known and the corresponding epidemiological burden has been widely described. However, less is known about the role of HPV in anal, penile and head and neck cancer, and the burden of malignant and non-malignant HPV-related diseases in men. The objective of this review is to estimate the epidemiological burden of HPV-related cancers and non-malignant diseases in men in Europe. Methods The annual number of new HPV-related cancers in men in Europe was estimated using Eurostat population data and applying cancer incidence rates published by the International Agency for Research on Cancer. The number of cancer cases attributable to HPV, and specifically to HPV16/18, was calculated based on the most relevant prevalence estimates. The annual number of new cases of genital warts was calculated from the most robust European studies; and latest HPV6/11 prevalence estimates were then applied. A literature review was also performed to retrieve exhaustive data on HPV infection at all anatomical sites under study, as well as incidence and prevalence of external genital warts, recurrent respiratory papillomatosis and HPV-related cancer trends in men in Europe. Results A total of 72, 694 new cancer cases at HPV-related anatomical sites were estimated to occur each year in men in Europe. 17,403 of these cancer cases could be attributable to HPV, with 15,497 of them specifically attributable to HPV16/18. In addition, between 286,682 and 325,722 new cases of genital warts attributable to HPV6/11were estimated to occur annually in men in Europe. Conclusions The overall estimated epidemiological burden of HPV-related cancers and non-malignant diseases is high in men in Europe. Approximately 30% of all new cancer cases attributable to HPV16/18 that occur yearly in Europe were estimated to occur in men. As in women, the vast majority of HPV-positive cancer in men is related to HPV16/18, while almost all HPV-related non-malignant diseases are due to HPV6/11. A substantial number of these malignant and non-malignant diseases may potentially be prevented by quadrivalent HPV vaccination. PMID:22260541

2012-01-01

248

Preferential cytotoxicity of bortezomib toward highly malignant human liposarcoma cells via suppression of MDR1 expression and function.  

PubMed

Liposarcoma is the most common soft tissue sarcoma with a high risk of relapse. Few therapeutic options are available for the aggressive local or metastatic disease. Here, we report that the clinically used proteasome inhibitor bortezomib exhibits significantly stronger cytotoxicity toward highly malignant human liposarcoma SW872-S cells compared with its parental SW872 cells, which is accompanied by enhanced activation of apoptotic signaling both in vitro and in vivo. Treatment of cells with Jun-N-terminal kinase (JNK) inhibitor SP60015 or the translation inhibitor cycloheximide ameliorated this enhanced apoptosis. Bortezomib inhibited MDR1 expression and function more effectively in SW872-S cells than in SW872 cells, indicating that the increased cytotoxicity relies on the degree of proteasome inhibition. Furthermore, the pharmacological or genetic inhibition of sarco/endoplasmic reticulum calcium-ATPase (SERCA) 2, which is highly expressed in SW872-S cells, resulted in partial reversal of cell growth inhibition and increase of MDR1 expression in bortezomib-treated SW872-S cells. These results show that bortezomib exhibits preferential cytotoxicity toward SW872-S cells possibly via highly expressed SERCA2-associated MDR1 suppression and suggest that bortezomib may serve as a potent agent for treating advanced liposarcoma. PMID:25576094

Hu, Yamei; Wang, Lingxian; Wang, Lu; Wu, Xuefeng; Wu, Xudong; Gu, Yanhong; Shu, Yongqian; Sun, Yang; Shen, Yan; Xu, Qiang

2015-02-15

249

Somatic mutations of the Parkinson's disease–associated gene PARK2 in glioblastoma and other human malignancies  

PubMed Central

Mutation of the gene PARK2, which encodes an E3 ubiquitin ligase, is the most common cause of early-onset Parkinson's disease1, 2, 3. In a search for multisite tumor suppressors, we identified PARK2 as a frequently targeted gene on chromosome 6q25.2–q27 in cancer. Here we describe inactivating somatic mutations and frequent intragenic deletions of PARK2 in human malignancies. The PARK2 mutations in cancer occur in the same domains, and sometimes at the same residues, as the germline mutations causing familial Parkinson's disease. Cancer-specific mutations abrogate the growth-suppressive effects of the PARK2 protein. PARK2 mutations in cancer decrease PARK2's E3 ligase activity, compromising its ability to ubiquitinate cyclin E and resulting in mitotic instability. These data strongly point to PARK2 as a tumor suppressor on 6q25.2–q27. Thus, PARK2, a gene that causes neuronal dysfunction when mutated in the germline, may instead contribute to oncogenesis when altered in non-neuronal somatic cells. PMID:19946270

Veeriah, Selvaraju; Taylor, Barry S; Meng, Shasha; Fang, Fang; Yilmaz, Emrullah; Vivanco, Igor; Janakiraman, Manickam; Schultz, Nikolaus; Hanrahan, Aphrothiti J; Pao, William; Ladanyi, Marc; Sander, Chris; Heguy, Adriana; Holland, Eric C; Paty, Philip B; Mischel, Paul S; Liau, Linda; Cloughesy, Timothy F; Mellinghoff, Ingo K; Solit, David B; Chan, Timothy A

2014-01-01

250

Prognostic role of microRNA-205 in multiple human malignant neoplasms: a meta-analysis of 17 studies  

PubMed Central

Objective MicroRNA-205 (miRNA-205) was revealed as an attractive prognostic tumour biomarker in recent studies. However, the results of different studies have been inconsistent. We conducted a meta-analysis to elucidate the precise predictive value of miRNA-205 in various human malignant neoplasms. Design Meta-analysis. Data sources Qualified studies were identified up to 5 June 2014 by performing online searches in PubMed, EMBASE and Web of Science, and additional quality evaluations. Participants Seventeen eligible studies with 4827 patients were ultimately enrolled in this meta-analysis. Outcome measures The heterogeneity between studies was assessed using I2 statistics. Pooled HRs with 95% CIs for patient survival and disease recurrence were calculated to investigate the correlation between miRNA-205 expression and cancer prognosis. Results Our results indicate that elevated miRNA-205 was significantly associated with enhanced overall survival in the breast cancer subgroup (HR=0.78, 95% CI 0.67 to 0.91) and superior disease-free survival/recurrence-free survival in the adenocarcinoma subgroup (HR=0.68, 95% CI 0.49 to 0.94). Conclusions miRNA-205 is a promising biomarker for predicting the recurrence and progression of patients with adenocarcinomas or breast cancer. Owing to its complex roles, further relevant studies are warranted. PMID:25613953

Zhang, Jia-yi; Sun, Meng-yan; Song, Ning-hong; Deng, Zhong-lei; Xue, Chun-yu; Yang, Jie

2015-01-01

251

Xanthohumol induces apoptosis in human malignant glioblastoma cells by increasing reactive oxygen species and activating MAPK pathways.  

PubMed

The effect of the biologically active prenylated chalcone and potential anticancer agent xanthohumol (1) has been investigated on apoptosis of the T98G human malignant glioblastoma cell line. Compound 1 decreased the viability of T98G cells by induction of apoptosis in a time- and concentration-dependent manner. Apoptosis induced by 1 was associated with activation of caspase-3, caspase-9, and PARP cleavage and was mediated by the mitochondrial pathway, as exemplified by mitochondrial depolarization, cytochrome c release, and downregulation of the antiapoptotic Bcl-2 protein. Xanthohumol induced intracellular reactive oxygen species (ROS), an effect that was reduced by pretreatment with the antioxidant N-acetyl-L-cysteine (NAC). Intracellular ROS production appeared essential for the activation of the mitochondrial pathway and induction of apoptosis after exposure to 1. Oxidative stress due to treatment with 1 was associated with MAPK activation, as determined by ERK1/2 and p38 phosphorylation. Phosphorylation of ERK1/2 and p38 was attenuated using NAC to inhibit ROS production. After treatment with 1, ROS provided a specific environment that resulted in MAPK-induced cell death, with this effect reduced by the ERK1/2 specific inhibitor PD98059 and partially inhibited by the p38 inhibitor SB203580. These findings suggest that xanthohumol (1) is a potential chemotherapeutic agent for the treatment of glioblastoma multiforme. PMID:22111577

Festa, Michela; Capasso, Anna; D'Acunto, Cosimo W; Masullo, Milena; Rossi, Adriano G; Pizza, Cosimo; Piacente, Sonia

2011-12-27

252

Epigenetic activation of human kallikrein 13 enhances malignancy of lung adenocarcinoma by promoting N-cadherin expression and laminin degradation.  

PubMed

The tissue kallikrein (KLK) family contains 15 genes (KLK1-KLK15) tandemly arranged on chromosome 19q13.4 that forms the largest cluster of contiguous protease genes in the human genome. Here, we provide mechanistic evidence showing that the expression of KLK13, one of the most recently identified family members, is significantly up-regulated in metastatic lung adenocarcinoma. Whilst overexpression of KLK13 resulted in an increase in malignant cell behavior, knockdown of its endogenous gene expression caused a significant decrease in cell migratory and invasive properties. Functional studies further demonstrated that KLK13 is activated via demethylation of its upstream region. The elevated KLK13 protein then enhances the ability of tumor cells to degrade extracellular laminin that, subsequently, facilitates cell metastatic potential in the in vivo SCID mouse xenograft model. KLK13 was also found to induce the expression of N-cadherin to help promote tumor cell motility. Together, these results reveal the enhancing effects of KLK13 on tumor cell invasion and migration, and that it may serve as a diagnostic/prognostic marker and a potential therapeutic target for lung cancer. PMID:21596022

Chou, Ruey-Hwang; Lin, Sheng-Chieh; Wen, Hui-Chin; Wu, Cheng-Wen; Chang, Wun-Shaing Wayne

2011-06-10

253

Vascular endothelial growth factor expression is independent of hypoxia in human malignant glioma spheroids and tumours  

PubMed Central

We recently showed that severe hypoxia was not universally present adjacent to necrosis in human glioma xenografts and spheroids established from the M059K, M006, M006X, M006XLo and M010b cell lines. Using these glioma models, we wished to test whether oxygen serves as a regulator of cellular VEGF expression in situ. In situ hybridization (ISH) and immunohistochemistry (IHC) were used to detect vascular endothelial growth factor (VEGF) mRNA and protein expression in sections of glioma xenografts and spheroids in which hypoxic regions and regions with well-oxygenated necrosis were identified on contiguous sections by use of the hypoxia-specific marker,3H-misonidazole. Independent validation of the presence of radiobiologically hypoxic cells in M006 xenografts was undertaken using the comet assay. Northern blotting analyses of monolayer cells demonstrated significant up-regulation of VEGF mRNA in the M006X line at oxygen concentrations of 6% and below. ISH analysis of VEGF mRNA showed unexpectedly strong staining for VEGF mRNA across the entire viable rim of M006X and M006XLo glioma spheroids. Similarly, in virtually all xenograft tumours of the M059K, M006 and M010b lines, VEGF ISH showed similar staining across all regions of healthy cells up to the border of necrosis. Only in one M006X tumour was there a suggestion of increased VEGF expression in cells adjacent to necrosis. IHC for VEGF showed good concordance with the ISH results. IHC analysis of the VEGF receptor flt-1 showed strong tumour cell staining in M006XLo glioma cells. In human glioma spheroids and xenograft tumours, regions of severe hypoxia do not correspond to areas of up-regulated VEGF expression; in fact, VEGF expression is quite uniform. Furthermore, this and our previous study demonstrate that levels of VEGF expression vary among sublines (M006, M006X and M006XLo) derived from a single human glioma specimen. © 2000 Cancer Research Campaign PMID:10682677

Parliament, M B; Allalunis-Turner, M J; Franko, A J; Olive, P L; Mandyam, R; Santos, C; Wolokoff, B

2000-01-01

254

Human papillomavirus type 16 DNA-induced malignant transformation of NIH 3T3 cells  

SciTech Connect

A biological function for human papillomavirus 16 (HPV 16) DNA was demonstrated by transformation of NIH 3T3 cells. HPV 16 DNA has been found frequently in genital cancer and has been classified as a papillomavirus on the basis of DNA homology. A recombinant HPV 16 DNA (pSHPV16d), which contains a head-to-tail dimer of the full-length HPV 16 genome, induced morphologic transformation; the transformed cells were tumorigenic in nude mice. Expression of transforming activity was unique because of the long latency period (more than 4 weeks) required for induction of morphologic transformation and because the transfected DNA existed primarily in a multimeric form with some rearrangement. Furthermore, virus-specific RNAs were expressed in the transformants. The transformation of NIH 3T3 cells provides a model for analyzing the functions of HPV 16, which is associated with cervical carcinomas.

Yasumoto, S.; Burkhardt, A.L.; Doniger, J.; DiPaolo, J.A.

1986-02-01

255

Radiosensitization of head and neck squamous cell carcinoma by a SMAC-mimetic compound, SM-164, requires activation of caspases  

PubMed Central

Chemoradiation is the treatment of choice for locally advanced head and neck squamous cell carcinoma (HNSCC). However, radioresistance, which contributes to local recurrence, remains a significant therapeutic problem. In this study, we characterized SM-164, a small SMAC mimetic compound that promotes degradation of cIAP-1 (also known as BIRC2) and releases active caspases from XIAP inhibitory binding, as a radiosensitizing agent in HNSCC cells. We found that SM-164 at nanomolar concentrations induced radiosensitization in some HNSCC cell lines in a manner dependent on intrinsic sensitivity to caspase activation and apoptosis induction. Blockage of caspase activation via siRNA knockdown or a pan-caspase inhibitor, z-VAD-fmk largely abrogated SM-164 radiosensitization. On the other hand, the resistant lines with a high level of BCL-2 that blocks caspase activation and apoptosis induction became sensitive to radiation upon BCL-2 knockdown. Mechanistic studies revealed that SM-164 radiosensitization in sensitive cells was associated with NF?B activation and TNF? secretion, followed by activation of caspases-8 and -9, leading to enhanced apoptosis. Finally, SM-164 also radiosensitized human tumor xenograft, while causing minimal toxicity. Thus, SM-164 is a potent radiosensitizer via a mechanism involving caspase activation and holds promise for future clinical development as a novel class of radiosensitizer for the treatment of a subset of head and neck cancer patients. PMID:21282353

Yang, Jie; McEachern, Donna; Li, Wenyan; Davis, Mary A.; Li, Hua; Morgan, Meredith A.; Bai, Longchuan; Sebolt, Jonathan T.; Sun, Haiying; Lawrence, Theodore S.; Wang, Shaomeng; Sun, Yi

2011-01-01

256

Argon laser phototherapy of human malignancies using rhodamine-123 as a new laser dye: The intracellular role of oxygen  

SciTech Connect

Recent studies demonstrated that the cationic, mitochondrial-specific dye Rhodamine-123 (Rh-123), is an efficient tumor photosensitizer for Argon laser treatment of human cancer cells both in vitro and in tumors grown as xenografts in athymic mice. To demonstrate the photodynamic mechanism of action of this reaction, the intracellular role of oxygen and temperature changes in treated cells have to be defined. In the current study, a large panel of human tumor cell lines of diverse histologic origin were tested for in vitro sensitivity to Rh-123 and the Argon laser (514.5 nm) in oxygen, deuterium oxide (D2O), and nitrogen (N2) environment. Tumor cells in suspension were first sensitized to Rh-123 (1 or 20 micrograms/ml for 1 hour), cooled on ice to 4 degrees C, and then exposed to the Argon laser (delta T = 14 +/- 1 degree C). Cell proliferation measured by (3H)-thymidine uptake 24 hours after sensitization with Rh-123 and laser treatment was significantly decreased in tumor cells kept in oxygen and D2O atmospheres. No decrease in DNA synthesis was seen in Rh-123 and laser treated cells kept in an N2 environment. Control tumor cells treated with Rh-123 or the Argon laser separately did not show any decreased (3H)-thymidine uptake in oxygen, D2O or N2 environment. These results provide evidence of a photodynamic process since Rh-123 sensitization and Argon laser activation occur at nonthermal levels of energy and are oxygen dependent. The high effectiveness of this technique of photodynamic therapy with the Argon laser, and low toxicity of Rh-123 could make its clinical use very attractive for the treatment of superficial malignancies.

Castro, D.J.; Saxton, R.E.; Markley, J.; Foote, C.S.; Fetterman, H.R.; Castro, D.J.; Ward, P.H. (Univ. of California, Los Angeles (USA))

1990-08-01

257

Enhanced Anti-Tumor Effect of Zoledronic Acid Combined with Temozolomide against Human Malignant Glioma Cell Expressing O6-Methylguanine DNA Methyltransferase  

PubMed Central

Temozolomide (TMZ), a DNA methylating agent, is widely used in the adjuvant treatment of malignant gliomas. O6-methylguanine-DNA methyltranferase (MGMT), a DNA repair enzyme, is frequently discussed as the main factor that limits the efficacy of TMZ. Zoledronic acid (ZOL), which is clinically applied to treat cancer-induced bone diseases, appears to possess direct anti-tumor activity through apoptosis induction by inhibiting mevalonate pathway and prenylation of intracellular small G proteins. In this study, we evaluated whether ZOL can be effectively used as an adjuvant to TMZ in human malignant glioma cells that express MGMT. Malignant glioma cell lines, in which the expression of MGMT was detected, did not exhibit growth inhibition by TMZ even at a longer exposure. However, combination experiment of TMZ plus ZOL revealed that a supra-additive effect resulted in a significant decrease in cell growth. In combined TMZ/ZOL treatment, an increased apoptotic rate was apparent and significant activation of caspase-3 and cleavage of poly-(ADP-ribose) polymerase were observed compared with each single drug exposure. There were decreased amounts of Ras-GTP, MAPK and Akt phosphorylation and MGMT expression in the ZOL-treated cells. Subcutanous xenograft models showed significant decrease of tumor growth with combined TMZ/ZOL treatment. These results suggest that ZOL efficaciously inhibits activity of Ras in malignant glioma cells and potentiates TMZ-mediated cytotoxicity, inducing growth inhibition and apoptosis of malignant glioma cells that express MGMT and resistant to TMZ. Based on this work, combination of TMZ with ZOL might be a potential therapy in malignant gliomas that receive less therapeutic effects of TMZ due to cell resistance. PMID:25111384

Fukai, Junya; Koizumi, Fumiaki; Nakao, Naoyuki

2014-01-01

258

Enhanced anti-tumor effect of zoledronic acid combined with temozolomide against human malignant glioma cell expressing O6-methylguanine DNA methyltransferase.  

PubMed

Temozolomide (TMZ), a DNA methylating agent, is widely used in the adjuvant treatment of malignant gliomas. O6-methylguanine-DNA methyltranferase (MGMT), a DNA repair enzyme, is frequently discussed as the main factor that limits the efficacy of TMZ. Zoledronic acid (ZOL), which is clinically applied to treat cancer-induced bone diseases, appears to possess direct anti-tumor activity through apoptosis induction by inhibiting mevalonate pathway and prenylation of intracellular small G proteins. In this study, we evaluated whether ZOL can be effectively used as an adjuvant to TMZ in human malignant glioma cells that express MGMT. Malignant glioma cell lines, in which the expression of MGMT was detected, did not exhibit growth inhibition by TMZ even at a longer exposure. However, combination experiment of TMZ plus ZOL revealed that a supra-additive effect resulted in a significant decrease in cell growth. In combined TMZ/ZOL treatment, an increased apoptotic rate was apparent and significant activation of caspase-3 and cleavage of poly-(ADP-ribose) polymerase were observed compared with each single drug exposure. There were decreased amounts of Ras-GTP, MAPK and Akt phosphorylation and MGMT expression in the ZOL-treated cells. Subcutanous xenograft models showed significant decrease of tumor growth with combined TMZ/ZOL treatment. These results suggest that ZOL efficaciously inhibits activity of Ras in malignant glioma cells and potentiates TMZ-mediated cytotoxicity, inducing growth inhibition and apoptosis of malignant glioma cells that express MGMT and resistant to TMZ. Based on this work, combination of TMZ with ZOL might be a potential therapy in malignant gliomas that receive less therapeutic effects of TMZ due to cell resistance. PMID:25111384

Fukai, Junya; Koizumi, Fumiaki; Nakao, Naoyuki

2014-01-01

259

Human monoclonal antibody detects a cell surface antigen expressed on hematopoietic malignant cells of lymphoid lineage.  

PubMed

An antigen with a molecular weight of 150 kilodaltons expressed on certain leukemia and lymphoma cells was recognized by a human monoclonal antibody (3H12), which had been established by the fusion of lymphocytes from a small cell lung cancer patient with a mouse myeloma cell line (P3U1). Peripheral blood mononuclear cells from 3 out of 4 cases with lymphoid crisis of chronic myelogenous leukemia (CML) were positively stained by 3H12, while cells from 5 cases with myeloid crisis of CML did not react to this antibody. The antibody did not show any reactivity to cells from the chronic phase of CML, other types of leukemias or normal hematopoietic cells. We further examined 29 cell lines of hematopoietic origin and found that 2 undifferentiated cells (BV-173 and K-562) reacted to the 3H12 antibody. In addition, we found that 3 out of 6 Burkitt lymphoma cells (DAUDI, RAJI and HR1K) reacted to 3H12. Taken together, these results suggest that the antigen recognized by 3H12 is a differentiation-associated antigen expressed on immature lymphoid cells, and could potentially be a reliable cell lineage marker. PMID:1900825

Iizasa, T; Yamaguchi, Y; Tagawa, M; Fujisawa, T; Saito, H; Kondo, H; Matsuo, Y; Minowada, J; Taniguchi, M

1991-02-01

260

Wnt interaction and extracellular release of prominin-1/CD133 in human malignant melanoma cells.  

PubMed

Prominin-1 (CD133) is the first identified gene of a novel class of pentaspan membrane glycoproteins. It is expressed by various epithelial and non-epithelial cells, and notably by stem and cancer stem cells. In non-cancerous cells such as neuro-epithelial and hematopoietic stem cells, prominin-1 is selectively concentrated in plasma membrane protrusions, and released into the extracellular milieu in association with small vesicles. Previously, we demonstrated that prominin-1 contributes to melanoma cells pro-metastatic properties and suggested that it may constitute a molecular target to prevent prominin-1-expressing melanomas from colonizing and growing in lymph nodes and distant organs. Here, we report that three distinct pools of prominin-1 co-exist in cultures of human FEMX-I metastatic melanoma. Morphologically, in addition to the plasma membrane localization, prominin-1 is found within the intracellular compartments, (e.g., Golgi apparatus) and in association with extracellular membrane vesicles. The latter prominin-1-positive structures appeared in three sizes (small, ?40 nm; intermediates ~40-80 nm, and large, >80 nm). Functionally, the down-regulation of prominin-1 in FEMX-I cells resulted in a significant reduction of number of lipid droplets as observed by coherent anti-Stokes Raman scattering image analysis and Oil red O staining, and surprisingly in a decrease in the nuclear localization of beta-catenin, a surrogate marker of Wnt activation. Moreover, the T-cell factor/lymphoid enhancer factor (TCF/LEF) promoter activity was 2 to 4 times higher in parental than in prominin-1-knockdown cells. Collectively, our results point to Wnt signaling and/or release of prominin-1-containing membrane vesicles as mediators of the pro-metastatic activity of prominin-1 in FEMX-I melanoma. PMID:23318676

Rappa, Germana; Mercapide, Javier; Anzanello, Fabio; Le, Thuc T; Johlfs, Mary G; Fiscus, Ronald R; Wilsch-Bräuninger, Michaela; Corbeil, Denis; Lorico, Aurelio

2013-04-01

261

Vascular changes in a human malignant melanoma xenograft following single-dose irradiation.  

PubMed

The effects of single-dose irradiation (5.0-25.0 Gy) on the vascular structure, i.e., the vascular network architecture, of a human melanoma grown in athymic nude mice were studied. The vessels were filled with a radio-opaque medium administered via the abdominal aorta of the mice. X-ray images obtained from 720-micron thick tumor sections provided qualitative information on the vascular structure. Vessel length, surface, and volume per unit tumor volume for vessels with diameters in the ranges 5-15, 15-25, 25-35, 35-45, and greater than 45 micron were obtained by stereological analysis on 2-micron thick tumor sections. A considerable fraction of the vessels was severely damaged after irradiation. Manifestation of the damage as a reduction in the number of functional vessels appeared mainly 0.5-1.5 weeks after irradiation. About 35-45% of the original vessels with diameters in the range 5-15 micron was found to be nonfunctional 1 week after doses of 10.0-15.0 Gy while vessels with larger diameters required doses above 15.0 Gy to become nonfunctional 1 week after exposure. Loss of 50% of the functional vessels with diameters in the ranges 5-15, 15-25, and 25-35 micron was found to require doses of about 16, 21, and 20 Gy, respectively. In spite of a considerable early loss of functional vessels, tumors exposed to 20.0 and 25.0 Gy eventually became supervascularized after irradiation due to extensive radiation-induced tumor shrinkage. Regrowth of irradiated tumors appeared to be preceded by neovascularization, and regrowing tumors could even be better vascularized than unirradiated ones, probably as a result of efficient neovascularization. PMID:6718687

Solesvik, O V; Rofstad, E K; Brustad, T

1984-04-01

262

Wnt Interaction and extracellular release of prominin-1/CD133 in human malignant melanoma cells  

PubMed Central

Prominin-1 (CD133) is the first identified gene of a novel class of pentaspan membrane glycoproteins. It is expressed by various epithelial and non-epithelial cells, and notably by stem and cancer stem cells. In non-cancerous cells such as neuro-epithelial and hematopoietic stem cells, prominin-1 is selectively concentrated in plasma membrane protrusions, and released into the extracellular milieu in association with small vesicles. Previously, we demonstrated that prominin-1 contributes to melanoma cells pro-metastatic properties and suggested that it may constitute a molecular target to prevent prominin-1-expressing melanomas from colonizing and growing in lymph nodes and distant organs. Here, we report that three distinct pools of prominin-1 co-exist in cultures of human FEMX-I metastatic melanoma. Morphologically, in addition to the plasma membrane localization, prominin-1 is found within the intracellular compartments, (e.g., Golgi apparatus) and in association with extracellular membrane vesicles. The latter prominin-1–positive structures appeared in three sizes (small, ? 40 nm; intermediates ~40–80 nm, and large, >80 nm). Functionally, the down-regulation of prominin-1 in FEMX-I cells resulted in a significant reduction of number of lipid droplets as observed by coherent anti-Stokes Raman scattering image analysis and Oil red O staining, and surprisingly in a decrease in the nuclear localization of beta-catenin, a surrogate marker of Wnt activation. Moreover, the T-cell factor/lymphoid enhancer factor (TCF/LEF) promoter activity was 2 to 4 times higher in parental than in prominin-1-knockdown cells. Collectively, our results point to Wnt signaling and/or release of prominin-1–containing membrane vesicles as mediators of the pro-metastatic activity of prominin-1 in FEMX-I melanoma. PMID:23318676

Rappa, Germana; Mercapide, Javier; Anzanello, Fabio; Le, Thuc T.; G, Mary; Johlfs, Ronald R. Fiscus; Wilsch-Bräuninger, Michaela; Corbeil, Denis; Lorico, Aurelio

2013-01-01

263

Uncovering the role of p53 splice variants in human malignancy: a clinical perspective  

PubMed Central

Thirty-five years of research on p53 gave rise to more than 68,000 articles and reviews, but did not allow the uncovering of all the mysteries that this major tumor suppressor holds. How p53 handles the different signals to decide the appropriate cell fate in response to a stress and its implication in tumorigenesis and cancer progression remains unclear. Nevertheless, the uncovering of p53 isoforms has opened new perspectives in the cancer research field. Indeed, the human TP53 gene encodes not only one but at least twelve p53 protein isoforms, which are produced in normal tissues through alternative initiation of translation, usage of alternative promoters, and alternative splicing. In recent years, it became obvious that the different p53 isoforms play an important role in regulating cell fate in response to different stresses in normal cells by differentially regulating gene expression. In cancer cells, abnormal expression of p53 isoforms contributes actively to cancer formation and progression, regardless of TP53 mutation status. They can also be associated with response to treatment, depending on the cell context. The determination of p53 isoform expression and p53 mutation status helps to define different subtypes within a particular cancer type, which would have different responses to treatment. Thus, the understanding of the regulation of p53 isoform expression and their biological activities in relation to the cellular context would constitute an important step toward the improvement of the diagnostic, prognostic, and predictive values of p53 in cancer treatment. This review aims to summarize the involvement of p53 isoforms in cancer and to highlight novel potential therapeutic targets. PMID:24379683

Surget, Sylvanie; Khoury, Marie P; Bourdon, Jean-Christophe

2014-01-01

264

Uncovering the role of p53 splice variants in human malignancy: a clinical perspective.  

PubMed

Thirty-five years of research on p53 gave rise to more than 68,000 articles and reviews, but did not allow the uncovering of all the mysteries that this major tumor suppressor holds. How p53 handles the different signals to decide the appropriate cell fate in response to a stress and its implication in tumorigenesis and cancer progression remains unclear. Nevertheless, the uncovering of p53 isoforms has opened new perspectives in the cancer research field. Indeed, the human TP53 gene encodes not only one but at least twelve p53 protein isoforms, which are produced in normal tissues through alternative initiation of translation, usage of alternative promoters, and alternative splicing. In recent years, it became obvious that the different p53 isoforms play an important role in regulating cell fate in response to different stresses in normal cells by differentially regulating gene expression. In cancer cells, abnormal expression of p53 isoforms contributes actively to cancer formation and progression, regardless of TP53 mutation status. They can also be associated with response to treatment, depending on the cell context. The determination of p53 isoform expression and p53 mutation status helps to define different subtypes within a particular cancer type, which would have different responses to treatment. Thus, the understanding of the regulation of p53 isoform expression and their biological activities in relation to the cellular context would constitute an important step toward the improvement of the diagnostic, prognostic, and predictive values of p53 in cancer treatment. This review aims to summarize the involvement of p53 isoforms in cancer and to highlight novel potential therapeutic targets. PMID:24379683

Surget, Sylvanie; Khoury, Marie P; Bourdon, Jean-Christophe

2013-01-01

265

TPX2 in malignantly transformed human bronchial epithelial cells by anti-benzo[ a]pyrene-7,8-diol-9,10-epoxide  

Microsoft Academic Search

In order to elucidate the function of the targeting protein for Xenopus kinesin-like protein 2 (Xklp2) (TPX2) in the malignant transformation of human bronchial epithelial cells induced by anti-benzo[a]pyrene-trans-7, 8-dihydrodiol-9, 10-epoxide (anti-BPDE), TPX2 was characterized in cells at both the gene and the protein levels. TPX2 was present at higher levels in 16HBE-C cells than in 16HBE cells as demonstrated

Lijuan Zhang; He Huang; Luyao Deng; Ming Chu; Lan Xu; Juanling Fu; Yunlan Zhu; Xiuchun Zhang; Shulin Liu; Zongcan Zhou; Yuedan Wang

2008-01-01

266

Identification of a cDNA Encoding a Parathyroid Hormone-Like Peptide from a Human Tumor Associated with Humoral Hypercalcemia of Malignancy  

Microsoft Academic Search

Humoral hypercalcemia of malignancy is a common paraneoplastic syndrome that appears to be mediated in many instances by a parathyroid hormone-like peptide. Poly(A)+ RNA from a human renal carcinoma associated with this syndrome was enriched by preparative electrophoresis and used to construct an enriched cDNA library in phage lambda gt10. The library was screened with a codon-preference oligonucleotide synthesized on

Marguerite Mangin; Andrew C. Webb; Barbara E. Dreyer; James T. Posillico; Kyoji Ikeda; Eleanor C. Weir; Andrew F. Stewart; Neil H. Bander; Leonard Milstone; David E. Barton; Uta Francke; Arthur E. Broadus

1988-01-01

267

Loss of Caspase8 Expression in Highly Malignant Human Neuroblastoma Cells Correlates with Resistance to Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis1  

Microsoft Academic Search

Human neuroblastoma (NB) is a highly heterogeneous childhood can- cer that is aggressively malignant or can undergo spontaneous regression that may involve apoptosis. NB-derived cell lines were tested for their sensitivity to apoptosis induced by the tumor-selective ligand tumor ne- crosis factor-related apoptosis-inducing ligand (TRAIL). Noninvasive S- type cell lines (NB cell lines of substrate adherent phenotype) are highly sensitive

Sally Hopkins-Donaldson; Jean-Luc Bodmer; Katia Balmas Bourloud; Christine Beretta Brognara; Jurg Tschopp; Nicole Gross

2000-01-01

268

Mesenchymal Stem Cells Modified with a Single-Chain Antibody against EGFRvIII Successfully Inhibit the Growth of Human Xenograft Malignant Glioma  

Microsoft Academic Search

BackgroundGlioblastoma multiforme is the most lethal brain tumor with limited therapeutic options. Antigens expressed on the surface of malignant cells are potential targets for antibody-mediated gene\\/drug delivery.Principal FindingsIn this study, we investigated the ability of genetically modified human mesenchymal stem cells (hMSCs) expressing a single-chain antibody (scFv) on their surface against a tumor specific antigen, EGFRvIII, to enhance the therapy

Irina V. Balyasnikova; Sherise D. Ferguson; Sadhak Sengupta; Yu Han; Maciej S. Lesniak; Karen S. Aboody

2010-01-01

269

Wnt interaction and extracellular release of prominin-1/CD133 in human malignant melanoma cells  

SciTech Connect

Prominin-1 (CD133) is the first identified gene of a novel class of pentaspan membrane glycoproteins. It is expressed by various epithelial and non-epithelial cells, and notably by stem and cancer stem cells. In non-cancerous cells such as neuro-epithelial and hematopoietic stem cells, prominin-1 is selectively concentrated in plasma membrane protrusions, and released into the extracellular milieu in association with small vesicles. Previously, we demonstrated that prominin-1 contributes to melanoma cells pro-metastatic properties and suggested that it may constitute a molecular target to prevent prominin-1-expressing melanomas from colonizing and growing in lymph nodes and distant organs. Here, we report that three distinct pools of prominin-1 co-exist in cultures of human FEMX-I metastatic melanoma. Morphologically, in addition to the plasma membrane localization, prominin-1 is found within the intracellular compartments, (e.g., Golgi apparatus) and in association with extracellular membrane vesicles. The latter prominin-1–positive structures appeared in three sizes (small, ?40 nm; intermediates ?40–80 nm, and large, >80 nm). Functionally, the down-regulation of prominin-1 in FEMX-I cells resulted in a significant reduction of number of lipid droplets as observed by coherent anti-Stokes Raman scattering image analysis and Oil red O staining, and surprisingly in a decrease in the nuclear localization of beta-catenin, a surrogate marker of Wnt activation. Moreover, the T-cell factor/lymphoid enhancer factor (TCF/LEF) promoter activity was 2 to 4 times higher in parental than in prominin-1-knockdown cells. Collectively, our results point to Wnt signaling and/or release of prominin-1–containing membrane vesicles as mediators of the pro-metastatic activity of prominin-1 in FEMX-I melanoma. - Highlights: ? First report of release of prominin-1–containing microvesicles from cancer cells. ? Pro-metastatic role of prominin-1–containing microvesicles in FEMX-I melanoma. ? Down-regulation of prominin-1 results in decreased nuclear localization of ?-catenin. ? Wnt signaling as mediator of the pro-metastatic activity of prominin-1.

Rappa, Germana [Cancer Research Program, Roseman University of Health Sciences, 10530 Discovery Drive. Las Vegas, NV 89135 (United States); College of Pharmacy, Roseman University of Health Sciences, Henderson, NV 89104 (United States); Mercapide, Javier; Anzanello, Fabio [Cancer Research Program, Roseman University of Health Sciences, 10530 Discovery Drive. Las Vegas, NV 89135 (United States); Le, Thuc T. [Nevada Cancer Institute, Las Vegas, NV 89135 (United States); Johlfs, Mary G. [Cancer Research Program, Roseman University of Health Sciences, 10530 Discovery Drive. Las Vegas, NV 89135 (United States); Center for Diabetes and Obesity Prevention, Treatment, Research and Education, Roseman University of Health Sciences, Henderson, NV 89104 (United States); Fiscus, Ronald R. [Cancer Research Program, Roseman University of Health Sciences, 10530 Discovery Drive. Las Vegas, NV 89135 (United States); College of Pharmacy, Roseman University of Health Sciences, Henderson, NV 89104 (United States); Center for Diabetes and Obesity Prevention, Treatment, Research and Education, Roseman University of Health Sciences, Henderson, NV 89104 (United States); Wilsch-Bräuninger, Michaela [Max-Planck-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01307 Dresden (Germany); Corbeil, Denis [Tissue Engineering Laboratories (BIOTEC) and DFG Research Center and Cluster of Excellence for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Tatzberg 47–49, 01307 Dresden, Germany Technische Universitat Dresden, Dresden (Germany); Lorico, Aurelio, E-mail: alorico@roseman.edu [Cancer Research Program, Roseman University of Health Sciences, 10530 Discovery Drive. Las Vegas, NV 89135 (United States); College of Pharmacy, Roseman University of Health Sciences, Henderson, NV 89104 (United States)

2013-04-01

270

A Gene Expression Model of Intrinsic Tumor Radiosensitivity: Prediction of Response and Prognosis After Chemoradiation  

SciTech Connect

Purpose: Development of a radiosensitivity predictive assay is a central goal of radiation oncology. We reasoned a gene expression model could be developed to predict intrinsic radiosensitivity and treatment response in patients. Methods and Materials: Radiosensitivity (determined by survival fraction at 2 Gy) was modeled as a function of gene expression, tissue of origin, ras status (mut/wt), and p53 status (mut/wt) in 48 human cancer cell lines. Ten genes were identified and used to build a rank-based linear regression algorithm to predict an intrinsic radiosensitivity index (RSI, high index = radioresistance). This model was applied to three independent cohorts treated with concurrent chemoradiation: head-and-neck cancer (HNC, n = 92); rectal cancer (n = 14); and esophageal cancer (n = 12). Results: Predicted RSI was significantly different in responders (R) vs. nonresponders (NR) in the rectal (RSI R vs. NR 0.32 vs. 0.46, p = 0.03), esophageal (RSI R vs. NR 0.37 vs. 0.50, p = 0.05) and combined rectal/esophageal (RSI R vs. NR 0.34 vs. 0.48, p = 0.001511) cohorts. Using a threshold RSI of 0.46, the model has a sensitivity of 80%, specificity of 82%, and positive predictive value of 86%. Finally, we evaluated the model as a prognostic marker in HNC. There was an improved 2-year locoregional control (LRC) in the predicted radiosensitive group (2-year LRC 86% vs. 61%, p = 0.05). Conclusions: We validate a robust multigene expression model of intrinsic tumor radiosensitivity in three independent cohorts totaling 118 patients. To our knowledge, this is the first time that a systems biology-based radiosensitivity model is validated in multiple independent clinical datasets.

Eschrich, Steven A. [H Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States); Pramana, Jimmy [Netherlands Cancer Institute, Amsterdam (Netherlands); Zhang Hongling; Zhao Haiyan; Boulware, David; Lee, Ji-Hyun; Bloom, Gregory [H Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States); Rocha-Lima, Caio [Department of Medicine, University of Miami, Miami, FL (United States); Kelley, Scott; Calvin, Douglas P.; Yeatman, Timothy J. [H Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States); Begg, Adrian C. [Netherlands Cancer Institute, Amsterdam (Netherlands); Torres-Roca, Javier F. [H Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States)], E-mail: Javier.Torresroca@moffitt.org

2009-10-01

271

Malignant hyperthermia  

PubMed Central

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stresses such as vigorous exercise and heat. The incidence of MH reactions ranges from 1:5,000 to 1:50,000–100,000 anesthesias. However, the prevalence of the genetic abnormalities may be as great as one in 3,000 individuals. MH affects humans, certain pig breeds, dogs, horses, and probably other animals. The classic signs of MH include hyperthermia to marked degree, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. The syndrome is likely to be fatal if untreated. Early recognition of the signs of MH, specifically elevation of end-expired carbon dioxide, provides the clinical diagnostic clues. In humans the syndrome is inherited in autosomal dominant pattern, while in pigs in autosomal recessive. The pathophysiologic changes of MH are due to uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation. Due to ATP depletion, the muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 90 mutations have been identified in the RYR-1 gene located on chromosome 19q13.1, and at least 25 are causal for MH. Diagnostic testing relies on assessing the in vitro contracture response of biopsied muscle to halothane, caffeine, and other drugs. Elucidation of the genetic changes has led to the introduction, on a limited basis so far, of genetic testing for susceptibility to MH. As the sensitivity of genetic testing increases, molecular genetics will be used for identifying those at risk with greater frequency. Dantrolene sodium is a specific antagonist of the pathophysiologic changes of MH and should be available wherever general anesthesia is administered. Thanks to the dramatic progress in understanding the clinical manifestation and pathophysiology of the syndrome, the mortality from MH has dropped from over 80% thirty years ago to less than 5%. PMID:17456235

Rosenberg, Henry; Davis, Mark; James, Danielle; Pollock, Neil; Stowell, Kathryn

2007-01-01

272

Malignant hypertension  

MedlinePLUS

... for malignant hypertension if you have had: Kidney failure Renal hypertension caused by renal artery stenosis ... An eye examination will reveal changes that indicate high blood ... failure, as well as other complications, may develop. Tests ...

273

Survivin knockdown increased anti-cancer effects of (-)-epigallocatechin-3-gallate in human malignant neuroblastoma SK-N-BE2 and SH-SY5Y cells  

SciTech Connect

Neuroblastoma is a solid tumor that mostly occurs in children. Malignant neuroblastomas have poor prognosis because conventional chemotherapeutic agents are hardly effective. Survivin, which is highly expressed in some malignant neuroblastomas, plays a significant role in inhibiting differentiation and apoptosis and promoting cell proliferation, invasion, and angiogenesis. We examined consequences of survivin knockdown by survivin short hairpin RNA (shRNA) plasmid and then treatment with (-)-epigallocatechin-3-gallate (EGCG), a green tea flavonoid, in malignant neuroblastoma cells. Our Western blotting and laser scanning confocal immunofluorescence microscopy showed that survivin was highly expressed in malignant neuroblastoma SK-N-BE2 and SH-SY5Y cell lines and slightly in SK-N-DZ cell line. Expression of survivin was very faint in malignant neuroblastoma IMR32 cell line. We transfected SK-N-BE2 and SH-SY-5Y cells with survivin shRNA, treated with EGCG, and confirmed knockdown of survivin at mRNA and protein levels. Survivin knockdown induced morphological features of neuronal differentiation, as we observed following in situ methylene blue staining. Combination of survivin shRNA and EGCG promoted neuronal differentiation biochemically by increases in the expression of NFP, NSE, and e-cadherin and also decreases in the expression of Notch-1, ID2, hTERT, and PCNA. Our in situ Wright staining and Annexin V-FITC/PI staining showed that combination therapy was highly effective in inducing, respectively, morphological and biochemical features of apoptosis. Apoptosis occurred with activation of caspase-8 and cleavage of Bid to tBid, increase in Bax:Bcl-2 ratio, mitochondrial release of cytochrome c, and increases in the expression and activity of calpain and caspase-3. Combination therapy decreased migration of cells through matrigel and inhibited proliferative (p-Akt and NF-{kappa}B), invasive (MMP-2 and MMP-9), and angiogenic (VEGF and b-FGF) factors. Also, in vitro network formation ability of cells was significantly inhibited by survivin silencing and completely by combination of survivin silencing and EGCG treatment. Collectively, survivin silencing potentiated anti-cancer effects of EGCG in human malignant neuroblastoma cells having survivin overexpression. -- Highlights: Black-Right-Pointing-Pointer Survivin shRNA + EGCG controlled growth of human malignant neuroblastoma cells. Black-Right-Pointing-Pointer Survivin knockdown induced neuronal differentiation in neuroblastoma cells. Black-Right-Pointing-Pointer Survivin shRNA + EGCG induced morphological and biochemical features of apoptosis. Black-Right-Pointing-Pointer Combination therapy inhibited invasion, proliferation, and angiogenesis as well. Black-Right-Pointing-Pointer So, combination therapy showed multiple anti-cancer mechanisms in neuroblastoma.

Hossain, Md. Motarab [Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC (United States)] [Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC (United States); Banik, Naren L. [Department of Neurosciences, Medical University of South Carolina, Charleston, SC (United States)] [Department of Neurosciences, Medical University of South Carolina, Charleston, SC (United States); Ray, Swapan K., E-mail: swapan.ray@uscmed.sc.edu [Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC (United States)

2012-08-01

274

Systemic Therapy of Malignant Human Melanoma Tumors by a Common Cold-Producing Enterovirus, Coxsackievirus A21  

Microsoft Academic Search

Purpose: The incidence of malignant melanoma contin- ues to increase worldwide; however, treatment of metastatic melanoma remains unsatisfactory, and there is an urgent need for development of effective targeted therapeutics. A potential biological target on the surface of malignant mel- anoma cells is the up-regulated expression of intercellular adhesion molecule (ICAM)-1 and decay-accelerating factor (DAF), relative to surrounding benign tissue.

Darren R. Shafren; Gough G. Au; Tam Nguyen; Nicole G. Newcombe; Erin S. Haley; Leone Beagley; E. Susanne Johansson; Peter Hersey; Richard D. Barry

2004-01-01

275

Silencing SATB1 inhibits the malignant phenotype and increases sensitivity of human osteosarcoma U2OS cells to arsenic trioxide.  

PubMed

In a previous study, we found that the global genome organizer Special AT-rich binding protein 1 (SATB1) is highly expressed in mesenchymal-derived human osteosarcoma U2OS cells and that the knock-down of SATB1 results in the inhibition of cell proliferation. The present study was aimed at investigating the effect of silencing SATB1 on cell migration, invasion, apoptosis and resistance to the chemotherapeutic drug arsenic trioxide. Cell migration and invasion were detected by wound-healing assays and trans-well invasion assays, respectively. Cell apoptosis was analyzed by an in situ Cell Death Detection POD Kit, based on terminal deoxynucleotydyl transferase mediated dUTP nick-end labeling (TUNEL) staining and mRNAs were analyzed by real time qRT-PCR. We found that cell migration and invasion were inhibited and that the proportion of apoptotic cells and sensitivities to the chemotherapeutic drug arsenic trioxide were enhanced by knockdown of SATB1 in U2OS cells. Furthermore, mRNA of ABCC1 and ABCG2 were decreased strikingly after SATB1 silencing. It was concluded that the elevated expression of SATB1 in U2OS cells contributes to maintenance of the malignant phenotype and resistance to chemotherapeutic drugs ATO, suggesting that silencing SATB1 in the cells might improve the effects of arsenic trioxides in the treatment of osteosarcoma in which SATB1 is over-expressed and that ABCC1 and ABCG2 were involved in SATB1 mediated resistance of U2OS cells to ATO. PMID:25317073

Zhang, Haiying; Su, Xuejin; Guo, Li; Zhong, Lingzhi; Li, Wenxue; Yue, Zhen; Wang, Xiaotong; Mu, Yan; Li, Xinna; Li, Ronggui; Wang, Zonggui

2014-01-01

276

Interleukin-1 receptor antagonist (IL1RN) is associated with suppression of early carcinogenic events in human oral malignancies.  

PubMed

Inflammatory abnormalities have been implicated in the pathogenesis of various human diseases, including cancer. Interleukin-1 receptor antagonist (IL1RN) is a potent anti-inflammatory molecule that modulates the biological activity of the proinflammatory cytokine, interleukin-1. The aim of this study was to examine the expression of IL1RN in oral squamous cell carcinomas (OSCCs), and to determine its clinical significance. Expression levels of IL1RN in matched normal and tumor specimens from 39 OSCCs were evaluated using real-time quantitative polymerase chain reaction methods, and immunohistochemical analysis. Protein expression of IL1RN was also examined in 18 oral premalignant lesions (OPLs). Expression of IL1RN mRNA was significantly downregulated in OSCCs compared with normal tissues. Decreased expression of IL1RN protein was also observed in OPLs and OSCCs. The IL1RN expression level was lower in the OPL cases with severe dysplasia compared to those with mild/moderate dysplasia. Significantly downregulated IL1RN expression was observed in all OSCC lesion sites examined when compared with the matched normal tissues. However, the decreased level of IL1RN expression did not correspond with tumor progression. Noteworthy, IL1RN expression was higher in the advanced OSCC cases (T3/T4) compared to early cases (T1/T2). Among OSCC samples, relatively higher IL1RN expression was associated with active tumor development in the OSCCs occurring in the buccal mucosa, oral floor, fauces and gingiva, but not the tongue. These data suggest that IL1RN may exhibit opposing characteristics in oral malignancies depending on the stage of cancer development, suppressing early carcinogenic events, yet promoting tumor development in some lesion sites. Thus, IL1RN could represent a reliable biomarker for the early diagnosis of OSCCs. Furthermore, IL1RN may possess unknown and complex functions in the developed OSCC. PMID:25738940

Shiiba, Masashi; Saito, Kengo; Yamagami, Hitomi; Nakashima, Dai; Higo, Morihiro; Kasamatsu, Atsushi; Sakamoto, Yosuke; Ogawara, Katsunori; Uzawa, Katsuhiro; Takiguchi, Yuichi; Tanzawa, Hideki

2015-05-01

277

Effects of simultaneous knockdown of HER2 and PTK6 on malignancy and tumor progression in human breast cancer cells.  

PubMed

Breast cancer is the most common malignancy in women of the Western world. One prominent feature of breast cancer is the co- and overexpression of HER2 and protein tyrosine kinase 6 (PTK6). According to the current clinical cancer therapy guidelines, HER2-overexpressing tumors are routinely treated with trastuzumab, a humanized monoclonal antibody targeting HER2. Approximately, 30% of HER2-overexpressing breast tumors at least initially respond to the anti-HER2 therapy, but a subgroup of these tumors develops resistance shortly after the administration of trastuzumab. A PTK6-targeted therapy does not yet exist. Here, we show for the first time that the simultaneous knockdown in vitro, compared with the single knockdown of HER2 and PTK6, in particular in the trastuzumab-resistant JIMT-1 cells, leads to a significantly decreased phosphorylation of crucial signaling proteins: mitogen-activated protein kinase 1/3 (MAPK 1/3, ERK 1/2) and p38 MAPK, and (phosphatase and tensin homologue deleted on chromosome ten) PTEN that are involved in tumorigenesis. In addition, dual knockdown strongly reduced the migration and invasion of the JIMT-1 cells. Moreover, the downregulation of HER2 and PTK6 led to an induction of p27, and the dual knockdown significantly diminished cell proliferation in JIMT-1 and T47D cells. In vivo experiments showed significantly reduced levels of tumor growth following HER2 or PTK6 knockdown. Our results indicate a novel strategy also for the treatment of trastuzumab resistance in tumors. Thus, the inhibition of these two signaling proteins may lead to a more effective control of breast cancer. PMID:23364537

Ludyga, Natalie; Anastasov, Natasa; Rosemann, Michael; Seiler, Jana; Lohmann, Nadine; Braselmann, Herbert; Mengele, Karin; Schmitt, Manfred; Höfler, Heinz; Aubele, Michaela

2013-04-01

278

Silencing SATB1 Inhibits the Malignant Phenotype and Increases Sensitivity of Human Osteosarcoma U2OS Cells to Arsenic Trioxide  

PubMed Central

In a previous study, we found that the global genome organizer Special AT-rich binding protein 1 (SATB1) is highly expressed in mesenchymal-derived human osteosarcoma U2OS cells and that the knock-down of SATB1 results in the inhibition of cell proliferation. The present study was aimed at investigating the effect of silencing SATB1 on cell migration, invasion, apoptosis and resistance to the chemotherapeutic drug arsenic trioxide. Cell migration and invasion were detected by wound-healing assays and trans-well invasion assays, respectively. Cell apoptosis was analyzed by an in situ Cell Death Detection POD Kit, based on terminal deoxynucleotydyl transferase mediated dUTP nick-end labeling (TUNEL) staining and mRNAs were analyzed by real time qRT-PCR. We found that cell migration and invasion were inhibited and that the proportion of apoptotic cells and sensitivities to the chemotherapeutic drug arsenic trioxide were enhanced by knockdown of SATB1 in U2OS cells. Furthermore, mRNA of ABCC1 and ABCG2 were decreased strikingly after SATB1 silencing. It was concluded that the elevated expression of SATB1 in U2OS cells contributes to maintenance of the malignant phenotype and resistance to chemotherapeutic drugs ATO, suggesting that silencing SATB1 in the cells might improve the effects of arsenic trioxides in the treatment of osteosarcoma in which SATB1 is over-expressed and that ABCC1 and ABCG2 were involved in SATB1 mediated resistance of U2OS cells to ATO. PMID:25317073

Zhang, Haiying; Su, Xuejin; Guo, Li; Zhong, Lingzhi; Li, Wenxue; Yue, Zhen; Wang, Xiaotong; Mu, Yan; Li, Xinna; Li, Ronggui; Wang, Zonggui

2014-01-01

279

Decrease in S-adenosylmethionine synthesis by 6-mercaptopurine and methylmercaptopurine ribonucleoside in Molt F4 human malignant lymphoblasts.  

PubMed Central

6-Mercaptopurine (6-MP) and methylmercaptopurine ribonucleoside (Me-MPR) are purine anti-metabolites which are both metabolized to methylthio-IMP (Me-tIMP), a strong inhibitor of purine synthesis de novo. Me-MPR is converted directly into Me-tIMP by adenosine kinase. 6-MP is converted into tIMP, and thereafter it is methylated to Me-tIMP by thiopurine methyltransferase, an S-adenosylmethionine (S-Ado-Met)-dependent conversion. S-Ado-Met is formed from methionine and ATP by methionine adenosyltransferase, and is a universal methyl donor, involved in methylation of several macromolecules, e.g. DNA and RNA. Therefore, depletion of S-Ado-Met could result in an altered methylation state of these macromolecules, thereby affecting their functionality, leading to dysregulation of cellular processes and cytotoxicity. In this study the effects of 6-MP and Me-MPR on S-Ado-Met, S-adenosylhomocysteine (S-Ado-Hcy), homocysteine and methionine concentrations are determined. Both drugs cause a decrease in intracellular S-Ado-Met concentrations and an increase in S-Ado-Hcy and methionine concentrations in Molt F4 human malignant lymphoblasts. The effects of both 6-MP and Me-MPR can be ascribed to a decreased conversion of methionine into S-Ado-Met, due to the ATP depletion induced by the inhibition of purine synthesis de novo by Me-tIMP. Both 6-MP and Me-MPR thus affect the methylation state of the cells, and this may result in dysregulation of cellular processes and may be an additional mechanism of cytotoxicity for 6-MP and Me-MPR. PMID:7998928

Stet, E H; De Abreu, R A; Bökkerink, J P; Blom, H J; Lambooy, L H; Vogels-Mentink, T M; de Graaf-Hess, A C; van Raay-Selten, B; Trijbels, F J

1994-01-01

280

Alterations of Cellular Redox State During NNK-Induced Malignant Transformation and Resistance to Radiation  

PubMed Central

Cancer cells often exhibit increased reactive oxygen species generation and altered redox regulation. The current study was conducted to investigate the biochemical and molecular events associated with redox alterations during chemical-induced malignant transformation and to evaluate their potential roles in radiation sensitivity. Immortalized nonmalignant human bronchial epithelial cells were exposed to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and a clone of cells exhibiting malignant behaviors was isolated and characterized. This clone initially exhibited an increase in cellular superoxide that eventually decreased after a long-term culture in vitro, associated with altered expression of antioxidant molecules, including an increase in thioredoxin-1 and manganese superoxide dismutase, and a decrease in glutathione peroxidase-1. These cells also showed a significant decrease in sensitivity to ionizing radiation, as demonstrated by less cell death in acute apoptosis analyses and long-term cell proliferation assays. Using biochemical redox modulation and siRNA approach, we showed that the increase in thioredoxin-1 played a significant role in conferring resistance to IR. Although there was a substantial increase in cellular glutathione, inhibition of glutathione synthesis did not increase IR sensitivity. Our study showed complex redox alterations during NNK-induced malignant transformation, and identified Trx-1 as a radiosensitivity modulator. PMID:18257743

Demizu, Yusuke; Sasaki, Ryohei; Trachootham, Dunyaporn; Pelicano, Helene; Colacino, Justin A; Liu, Jinsong; Huang, Peng

2009-01-01

281

Human IgG responses to macrocyclic chelating agents (DOTA and TETA) in patients with B-lymphocytic malignancies  

SciTech Connect

Several metallic radionuclides have promise for immunoimaging and therapy. Macrocyclic chelating agents provide stable radioimmunoconjugates but have been reported to be immunogenic. The purpose of this study was to assess human antibody responses to macrocycles in 18 patients that were imaged and/or treated with In-111-21T-BAD-Lym-1 (5 patients) or Cu-67-21T-BAT-Lym-1 (13 patients) for B-lymphocytic malignancies. Lym-1 ranged from 1 to 6 doses (median 1) and from 6 to 285 mg (median 33) for each of the patients. A solid phase ELISA utilizing HSA-BAD, HSA-BAT, HSA-BABE or Lym-1 as the coating antigen was used to characterize and quantitate human antibodies in patient serum against DOTA, TETA, 21T or Lym-1, respectively. No patient that received In-111-21T-BAD-Lym-1 developed antibodies of any kind. Two (15%) of the 13 patients that received Cu-67-21T-BAT-Lym-1 developed antibodies against both TETA and Lym-1, and one additional patient developed antibodies against Lym-1 only. None of the patients had symptoms of serum sickness. The maximum number of doses of metal chelated Lym-1 without an immune response was 6. The smallest amount of TETA macrocycle that induced an anti-TETA response was 400 ug; the greatest amount of TETA that did not induce an anti-TETA response was 1,156 ug. The smallest amount of Lym-1 that induced a HAMA was 39 mg; the greatest amount of Lym-1 that did not induce a HAMA response was 285 mg. The relative amounts of anti-TETA to anti-Lym-1 were 1:30 and 1:95 in the two patients that developed both antibodies. None of the patients developed antibodies to the 2IT linker. Using different antibodies in patients with ovarian cancer, others have reported a high frequency of anti-macrocycle antibodies to DOTA. Although macrocycles such as DOTA and TETA can be haptens, our findings do not support the conclusion that they are more immunogenic than other radiometal chelating agents.

DeNardo, G.L.; Mirick, G.R.; Kroger, L.A. [Univ. of California-Davis, Sacramento, CA (United States)] [and others

1995-05-01

282

Prediction of the Number of Activated Genes in Multiple Independent Cd+2- and As+3-Induced Malignant Transformations of Human Urothelial Cells (UROtsa)  

PubMed Central

Background Many toxic environmental agents such as cadmium and arsenic are found to be epidemiologically linked to increasing rates of cancers. In vitro studies show that these toxic agents induced malignant transformation in human cells. It is not clear whether such malignant transformation induced by a single toxic agent is driven by a common set of genes. Although the advancement of high-throughput technology has facilitated the profiling of global gene expression, it remains a question whether the sample size is sufficient to identify this common driver gene set. Results We have developed a statistical method, SOFLR, to predict the number of common activated genes using a limited number of microarray samples. We conducted two case studies, cadmium and arsenic transformed human urothelial cells. Our method is able to precisely predict the number of stably induced and repressed genes and the number of samples to identify the common activated genes. The number of independent transformed isolates required for identifying the common activated genes is also estimated. The simulation study further validated our method and identified the important parameters in this analysis. Conclusions Our method predicts the degree of similarity and diversity during cell malignant transformation by a single toxic agent. The results of our case studies imply the existence of common driver and passenger gene sets in toxin-induced transformation. Using a pilot study with small sample size, this method also helps microarray experimental design by determining the number of samples required to identify the common activated gene set. PMID:24465620

Garrett, Scott H.; Somji, Seema; Sens, Donald A.; Zhang, Ke K.

2014-01-01

283

Long-term low-dose ?-particle enhanced the potential of malignant transformation in human bronchial epithelial cells through MAPK/Akt pathway.  

PubMed

Since the wide usage of ionizing radiation, the cancer risk of low dose radiation (LDR) (<0.1 Gy) has become attractive for a long time. However, most results are derived from epidemiologic studies on atomic-bomb survivors and nuclear accidents surrounding population, and the molecular mechanism of this risk is elusive. To explore the potential of a long-term LDR-induced malignant transformation, human bronchial epithelial cells Beas-2B were fractionally irradiated with 0.025 Gy ?-particles for 8 times in total and then further cultured for 1-2 months. It was found that the cell proliferation, the abilities of adhesion and invasion, and the protein expressions of p-ERK, p-Akt, especially p-P38 were not only increased in the multiply-irradiated cells but also in their offspring 1-2 months after the final exposure, indicating high potentiality of cell malignant transformation. On opposite, the expressions of p-JNK and p-P66 were diminished in the subcultures of irradiated cells and thus may play a role of negative regulation in canceration. When the cells were transferred with p38 siRNA, the LDR-induced enhancements of cell adhesion and invasion were significantly reduced. These findings suggest that long-term LDR of ?-particles could enhance the potential of malignant transformation incidence in human bronchial epithelial cells through MAPK/Akt pathway. PMID:24746471

Liu, Weili; Xiao, Linlin; Dong, Chen; He, Mingyuan; Pan, Yan; Xie, Yuexia; Tu, Wenzhi; Fu, Jiamei; Shao, Chunlin

2014-05-01

284

Effect of Paris saponin I on radiosensitivity in a gefitinib-resistant lung adenocarcinoma cell line  

PubMed Central

Previous studies have observed that Paris saponin I (PSI) exerts a wide range of pharmacological activities, including cytotoxic activity against a number of malignancies, such as non-small cell lung cancers. The present study aimed to investigate the radiosensitization of PSI treatment on a gefitinib-resistant lung adenocarcinoma cell line, PC-9-ZD, and its possible mechanism. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay was used to determine the growth inhibition effect of PSI. A clonogenic assay was performed to determine the radiosensitizing effect of PSI treatment on the PC-9-ZD cell line. A single-hit multi-target model was used to plot survival curves and calculate sensitizing enhancement ratios. The cell cycle was analyzed by flow cytometry and cell apoptosis was analyzed with fluorescein-isothiocyanate-Annexin V/propidium iodide and Hoechst staining. The expression levels of the proteins were detected by western blotting. There was a significant reduction observed in the proliferation of the PC-9-ZD cell lines that were treated with PSI. PSI enhanced the radiosensitivity of the PC-9-ZD cells with a sensitization enhancement ratio of 1.77. Furthermore, PSI induced G2/M arrest and apoptosis of the irradiated PC-9-ZD cells. Notably, B-cell lymphoma 2 (Bcl-2) was downregulated, and caspase-3, Bcl-2-like protein 4 (Bax) and cyclin-dependent kinase inhibitor 1 (P21waf1/cip1) were upregulated by the PSI treatment. The present study showed that PSI treatment exhibited potent radiosensitivity against gefitinib-resistant PC-9-ZD cells in vitro. This radiosensitivity was associated with cell cycle arrest at the G2/M phase, and apoptosis via an increase in caspase-3, Bax and P21waf1/cip1 as well as a decrease in Bcl-2 production. PMID:24932289

JIANG, HAO; ZHAO, PENGJUN; FENG, JIANGUO; SU, DAN; MA, SHENGLIN

2014-01-01

285

Aberrant cytokeratin expression during arsenic-induced acquired malignant phenotype in human HaCaT keratinocytes consistent with epidermal carcinogenesis.  

PubMed

Inorganic arsenic is a known human skin carcinogen. Chronic arsenic exposure results in various human skin lesions, including hyperkeratosis and squamous cell carcinoma (SCC), both characterized by distorted cytokeratin (CK) production. Prior work shows the human skin keratinocyte HaCaT cell line, when exposed chronically for >25 weeks to a low level of inorganic arsenite (100nM) results in cells able to produce aggressive SCC upon inoculation into nude mice. In the present study, CK expression analysis was performed in arsenic-exposed HaCaT cells during the progressive acquisition of this malignant phenotype (0-20 weeks) to further validate this model as relevant to epidermal carcinogenesis induced by arsenic in humans. Indeed, we observed clear evidence of acquired cancer phenotype by 20 weeks of arsenite exposure including the formation of giant cells, a >4-fold increase in colony formation in soft agar and a approximately 2.5-fold increase in matrix metalloproteinase-9 secretion, an enzyme often secreted by cancer cells to help invade through the local extra-cellular matrix. During this acquired malignant phenotype, various CK genes showed markedly altered expression at the transcript and protein levels in a time-dependent manner. For example, CK1, a marker of hyperkeratosis, increased up to 34-fold during arsenic-induced transformation, while CK13, a marker for dermal cancer progression, increased up to 45-fold. The stem cell marker, CK15, increased up to 7-fold, particularly during the later stages of arsenic exposure, indicating a potential emergence of cancer stem-like cells with arsenic-induced acquired malignant phenotype. The expression of involucrin and loricrin, markers for keratinocyte differentiation, increased up to 9-fold. Thus, during arsenic-induced acquired cancer phenotype in human keratinocytes, dramatic and dynamic alterations in CK expression occur which are consistent with the process of epidermal carcinogenesis helping validate this as an appropriate model for the study of arsenic-induced skin cancer. PMID:19524636

Sun, Yang; Pi, Jingbo; Wang, Xueqian; Tokar, Erik J; Liu, Jie; Waalkes, Michael P

2009-08-01

286

Aberrant Cytokeratin Expression During Arsenic-induced Acquired Malignant Phenotype in Human HaCaT Keratinocytes Consistent with Epidermal Carcinogenesis  

PubMed Central

Inorganic arsenic is a known human skin carcinogen. Chronic arsenic exposure results in various human skin lesions, including hyperkeratosis and squamous cell carcinoma (SCC), both characterized by distorted cytokeratin (CK) production. Prior work shows the human skin keratinocyte HaCaT cell line, when exposed chronically for >25 weeks to a low level of inorganic arsenite (100 nM) results in cells able to produce aggressive SCC upon inoculation into nude mice. In the present study, CK expression analysis was performed in arsenic-exposed HaCaT cells during the progressive acquisition of this malignant phenotype (0 to 20 weeks) to further validate this model as relevant to epidermal carcinogenesis induced by arsenic in humans. Indeed, we observed clear evidence of acquired cancer phenotype by 20 weeks of arsenite exposure including the formation of giant cells, a >4-fold increase in colony formation in soft agar and a ?2.5-fold increase in matrix metalloproteinase-9 secretion, an enzyme often secreted by cancer cells to help invade through the local extra-cellular matrix. During this acquired malignant phenotype, various CK genes showed markedly altered expression at the transcript and protein levels in a time-dependent manner. For example, CK1, a marker of hyperkeratosis, increased up to 34-fold during arsenic-induced transformation, while CK13, a marker for dermal cancer progression, increased up to 45-fold. The stem cell marker, CK15, increased up to 7-fold, particularly during the later stages of arsenic exposure, indicating a potential emergence of cancer stem-like cells with arsenic-induced acquired malignant phenotype. The expression of involucrin and loricrin, markers for keratinocyte differentiation, increased up to 9-fold. Thus, during arsenic-induced acquired cancer phenotype in human keratinocytes, dramatic and dynamic alterations in CK expression occur which are consistent with the process of epidermal carcinogenesis helping validate this as an appropriate model for the study of arsenic-induced skin cancer. PMID:19524636

Sun, Yang; Pi, Jingbo; Wang, Xueqian; Tokar, Erik J.; Liu, Jie; Waalkes, Michael P.

2009-01-01

287

Augmented antitumor effect of combined human natural interferon-alpha and mismatched double-stranded RNA treatment against a human malignant melanoma xenograft.  

PubMed

The antitumor effect of combined natural human interferon-alpha (IFN) and mismatched double-stranded RNA (dsRNA) treatment against the human malignant melanoma cell line, BRO, was studied. In vitro results, using a tissue culture antiproliferative assay, indicated that these cells were moderately sensitive to IFN-alpha. In contrast, mismatched dsRNA had no antitumor effect, and a minimal stimulation of cell growth, over part of the concentration range tested, was observed. Mismatched dsRNA did not potentiate the antitumor effect of IFN-alpha in cells receiving combination treatment. Xenografts of BRO cells, inoculated subcutaneously into nude mice, were used to evaluate the antitumor effects of IFN-alpha and mismatched dsRNA. Growth of the primary tumor was inhibited by both drugs alone or in combination (p less than 0.001), but the combined treatment was most effective and appeared to be additive. The number of spontaneous lung metastases was also inhibited (p less than 0.02) in all treatment groups. Survival, however, was significantly increased only in the IFN-alpha/mismatched dsRNA group (p less than 0.02 compared to controls, p less than 0.05 compared to mismatched dsRNA alone). Determination of splenic natural killer (NK) cell activity against BRO cells demonstrated that significantly augmented NK activity to the same extent, but that the IFN-alpha alone had no effect. These results indicate that IFN-alpha worked through direct antiproliferative mechanisms while mismatched dsRNA stimulated host immunomodulatory effects. The increased tumor growth inhibition and survival in the dual treatment group appears to result from the combined direct antiproliferative and indirect immunomodulatory effects. PMID:3681346

Hubbell, H R; Pequignot, E C; Todd, J; Raymond, L C; Mayberry, S D; Carter, W A; Strayer, D R

1987-10-01

288

V?set and transmembrane domain?containing 1 is silenced in human hematopoietic malignancy cell lines with promoter methylation and has inhibitory effects on cell growth.  

PubMed

Numerous leukocyte differentiation antigens act as important markers for research, diagnosis, triage and eventually treatment targets for hematopoietic malignancies. V?set and transmembrane domain?containing 1 (VSTM1) was identified by immunogenomic analysis as a potential leukocyte differentiation antigen gene. VSTM1 is located at 19q13.4 on human chromosomes, an important genomic region prone to genetic and epigenetic modifications in numerous hematopoietic malignancies. VSTM1?v1, a primary splicing form encoded by VSTM1, is a type I transmembrane molecule with an extracellular immunoglobulin V?like domain and two cytoplasmic immunoreceptor tyrosine-based inhibitory motifs. In the present study, VSTM1 expression was examined in normal human peripheral leukocytes and hematopoietic tumor cell lines; in addition, the aberrant methylation of the VSTM1 gene was evaluated using methylation?specific polymerase chain reaction (MSP). The results of the present study demonstrated that VSTM1 was widely expressed in normal human peripheral blood leukocytes, including granulocytes and monocytes, in concurrence with previous studies, as well as lymphocytes; in addition, the molecular size and expression levels of VSTM1 varied considerably between leukocytes. However, VSTM1 was undetectable in numerous hematopoietic tumor cell lines following promoter hypermethylation. The effects of pharmacologically?induced demethylation of the VSTM1 gene and promoter region were analyzed using MSP and biosulfite genomic sequencing, and the results revealed that VSTM1 expression was restored in methylation?silenced Jurkat cells. In addition, CKK?8 assays revealed that VSTM1?v1 overexpression in Jurkat cells resulted in growth suppression. Furthermore, the inhibitory effect on cell growth was enhanced following antibody?induced cross?linking of VSTM1?v1. In conclusion, the results of the present study indicated that promoter methylation silenced VSTM1 and negatively regulated cell growth in human hematopoietic malignancy cell lines. PMID:25351446

Li, Ting; Guo, Xiaohuan; Wang, Wenyan; Mo, Xiaoning; Wang, Pingzhang; Han, Wenling

2015-02-01

289

Novel ZnO:Ag nanocomposites induce significant oxidative stress in human fibroblast malignant melanoma (Ht144) cells  

PubMed Central

Summary The use of photoactive nanoparticles (NPs) such as zinc oxide (ZnO) and its nanocomposites has become a promising anticancer strategy. However, ZnO has a low photocatalytic decomposition rate and the incorporation of metal ions such as silver (Ag) improves their activity. Here different formulations of ZnO:Ag (1, 3, 5, 10, 20 and 30% Ag) were synthesized by a simple co-precipitation method and characterized by powder X-ray diffraction, scanning electron microscopy, Rutherford back scattering and diffuse reflectance spectroscopy for their structure, morphology, composition and optical band gap. The NPs were investigated with regard to their different photocatalytic cytotoxic effects in human malignant melanoma (HT144) and normal (HCEC) cells. The ZnO:Ag nanocomposites killed cancer cells more efficiently than normal cells under daylight exposure. Nanocomposites having higher Ag content (10, 20 and 30%) were more toxic compared to low Ag content (1, 3 and 5%). For HT144, under daylight exposure, the IC50 values were ZnO:Ag (10%): 23.37 ?g/mL, ZnO:Ag (20%): 19.95 ?g/mL, and ZnO:Ag (30%): 15.78 ?g/mL. ZnO:Ag (30%) was toxic to HT144 (IC50: 23.34 ?g/mL) in dark as well. The three nanocomposites were further analyzed with regard to their ability to generate reactive oxygen species (ROS) and induce lipid peroxidation. The particles led to an increase in levels of ROS at cytotoxic concentrations, but only HT144 showed strongly induced MDA level. Finally, NPs were investigated for the ROS species they generated in vitro. A highly significant increase of 1O2 in the samples exposed to daylight was observed. Hydroxyl radical species, HO•, were also generated to a lesser extent. Thus, the incorporation of Ag into ZnO NPs significantly improves their photo-oxidation capabilities. ZnO:Ag nanocomposites could provide a new therapeutic option to selectively target cancer cells.

Arooj, Syeda; Nazir, Samina; Nadhman, Akhtar; Ahmad, Nafees; Muhammad, Bakhtiar; Ahmad, Ishaq; Mazhar, Kehkashan

2015-01-01

290

Hematologic malignancies  

SciTech Connect

The principle aim of this book is to give practical guidelines to the modern treatment of the six important hematologic malignancies. Topics considered include the treatment of the chronic leukemias; acute leukemia in adults; the myeloproliferative disorders: polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis/agnogenic myeloid metaplasia; Hodgkin's Disease; non-Hodgkin's lymphoma; and Multiple Myeloma.

Hoogstraten, B.

1986-01-01

291

In vivo tracing of indium-111 oxine-labeled human peripheral blood mononuclear cells in patients with lymphatic malignancies  

SciTech Connect

The in vivo migration of (/sup 111/In)oxine-labeled peripheral mononuclear cells (PMNC) was studied in 20 patients with various lymphatic malignancies and palpable enlarged lymph nodes. The maximal labeling dose of 10 microCi (0.37 MBq) (/sup 111/In)oxine/10(8) PMNC was found not to adversely influence either cell viability or lymphocyte proliferation in vitro. For in vivo studies, 1.5 X 10(9) PMNC were gained by lymphapheresis and reinjected intravenously after radioactive labeling, 150 microCi (5.55 MBq). The labeling of enlarged palpable lymph nodes was achieved in three out of three patients with Hodgkin's disease and in five out of five with high-malignant lymphoma, whereas three out of seven patients with low malignant lymphoma and no patient with chronic lymphatic leukemia had positive lymph node imaging. We thus conclude that PMNC retain their ability to migrate after (/sup 111/In)oxine labeling and that these cells traffic to involved lymph nodes of some, but not all hematologic malignancies.

Mueller, C.Z.; Zielinski, C.C.; Linkesch, W.; Ludwig, H.; Sinzinger, H.

1989-06-01

292

Factors associated with radiosensitivity of cervical cancer.  

PubMed

Radiation therapy plays a critical role in women with advanced-stage cervical cancer worldwide, particularly in developing countries, and most of the time it may be the only available treatment. The efficacy of radiation largely depends on the radiosensitivity of the tumor. The high radiation dose associated with therapy for cervical cancer may have severe side-effects and low-dose radiation has little effect on cervical cancer. A safe and effective radiosensitizing agent is required to allow reduction of radiation doses used and of side-effects associated with radiation for cervical cancer. In recent years, great knowledge has been gained about the effects of apoptosis, cyclo-oxygenases, angiogenesis, hypoxia and temperature on radiation, making it possible to manipulate the radiation response of cervical cancer to achieve a better treatment outcome. In this mini review, some of these factors associated with the radiosensitivity of cervical cancer are discussed. PMID:25202040

Qin, Chenglu; Chen, Xuhui; Bai, Qian; Davis, Matthew R; Fang, Yujiang

2014-09-01

293

ROS-dependent prostate apoptosis response-4 (Par-4) up-regulation and ceramide generation are the prime signaling events associated with curcumin-induced autophagic cell death in human malignant glioma  

PubMed Central

Malignant gliomas are extremely resistant to therapies that induce apoptosis, but are less resistant to therapies that induce autophagy. Therefore, drugs targeting autophagy are promising in the management of malignant gliomas. In this study, we investigated the anti-glioma potential of curcumin in vitro, and further examined the molecular mechanisms of curcumin-induced cell death in human malignant glioma. Here, we provide evidence that curcumin is cytotoxic against human malignant glioma cell lines, and the mechanism of cell death caused by curcumin is associated with features of autophagy. Curcumin suppresses the growth of human malignant glioma cells via ROS-dependent prostate apoptosis response-4 (Par-4) induction and ceramide generation. Extracellular supplementation of antioxidants such as glutathione and N-acetylcysteine to glioma cells abrogated the Par-4 induction, ceramide generation, and in turn, prevented curcumin-induced autophagic cell death. Moreover, tumor cells transfected with Par-4 gene sensitized the curcumin-induced autophagic cell death. Overall, this study describes a novel signaling pathway by which curcumin induces ROS-dependent Par-4 activation and ceramide generation, leading to autophagic cell death in human malignant glioma cells. PMID:25349781

Thayyullathil, Faisal; Rahman, Anees; Pallichankandy, Siraj; Patel, Mahendra; Galadari, Sehamuddin

2014-01-01

294

Tumor radiosensitization by monomethyl auristatin e: mechanism of action and targeted delivery.  

PubMed

Intrinsic tumor resistance to radiotherapy limits the efficacy of ionizing radiation (IR). Sensitizing cancer cells specifically to IR would improve tumor control and decrease normal tissue toxicity. The development of tumor-targeting technologies allows for developing potent radiosensitizing drugs. We hypothesized that the anti-tubulin agent monomethyl auristatin E (MMAE), a component of a clinically approved antibody-directed conjugate, could function as a potent radiosensitizer and be selectively delivered to tumors using an activatable cell-penetrating peptide targeting matrix metalloproteinases and RGD-binding integrins (ACPP-cRGD-MMAE). We evaluated the ability of MMAE to radiosensitize both established cancer cells and a low-passage cultured human pancreatic tumor cell line using clonogenic and DNA damage assays. MMAE sensitized colorectal and pancreatic cancer cells to IR in a schedule- and dose-dependent manner, correlating with mitotic arrest. Radiosensitization was evidenced by decreased clonogenic survival and increased DNA double-strand breaks in irradiated cells treated with MMAE. MMAE in combination with IR resulted in increased DNA damage signaling and activation of CHK1. To test a therapeutic strategy of MMAE and IR, PANC-1 or HCT-116 murine tumor xenografts were treated with nontargeted free MMAE or tumor-targeted MMAE (ACPP-cRGD-MMAE). While free MMAE in combination with IR resulted in tumor growth delay, tumor-targeted ACPP-cRGD-MMAE with IR produced a more robust and significantly prolonged tumor regression in xenograft models. Our studies identify MMAE as a potent radiosensitizer. Importantly, MMAE radiosensitization can be localized to tumors by targeted activatable cell-penetrating peptides. Cancer Res; 75(7); 1376-87. ©2015 AACR. PMID:25681274

Buckel, Lisa; Savariar, Elamprakash N; Crisp, Jessica L; Jones, Karra A; Hicks, Angel M; Scanderbeg, Daniel J; Nguyen, Quyen T; Sicklick, Jason K; Lowy, Andrew M; Tsien, Roger Y; Advani, Sunil J

2015-04-01

295

Phenethyl isothiocyanate triggers apoptosis in human malignant melanoma A375.S2 cells through reactive oxygen species and the mitochondria-dependent pathways.  

PubMed

We have reported previously that phenethyl isothiocyanate (PEITC) induces apoptosis in human osteosarcoma U-2 OS cells. Cytotoxic activity of PEITC towards other cancer cells such as human malignant melanoma and skin cancer cells has not been reported. In this study, the anticancer activity of PEITC towards human malignant melanoma cancer A375.S2 cells was investigated. To determine the mechanisms of PEITC inhibition of cell growth, the following end points were determined in A375.S2 cells: cell morphological changes, cell cycle arrest, DNA damage and fragmentation assays and morphological assessment of nuclear change, reactive oxygen species (ROS) and Ca(2+) generations, mitochondrial membrane potential disruption, and nitric oxide and 10-N-nonyl acridine orange productions, expression and activation of caspase-3 and -9, B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2, poly (adenosine diphosphate-ribose) polymerase, and cytochrome c release, apoptosis-inducing factor and endonuclease G. PEITC induced morphological changes in time- and dose-dependent manner. PEITC induced G2/M phase arrest and induced apoptosis via endoplasmic reticulum stress-mediated mitochondria-dependent pathway. Western blot analysis showed that PEITC promoted Bax expression and inhibited Bcl-2 expression associated with the disintegration of the outer mitochondrial membrane causing cytochrome c release, and activation of caspase-9 and -3 cascade leading to apoptosis. We conclude that PEITC-triggered apoptotic death in A375.S2 cells occurs through ROS-mediated mitochondria-dependent pathways. PMID:23760257

Huang, S-H; Hsu, M-H; Hsu, S-C; Yang, J-S; Huang, W-W; Huang, A-C; Hsiao, Y-P; Yu, C-C; Chung, J-G

2014-03-01

296

Immunohistochemical evidence for ubiquitous distribution of metalloendoprotease insulin-degrading enzyme (IDE; insulysin) in human non-malignant tissues and tumor cell lines  

PubMed Central

Immunohistochemical evidence for ubiquitous distribution of metalloprotease insulin-degrading enzyme (IDE; insulysin) in human non-malignant tissues and tumor cells is presented. Immunohistochemical staining was performed on a multi-organ tissue microarray (pancreas, lung, kidney, central/peripheral nervous system, liver, breast, placenta, myocardium, striated muscle, bone marrow, thymus, spleen) and on a cell microarray encompassing 31 tumor cell lines of different origin plus trophoblast cells, and normal blood lymphocytes and granulocytes. IDE protein is expressed by all of the tissues assessed and in all of the tumor cell lines except Raji and HL-60; trophoblast cells and granulocytes but not normal lymphocytes are also IDE-positive. PMID:18783335

Weirich, Gregor; Mengele, Karin; Yfanti, Christina; Gkazepis, Apostolos; Hellmann, Daniela; Welk, Anita; Giersig, Cecylia; Kuo, Wen-Liang; Rosner, Marsha Rich; Tang, Wei-Jen; Schmitt, Manfred

2013-01-01

297

The CD133+ tumor stem-like cell-associated antigen may elicit highly intense immune responses against human malignant glioma  

Microsoft Academic Search

To explore the immunogenicity of glioma stem-like cell-associated antigens (SAAs) from sorted or unsorted glioma tumor stem-like\\u000a cells (TSCs) as well as irradiated TSCs. Two primary human malignant glioma lines (SHG62, SHG66) and U87 cell line were primarily\\u000a cultured in the serum-free medium (SFM) supplemented with EGF\\/bFGF. TSCs were identified by their self-renewal, multi-lineage\\u000a differentiation and tumorigenic activity. To prepare

Wei HuaYu; Yu Yao; Yiwei Chu; Ping Zhong; Xiaofang Sheng; Baoguo Xiao; Jingsong Wu; Bojie Yang; Ying Mao; Liangfu Zhou

298

Analysis of ras mutations in human melanocytic lesions: activation of the ras gene seems to be associated with the nodular type of human malignant melanoma  

Microsoft Academic Search

We have analyzed the Ha-ras, Ki-ras and N-ras gene for point mutations at codons 12, 13 and 61 via restriction fragment length polymorphism\\/polymerase chain reaction analysis\\u000a and subsequent direct sequencing in non-cultured fresh-frozen tissues of 16 superficial spreading melanomas (SSM), 13 nodular\\u000a malignant melanomas (NMM), 2 lentigo malignant melanomas (LMM), 1 dysplastic nevus, 1 congenital nevus and 5 normal nevi

Mehrdad Jafari; Thilo Papp; Stephan Kirchner; Ulrike Kiener; Dietrich Henschler; Günter Burg; Dietmar Schiffmann

1995-01-01

299

Downregulation of the expression of B?cell lymphoma?extra large by RNA interference induces apoptosis and enhances the radiosensitivity of non?small cell lung cancer cells.  

PubMed

B?cell lymphoma?extra large (Bcl?xL), an important member of anti?apoptotic Bcl?2 family, is involved in tumor progression and development. The overexpression of Bcl?xL is associated with radioresistance of human malignancies. The present study aimed to investigate the inhibitory effect of small interfering RNA (siRNA) on the expression of Bcl?xL in the A549 non?small lung cancer (NSCLC) cell line, and its role in inducing the apoptosis and increasing the radiosensitivity of A549 cells. An siRNA expression vector, pSilencer4?CMVneo?short hairpin (sh)RNA, was constructed and stably transfected into A549 cells. The effects of Bcl?xL?shRNA on cell proliferation, apoptosis and the protein expression levels of associated proteins were assessed in vitro in the A549 cells. The radiosensitivity of the A549 cells was evaluated using a clonogenic cell survival assay. The results demonstrated that the sequence?specific siRNA targeting Bcl?xL efficiently and specifically downregulated the mRNA and protein expression levels of Bcl?xL. The RNA interference?mediated downregulation in the expression of Bcl?xL inhibited cell proliferation, induced apoptosis and reduced the radioresistance of the NSCLC cells. These findings suggested that Bcl?xL may be a promising therapeutic approach for the treatment of NSCLC. PMID:25683634

Yang, Changbin; Huang, Wei; Yan, Ling; Wang, Yu; Wang, Weili; Liu, Dezhi; Zuo, Xiaojun

2015-07-01

300

Ocular penetration, toxicity, and radiosensitization effects of two hypoxic cell radiosensitizers on retinoblastoma  

SciTech Connect

Two new radiosensitizing drugs, SR-2508 and SR-2555, were studied for their in vivo toxicity and absorption properties. For both drugs, 100 mg dissolved in 0.5 mL of normal saline resulted in the maximum acceptable level of toxicity when injected subconjunctivally in rabbit eyes as determined by ocular and histopathologic changes. SR-2508 showed higher ocular and systemic absorption than SR-2555. The radiosensitizing ability of these drugs was studied using Chinese hamster ovary cells and the retinoblastoma cell line, V79c6. Results of the in vitro radiation experiments indicate that both drugs are comparable with misonidazole in their radiosensitizing ability, with SR-2508 being slightly more effective than SR-2555. Because of their relative high ocular absorption and low toxicity in comparison with misonidazole, these two drugs, particularly SR-2508, may be of clinical value and could be considered for adjunctive use as radiosensitizers of hypoxic tumors such as retinoblastoma.

Rootman, J.; Gallie, B.; Kumi, C.; Bussanich, N.; Rogers, B.; Palcic, B.

1986-11-01

301

Epigenetic alteration by DNA-demethylating treatment restores apoptotic response to glucocorticoids in dexamethasone-resistant human malignant lymphoid cells  

PubMed Central

Background Glucocorticoids (GCs) are often included in the therapy of lymphoid malignancies because they kill several types of malignant lymphoid cells. GCs activate the glucocorticoid receptor (GR), to regulate a complex genetic network, culminating in apoptosis. Normal lymphoblasts and many lymphoid malignancies are sensitive to GC-driven apoptosis. Resistance to GCs can be a significant clinical problem, however, and correlates with resistance to several other major chemotherapeutic agents. Methods We analyzed the effect of treatment with the cytosine analogue 5 aza-2’ deoxycytidine (AZA) on GC resistance in two acute lymphoblastic leukemia (T or pre-T ALL) cell lines- CEM and Molt-4- and a (B-cell) myeloma cell line, RPMI 8226. Methods employed included tissue culture, flow cytometry, and assays for clonogenicity, cytosine extension, immunochemical identification of proteins, and gene transactivation. High throughput DNA sequencing was used to confirm DNA methylation status. Conclusions Treatment of these cells with AZA resulted in altered DNA methylation and restored GC-evoked apoptosis in all 3 cell lines. In CEM cells the altered epigenetic state resulted in site-specific phosphorylation of the GR, increased GR potency, and GC-driven induction of the GR from promoters that lie in CpG islands. In RPMI 8226 cells, expression of relevant coregulators of GR function was altered. Activation of p38 mitogen-activated protein kinase (MAPK), which is central to a feed-forward mechanism of site-specific GR phosphorylation and ultimately, apoptosis, occurred in all 3 cell lines. These data show that in certain malignant hematologic B- and T-cell types, epigenetically controlled GC resistance can be reversed by cell exposure to a compound that causes DNA demethylation. The results encourage studies of application to in vivo systems, looking towards eventual clinical applications. PMID:24795534

2014-01-01

302

Basic Fibroblast Growth Factor Confers a Less Malignant Phenotype in MDA-MB- 231 Human Breast Cancer Cells1  

Microsoft Academic Search

Basic fibroblast growth factor (FGF-2) expression is associated with a more differentiated phenotype, earlier stage of disease, and a better prognosis in breast cancer patients. To determine whether expression of FGF-2 can cause a less malignant phenotype, we engineered MDA-MB- 231 cells, a highly dedifferentiated, invasive breast cancer cell line, to express different isoforms of FGF-2. Cells expressed either cytoplasmic,

Reju M. Korah; Vilayvanh Sysounthone; Yosef Golowa; Robert Wieder

2000-01-01

303

Cadmium Induced Cell Apoptosis, DNA Damage, Decreased DNA Repair Capacity, and Genomic Instability during Malignant Transformation of Human Bronchial Epithelial Cells  

PubMed Central

Cadmium and its compounds are well-known human carcinogens, but the mechanisms underlying the carcinogenesis are not entirely understood. Our study was designed to elucidate the mechanisms of DNA damage in cadmium-induced malignant transformation of human bronchial epithelial cells. We analyzed cell cycle, apoptosis, DNA damage, gene expression, genomic instability, and the sequence of exons in DNA repair genes in several kinds of cells. These cells consisted of untreated control cells, cells in the fifth, 15th, and 35th passage of cadmium-treated cells, and tumorigenic cells from nude mice using flow cytometry, Hoechst 33258 staining, comet assay, quantitative real-time polymerase chain reaction (PCR), Western blot analysis, random amplified polymorphic DNA (RAPD)-PCR, and sequence analysis. We observed a progressive increase in cell population of the G0/G1 phase of the cell cycle and the rate of apoptosis, DNA damage, and cadmium-induced apoptotic morphological changes in cerebral cortical neurons during malignant transformation. Gene expression analysis revealed increased expression of cell proliferation (PCNA), cell cycle (CyclinD1), pro-apoptotic activity (Bax), and DNA damage of the checkpoint genes ATM, ATR, Chk1, Chk2, Cdc25A. Decreased expression of the anti-apoptotic gene Bcl-2 and the DNA repair genes hMSH2, hMLH1, ERCC1, ERCC2, and hOGG1 was observed. RAPD-PCR revealed genomic instability in cadmium-exposed cells, and sequence analysis showed mutation of exons in hMSH2, ERCC1, XRCC1, and hOGG1 in tumorigenic cells. This study suggests that Cadmium can increase cell apoptosis and DNA damage, decrease DNA repair capacity, and cause mutations, and genomic instability leading to malignant transformation. This process could be a viable mechanism for cadmium-induced cancers. PMID:24046522

Zhou, Zhiheng; Wang, Caixia; Liu, Haibai; Huang, Qinhai; Wang, Min; Lei, Yixiong

2013-01-01

304

Sodium ascorbate inhibits growth via the induction of cell cycle arrest and apoptosis in human malignant melanoma A375.S2 cells.  

PubMed

Vitamin C has been reported to be useful in the treatment and prevention of cancer. Inconsistent effects from growth stimulation to induction of apoptosis of malignant tumor cells, however, have been reported. Melanoma is an increasingly common and potentially lethal malignancy. It was reported that melanoma cells were more susceptible to ascorbate toxicity than any other tumor cells. The mechanisms accounting for ascorbate-induced apoptosis in human melanoma cells, however, have remained unclear. This study was undertaken to investigate the effect of sodium ascorbate on cytotoxicity and apoptosis in human malignant melanoma A375.S2 cells. A375.S2 cells were incubated with a certain range of concentrations of sodium ascorbate for various time periods. In order to examine the effects of sodium ascorbate on cell proliferation, cell cycle, apoptosis and necrosis, we performed 4,6-diamidino-2-phenylindole dihydrochloride assays and flow cytometry analysis. Polymerase chain reaction was used to examine the mRNA levels of p53, p21, p27, cyclin A, cyclin E, CDK2 and CDK4, which are associated with cell cycle S-phase arrest and apoptosis. Flow cytometric analysis showed that sodium ascorbate significantly induced cell cycle arrest and apoptosis in the A375.S2 cell line in a dose-dependent manner. The increased expressions of p53 and p21, and the decreased expressions of cyclin A, cyclin E, CDK2 and CDK4, indicated the cell cycle arrest at G1/S phase after the cells had been treated with sodium ascorbate. Induction of apoptosis involved an increase in the levels of p53, p21 and cellular Ca, and a decrease in mitochondrial membrane potential and activation of caspase 3 before culminating in apoptosis in sodium ascorbate-treated A375.S2 cells. PMID:17119452

Lin, Shuw-Yuan; Lai, Wan-Wen; Chou, Chi-Chung; Kuo, Hsiu-Maan; Li, Te-Mao; Chung, Jing-Gung; Yang, Jen-Hung

2006-12-01

305

Differential Radiosensitizing Potential of Temozolomide in MGMT Promoter Methylated Glioblastoma Multiforme Cell Lines  

Microsoft Academic Search

Purpose: To investigate the radiosensitizing potential of temozolomide (TMZ) for human glioblastoma multiforme (GBM) cell lines using single-dose and fractionated -irradiation. Methods and Materials: Three genetically characterized human GBM cell lines (AMC-3046, VU-109, and VU-122) were exposed to various single (0-6 Gy) and daily fractionated doses (2 Gy per fraction) of -irradiation. Repeated TMZ doses were given before and concurrent

Krista A. van Nifterik; Jaap van den Berg; Lukas J. A. Stalpers; M. Vincent M. Lafleur; Sieger Leenstra; Ben J. Slotman; Theo J. M. Hulsebos; Peter Sminia

2007-01-01

306

Effect of Antisense Oligodeoxynucleotides Glucose Transporter-1 on Enhancement of Radiosensitivity of Laryngeal Carcinoma  

PubMed Central

Purpose: Laryngeal carcinomas always resist to radiotherapy. Hypoxia is an important factor in radioresistance of laryngeal carcinoma. Glucose transporter-1 (GLUT-1) is considered to be a possible intrinsic marker of hypoxia in malignant tumors. We speculated that the inhibition of GLUT-1 expression might improve the radiosensitivity of laryngeal carcinoma. Methods: We assessed the effect of GLUT-1 expression on radioresistance of laryngeal carcinoma and the effect of GLUT-1 expressions by antisense oligodeoxynucleotides (AS-ODNs) on the radiosensitivity of laryngeal carcinoma in vitro and in vivo. Results: After transfection of GLUT-1 AS-ODNs: MTS assay showed the survival rates of radiation groups were reduced with the prolongation of culture time (p<0.05); Cell survival rates were significantly reduced along with the increasing of radiation dose (p<0.05). There was significant difference in the expression of GLUT-1mRNA and protein in the same X-ray dose between before and after X-ray radiation (p<0.05). In vivo, the expressions of GLUT-1 mRNA and protein after 8Gy radiation plus transfection of GLUT-1 AS-ODNs were significant decreased compared to 8Gy radiation alone (p<0.001). Conclusion: Radioresistance of laryngeal carcinoma may be associated with increased expression of GLUT-1 mRNA and protein. GLUT-1 AS-ODNs may enhance the radiosensitivity of laryngeal carcinoma mainly by inhibiting the expression of GLUT-1. PMID:23983599

Yan, Sen-Xiang; Luo, Xing-Mei; Zhou, Shui-Hong; Bao, Yang-Yang; Fan, Jun; Lu, Zhong-Jie; Liao, Xin-Biao; Huang, Ya-Ping; Wu, Ting-Ting; Wang, Qin-Ying

2013-01-01

307

Inhibition of human brain malignant glioblastoma cells using carmustine-loaded catanionic solid lipid nanoparticles with surface anti-epithelial growth factor receptor.  

PubMed

Innovated catanionic solid lipid nanoparticles (CASLNs) carrying carmustine (BCNU) (BCNU-CASLNs) were grafted with anti-epithelial growth factor receptor (EGFR) (anti-EGFR/BCNU-CASLNs) and applied to inhibiting the propagation of human brain malignant glioblastomas cells. U87MG cells were treated with anti-EGFR/BCNU-CASLNs and stained for the expression of EGFR. The minimal average diameter of BCNU-CASLNs and maximal entrapment efficiency of BCNU emerged when the concentration of catanionic surfactants was 1 mm. An increase in the weight percentage of cacao butter (CB) reduced the zeta potential, enhanced the viability of human brain microvasscular endothelial cells (HBMECs), and decreased the expression of tumor necrosis factor-? by HBMECs. The dissolution rate of BCNU and inhibition against the multiplication of U87MG cells using anti-EGFR/BCNU-CASLNs followed the order: 100% CB > 0% CB > 50% CB. Anti-EGFR/BCNU-CASLNs demonstrated the properties including an effective delivery to U87MG cells and antiproliferative efficacy against the growth of malignant brain tumors. PMID:21296415

Kuo, Yung-Chih; Liang, Cheng-Te

2011-04-01

308

Exploratory study on the effects of biodegradable nanoparticles with drugs on malignant B cells and on a human/mouse model of Burkitt lymphoma.  

PubMed

The aim of this study was to determine if Rituximab coated Biodegradable Nanoparticles (BNPs) loaded with Chlorambucil and Hydroxychloroquine could induce apoptosis of B-Chronic Lymphocytic Leukemia (B-CLL), MEC-1 and BJAB cells in vitro and evaluate their toxic and therapeutic effects on a Human/Mouse Model of Burkitt Lymphoma at an exploratory, proof of concept scale. We found that Rituximab-Chlorambucil-Hydroxychloroquine BNPs induce a decrease in cell viability of malignant B cells in a dose-dependent manner. The mediated cytotoxicity resulted from apoptosis, and was confirmed by monitoring the B-CLL cells after Annexin V/propidium iodide staining. Additional data revealed that these BNPs were non toxic for healthy animals, and had prolonged survival in this mice model of human lymphoma. PMID:20925646

Marín, Gustavo H; Mansilla, Eduardo; Mezzaroba, Nelly; Zorzet, Sonia; Núñez, Luis; Larsen, Gustavo; Tau, José M; Maceira, Alberto; Spretz, Ruben; Mertz, Carol; Ingrao, Sabrina; Tripodo, Claudio; Tedesco, Francesco; Macor, Paolo

2010-11-01

309

Development of a Preclinical Orthotopic Xenograft Model of Ewing Sarcoma and Other Human Malignant Bone Disease Using Advanced In Vivo Imaging  

PubMed Central

Ewing sarcoma and osteosarcoma represent the two most common primary bone tumours in childhood and adolescence, with bone metastases being the most adverse prognostic factor. In prostate cancer, osseous metastasis poses a major clinical challenge. We developed a preclinical orthotopic model of Ewing sarcoma, reflecting the biology of the tumour-bone interactions in human disease and allowing in vivo monitoring of disease progression, and compared this with models of osteosarcoma and prostate carcinoma. Human tumour cell lines were transplanted into non-obese diabetic/severe combined immunodeficient (NSG) and Rag2?/?/?c?/? mice by intrafemoral injection. For Ewing sarcoma, minimal cell numbers (1000–5000) injected in small volumes were able to induce orthotopic tumour growth. Tumour progression was studied using positron emission tomography, computed tomography, magnetic resonance imaging and bioluminescent imaging. Tumours and their interactions with bones were examined by histology. Each tumour induced bone destruction and outgrowth of extramedullary tumour masses, together with characteristic changes in bone that were well visualised by computed tomography, which correlated with post-mortem histology. Ewing sarcoma and, to a lesser extent, osteosarcoma cells induced prominent reactive new bone formation. Osteosarcoma cells produced osteoid and mineralised “malignant” bone within the tumour mass itself. Injection of prostate carcinoma cells led to osteoclast-driven osteolytic lesions. Bioluminescent imaging of Ewing sarcoma xenografts allowed easy and rapid monitoring of tumour growth and detection of tumour dissemination to lungs, liver and bone. Magnetic resonance imaging proved useful for monitoring soft tissue tumour growth and volume. Positron emission tomography proved to be of limited use in this model. Overall, we have developed an orthotopic in vivo model for Ewing sarcoma and other primary and secondary human bone malignancies, which resemble the human disease. We have shown the utility of small animal bioimaging for tracking disease progression, making this model a useful assay for preclinical drug testing. PMID:24409320

Batey, Michael A.; Almeida, Gilberto S.; Wilson, Ian; Dildey, Petra; Sharma, Abhishek; Blair, Helen; Hide, I. Geoff; Heidenreich, Olaf; Vormoor, Josef; Maxwell, Ross J.; Bacon, Chris M.

2014-01-01

310

Development of a preclinical orthotopic xenograft model of ewing sarcoma and other human malignant bone disease using advanced in vivo imaging.  

PubMed

Ewing sarcoma and osteosarcoma represent the two most common primary bone tumours in childhood and adolescence, with bone metastases being the most adverse prognostic factor. In prostate cancer, osseous metastasis poses a major clinical challenge. We developed a preclinical orthotopic model of Ewing sarcoma, reflecting the biology of the tumour-bone interactions in human disease and allowing in vivo monitoring of disease progression, and compared this with models of osteosarcoma and prostate carcinoma. Human tumour cell lines were transplanted into non-obese diabetic/severe combined immunodeficient (NSG) and Rag2(-/-/)?c(-/-) mice by intrafemoral injection. For Ewing sarcoma, minimal cell numbers (1000-5000) injected in small volumes were able to induce orthotopic tumour growth. Tumour progression was studied using positron emission tomography, computed tomography, magnetic resonance imaging and bioluminescent imaging. Tumours and their interactions with bones were examined by histology. Each tumour induced bone destruction and outgrowth of extramedullary tumour masses, together with characteristic changes in bone that were well visualised by computed tomography, which correlated with post-mortem histology. Ewing sarcoma and, to a lesser extent, osteosarcoma cells induced prominent reactive new bone formation. Osteosarcoma cells produced osteoid and mineralised "malignant" bone within the tumour mass itself. Injection of prostate carcinoma cells led to osteoclast-driven osteolytic lesions. Bioluminescent imaging of Ewing sarcoma xenografts allowed easy and rapid monitoring of tumour growth and detection of tumour dissemination to lungs, liver and bone. Magnetic resonance imaging proved useful for monitoring soft tissue tumour growth and volume. Positron emission tomography proved to be of limited use in this model. Overall, we have developed an orthotopic in vivo model for Ewing sarcoma and other primary and secondary human bone malignancies, which resemble the human disease. We have shown the utility of small animal bioimaging for tracking disease progression, making this model a useful assay for preclinical drug testing. PMID:24409320

Vormoor, Britta; Knizia, Henrike K; Batey, Michael A; Almeida, Gilberto S; Wilson, Ian; Dildey, Petra; Sharma, Abhishek; Blair, Helen; Hide, I Geoff; Heidenreich, Olaf; Vormoor, Josef; Maxwell, Ross J; Bacon, Chris M

2014-01-01

311

The toxic effects, GSH depletion and radiosensitivity by BSO on retinoblastoma  

SciTech Connect

Retinoblastoma is the most common intraocular malignant tumor in children. Previous investigations have reported that buthionine sulfoximine (BSO) can deplete intracellular glutathione (GSH) by specific inhibition and increase cellular radiosensitivity. The toxic effects, GSH depletion and radiosensitivity effects of BSO on retinoblastoma cells are reported in this paper. GSH content of retinoblastoma cell lines Y-79, So-Rb50 and retinoblastoma xenograft is 2.7 [+-] 1.3 X 1.0[sup [minus]12] mmol/cell, 1.4 [+-] 0.2 X 1.0[sup [minus]12] mmol/cell, and 2.8 [+-] 1.2 [mu]mol/g, respectively. The ID[sub 50] of BSO on Y-79 and So-Rb50 in air for 3 h exposure is 2.5 mM and 0.2 mM, respectively. GSH depletion by 0.1 mM BSO for 24 h on Y-79 cells and 0.01 mM BSO for 24 h on So-Rb50 cells is 16.35%, and 4.7% of control. GSH depletion in tumor and other organ tissues in retinoblastoma-bearing nude mice after BSO administration is differential. GSH depletion after BSO exposure in Y-79 cells in vitro decreases the Do value of retinoblastoma cells. The SER of 0.01 mM and 0.05 mM BSO for 24 h under hypoxic conditions is 1.21 and 1.36, respectively. Based on these observations, the authors conclude that BSO toxicity on retinoblastoma cells depends on the characteristics of the cell line and that BSO can increase hypoxic retinoblastoma cells' radiosensitivity in vitro. Further study of BSO radiosensitization on retinoblastoma in vivo using nude mouse xenografts is needed. 25 refs., 3 figs., 3 tabs.

Xianjin Yi; Li Ding; Yizun Jin; Chuo Ni; Wenji Wang (Shanghai Medical Univ., Shanghai (China))

1994-05-15

312

[Malignant pheochromocytoma].  

PubMed

A case of metastatic malignant pheochromocytoma which was operated on is discussed. The benefits derived from the most recent localizing techniques such as CT scan and MIBG scintigraphic scanning are stressed. In the case presented these enabled the adrenal tumor to be detected but also demonstrated the presence of a costal metastasis and two metastases in the axial skeleton. A therapeutic trial with MIBG at doses of 100 mCi per treatment only enabled a survival of a little more than one year to be achieved. PMID:2794545

Pailler, J L; Vicq, P; Jancovici, R; Essoussi, J; Seigneuric, A

1989-01-01

313

Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy  

SciTech Connect

Humoral hypercalcemia of malignancy is a common paraneoplastic syndrome that appears to be mediated in many instances by a parathyroid hormone-like peptide. Poly(A)/sup +/ RNA from a human renal carcinoma associated with this syndrome was enriched by preparative electrophoresis and used to construct an enriched cDNA library in phage lambdagt10. The library was screened with a codon-preference oligonucleotide synthesized on the basis of a partial N-terminal amino acid sequence from a human tumor-derived peptide, and a 2.0 kilo-base cDNA was identified. The cDNA encodes a 177 amino acid protein consisting of a 36 amino acid leader sequence and a 141 amino acid mature peptide. The first 13 amino acids of the deduced sequence of the mature peptide display strong homology to human PTH, with complete divergence thereafter. RNA blot-hybridization analysis revealed multiple transcripts in mRNA from tumors associated with the humor syndrome and also in mRNA from normal human keratinocytes. Southern blot analysis of genomic DNA from humans and rodents revealed a simple pattern compatible with a single-copy gene. The gene has been mapped to chromosome 12.

Mangin, M.; Webb, A.C.; Dreyer, B.E.; Posillico, J.T.; Ikeda, K.; Weir, E.C.; Stewart, A.F.; Bander, N.H.; Milstone, L.; Barton, D.E.

1988-01-01

314

The Origin of Malignant Malaria  

Technology Transfer Automated Retrieval System (TEKTRAN)

Plasmodium falciparum is the causative agent of malignant malaria, which is among the most severe human infectious diseases. Despite its overwhelming significance to human health, the parasite’s origins remain unclear. The favored origin hypothesis holds that P. falciparum and its closest known rel...

315

Malignant hyperthermia  

PubMed Central

Malignant hyperthermia (MH) is an uncommon, life-threatening pharmacogenetic disorder of the skeletal muscle. It presents as a hypermetabolic response in susceptible individuals to potent volatile anesthetics with/without depolarizing muscle relaxants; in rare cases, to stress from exertion or heat stress. Susceptibility to malignant hyperthermia (MHS) is inherited as an autosomally dominant trait with variable expression and incomplete penetrance. It is known that the pathophysiology of MH is related to an uncontrolled rise of myoplasmic calcium, which activates biochemical processes resulting in hypermetabolism of the skeletal muscle. In most cases, defects in the ryanodine receptor are responsible for the functional changes of calcium regulation in MH, and more than 300 mutations have been identified in the RYR1 gene, located on chromosome 19q13.1. The classic signs of MH include increase of end-tidal carbon dioxide, tachycardia, skeletal muscle rigidity, tachycardia, hyperthermia and acidosis. Up to now, muscle contracture test is regarded as the gold standard for the diagnosis of MHS though molecular genetic test is used, on a limited basis so far to diagnose MHS. The mortality of MH is dramatically decreased from 70-80% to less than 5%, due to an introduction of dantrolene sodium for treatment of MH, early detection of MH episode using capnography, and the introduction of diagnostic testing for MHS. This review summarizes the clinically essential and important knowledge of MH, and presents new developments in the field. PMID:23198031

2012-01-01

316

Synergistic anticancer activity of curcumin and bleomycin: an in vitro study using human malignant testicular germ cells.  

PubMed

Testicular cancer is the most common cancer among young men of reproductive age. Bleomycin is a frequently used drug for the treatment of several malignancies and is part of the chemotherapy protocols used for testicular cancer; however, side-effects are common. Bleomycin causes an increase in oxidative stress which has been shown to induce apoptosis in cancer cells. Curcumin (diferuloylmethane), an active component of the spice turmeric, has been demonstrated to induce apoptosis in a number of malignancies. However, to date no study has been carried out to elucidate its anticancer activity and interaction with bleomycin in testicular cancer cells. In this study, we investigated and compared the effects of curcumin, bleomycin and hydrogen peroxide (H2O2) on apoptotic signaling pathways. Curcumin (20 µM), bleomycin (400 µg/ml) and H2O2 (400 µM) incubation for 24 h decreased the viability of NTera-2 cells, and increased caspase-3, -8 and -9 activities, Bax and cytoplasmic cytochrome c levels and decreased Bcl-2 levels. The concurrent use of curcumin with bleomycin induced caspase-3, -8 and -9 activities to a greater extent in NTera-2 cells than the use of each drug alone. Our observations suggest that the effects of curcumin and bleomycin on apoptotic signaling pathways are synergistic. Therefore, we propose to use curcumin together with bleomycin to decrease its therapeutic dose and, therefore, its side-effects. PMID:22469952

Cort, Aysegul; Timur, Mujgan; Ozdemir, Evrim; Kucuksayan, Ertan; Ozben, Tomris

2012-06-01

317

Potential of radiosensitizing agents in cancer chemo-radiotherapy.  

PubMed

Potential of herbs and other plant-based formulations have been increasingly recognized in prevention and treatment of human diseases including cancer. There exist enormous prospect for screening and evaluation of herbal/plant products for developing effective radiosensitization and radioprotection relevant to nuclear research program. Investigations in our laboratory have focused on the mechanism of activity of variety of anticancer and antioxidant agents, namely, Eugenol, (EU), Ellagic acid (EA), Triphala (TPL), Tocopherol Succinate (TOS) and Arachidonic acid on normal and cancer cells with view to design effective protocols in practical radioprotection and cancer radiotherapy. This paper is mainly focused on studies on cytotoxic effects on cancer cell lines. Results have shown that these agents produced radiosensitizing action involving oxidative damage, membrane alteration and damage to nucleic acid in various human cell lines. Studies were performed employing fluorescence probes and electron spin resonance methods and gel electrophoresis protocols. It has been found that cytotoxic effect was induced by initiating membrane oxidative damage and by triggering intracellular generation of reactive oxygen species (ROS) by gamma radiation in combination with phytochemicals like TPL, EA and TOS in tumor cell line Ehrlich Ascites (EAC), Human cervical (HeLa) and breast (MCF-7) cells. Membrane damage and ROS generation was measured by DPH and DCF-FDA fluorescent probes respectively after exposure to low to moderate doses of gamma radiation. This talk will present the cytotoxic effects of phytochemicals in combination with ionizing radiation. It is emphasized that modulation of membrane peroxidative damage and intra cellular ROS may help achieve efficient killing of cancer cells which may provide a new approach to developing effective treatment of cancer. PMID:17998642

Girdhani, S; Bhosle, S M; Thulsidas, S A; Kumar, A; Mishra, K P

2005-01-01

318

Malignancy from Radium  

PubMed Central

Human experience of the toxicity of radium acts as a guide for the setting of occupationally permissible levels for radioactive nucleides, especially bone-seekers. Reviewing the published statements and photomicrographs in early reports especially those of Martland (1931) one can make a case that malignancy was induced in bone-marrow (leukaemia, malignant myelosclerosis) as well as in bone (osteosarcoma) by radium, especially with large doses. Three case reports of radium intoxication in Britons are noted as compatible with this suggestion, after revised interpretation in two of them. ImagesFigs. 9-10Fig. 4Fig. 5Figs. 11-12Figs. 6-7Fig. 8Figs. 13-14 PMID:5271269

Loutit, J. F.

1970-01-01

319

A Mouse Model of Human Primitive Neuroectodermal Tumors Resulting from Microenvironmentally-Driven Malignant Transformation of Orthotopically Transplanted Radial Glial Cells  

PubMed Central

There is growing evidence and a consensus in the field that most pediatric brain tumors originate from stem cells, of which radial glial cells constitute a subtype. Here we show that orthotopic transplantation of human radial glial (RG) cells to the subventricular zone of the 3rd ventricle - but not to other transplantation sites - of the brain in immunocompromised NOD-SCID mice, gives rise to tumors that have the hallmarks of CNS primitive neuroectodermal tumors (PNETs). The resulting mouse model strikingly recapitulates the phenotype of PNETs. Importantly, the observed tumorigenic transformation was accompanied by aspects of an epithelial to mesenchymal transition (EMT)-like process. It is also noteworthy that the tumors are highly invasive, and that they effectively recruit mouse endothelial cells for angiogenesis. These results are significant for several reasons. First, they show that malignant transformation of radial glial cells can occur in the absence of specific mutations or inherited genomic alterations. Second, they demonstrate that the same radial glial cells may either give rise to brain tumors or differentiate normally depending upon the microenvironment of the specific region of the brain to which the cells are transplanted. In addition to providing a prospect for drug screening and development of new therapeutic strategies, the resulting mouse model of PNETs offers an unprecedented opportunity to identify the cancer driving molecular alterations and the microenvironmental factors that are responsible for committing otherwise normal radial glial cells to a malignant phenotype. PMID:25826270

Malchenko, Sergey; Sredni, Simone Treiger; Hashimoto, Hitoshi; Kasai, Atsushi; Nagayasu, Kazuki; Xie, Jianping; Margaryan, Naira V.; Seiriki, Kaoru; Lulla, Rishi R.; Seftor, Richard E. B.; Pachman, Lauren M.; Meltzer, Herbert Y.; Hendrix, Mary J. C.; Soares, Marcelo B.

2015-01-01

320

Artemether combined with shRNA interference of vascular cell adhesion molecule-1 significantly inhibited the malignant biological behavior of human glioma cells.  

PubMed

Artemether is the derivative extracted from Chinese traditional herb and originally used for malaria. Artemether also has potential therapeutic effects against tumors. Vascular cell adhesion molecule-1 (VCAM-1) is an important cell surface adhesion molecule associated with malignancy of gliomas. In this work, we investigated the role and mechanism of artemether combined with shRNA interference of VCAM-1 (shRNA-VCAM-1) on the migration, invasion and apoptosis of glioma cells. U87 human glioma cells were treated with artemether at various concentrations and shRNA interfering technology was employed to silence the expression of VCAM-1. Cell viability, migration, invasiveness and apoptosis were assessed with MTT, wound healing, Transwell and Annexin V-FITC/PI staining. The expression of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and phosphorylated Akt (p-Akt) was checked by Western blot assay. Results showed that artemether and shRNA-VCAM-1 not only significantly inhibited the migration, invasiveness and expression of MMP-2/9 and p-Akt, but also promoted the apoptosis of U87 cells. Combined treatment of both displayed the maximum inhibitory effects on the malignant biological behavior of glioma cells. Our work revealed the potential therapeutic effects of artemether and antiVCAM-1 in the treatments of gliomas. PMID:23593320

Wang, Ying-Bin; Hu, Yi; Li, Zhen; Wang, Ping; Xue, Yi-Xue; Yao, Yi-Long; Yu, Bo; Liu, Yun-Hui

2013-01-01

321

Detection of Epstein-Barr virus and human T-cell lymphotropic virus type 1 in malignant nodal lymphoma, studied in Okinawa, a subtropical area in Japan.  

PubMed

Formalin-fixed paraffin-embedded lymph node samples were collected from 100 cases of malignant nodal lymphoma documented in Okinawa in the period from 1973 through 1998. According to the new World Health Organization classification, 12 cases were Hodgkin's lymphoma (HL). Eighty-eight cases of non-Hodgkin's lymphoma (NHL) included 54 cases of T-cell type and 34 cases of B-cell type. Using polymerase chain reaction (PCR), Epstein-Barr virus (EBV) was detected in 11 cases (91.7%) of HL and in 57 cases (64.8%) of NHL, and human T-cell lymphotropic virus type 1 (HTLV-1) was detected in 23 cases (26.1%) of NHL. Clonal integration of HTLV-1 was detected in 10 (43.5%) of 23 HTLV-1 PCR-positive cases by the inverse PCR technique. The EBV-infected cells were detected by EBER-1 in situ hybridization in 11 (91.7%) of 12 HL cases and in 64 (72.7%) of 88 NHL cases. Irrespective of phenotype and tissue type of the malignant lymphoma, the rate of EBV-positive infection in Okinawa was higher than that in any other districts reported in Japan. This characteristic high rate of EBV-positive infection in Okinawa can be ascribed to various factors, such as racial and geographical differences. PMID:11843296

Miyagi, Jun-ichi; Toda, Takayoshi; Uezato, Hiroshi; Ohshima, Kouichi; Miyakuni, Tsuyoshi; Takasu, Nobuyuki; Masuda, Masato

2002-01-01

322

Absence of IFNA and IFNB genes from human malignant glioma cell lines and lack of correlation with cellular sensitivity to interferons.  

PubMed

We report that 5 of 19 human malignant glioma cell lines have neither interferon alpha (IFNA) nor interferon beta (IFNB) genes that are detectable by Southern blotting. Of 5 other of these malignant glioma lines that have a single IFNB gene copy, 3 lack the IFNA genes entirely and two have one copy. One of the lines that lacks the IFNA genes entirely but has one copy of the IFNB gene has a rearrangement near the IFNB gene that is most easily interpreted as an insertion of a large segment of DNA (at least 50 kilobases) the 3' end of which is less than 1.3 kilobases 5' to the known regulatory sequences of the IFNB gene. In spite of the rearrangement, IFNB-specific RNA is highly inducible in this line by poly(I)-poly(C). The ability of interferon alpha or interferon beta to inhibit cell growth does not depend upon the presence or absence of the respective gene. This finding adds solid tumors to those tumor cell lines (acute lymphocytic leukemia, chronic myelogeneous leukemia) previously determined to lack the IFNA and IFNB genes (Diaz et al., Proc. Natl. Acad. Sci. USA, 85:5259-5263, 1988). PMID:2295067

Miyakoshi, J; Dobler, K D; Allalunis-Turner, J; McKean, J D; Petruk, K; Allen, P B; Aronyk, K N; Weir, B; Huyser-Wierenga, D; Fulton, D

1990-01-15

323

TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages  

PubMed Central

Background Malignant pleural mesothelioma (MPM) is an aggressive malignancy closely associated with asbestos exposure and extremely resistant to current treatments. It exhibits a steady increase in incidence, thus necessitating an urgent development of effective new treatments. Methods Proteasome inhibitors (PIs) and TNF?-Related Apoptosis Inducing Ligand (TRAIL), have emerged as promising new anti-MPM agents. To develop effective new treatments, the proapoptotic effects of PIs, MG132 or Bortezomib, and TRAIL were investigated in MPM cell lines NCI-H2052, NCI-H2452 and NCI-H28, which represent three major histological types of human MPM. Results Treatment with 0.5-1 ?M MG132 alone or 30 ng/mL Bortezomib alone induced a limited apoptosis in MPM cells associated with the elevated Mcl-1 protein level and hyperactive PI3K/Akt signaling. However, whereas 10–20 ng/ml TRAIL alone induced a limited apoptosis as well, TRAIL and PI combination triggered a robust apoptosis in all three MPM cell lines. The robust proapoptotic activity was found to be the consequence of a positive feedback mechanism-governed amplification of caspase activation and cleavage of both Mcl-1 and Akt proteins, and exhibited a relative selectivity in MPM cells than in non-tumorigenic Met-5A mesothelial cells. Conclusion The combinatorial treatment using TRAIL and PI may represent an effective new treatment for MPMs. PMID:23517112

2013-01-01

324

Infectious pathogens and hematologic malignancy.  

PubMed

Infectious pathogens have been linked to the genesis of malignancy in a variety of different settings. Initial studies in virology led to the important discovery of key genetic alterations underlying common malignancies, and further, lent support to the notion that malignancy can be promoted by the process of viral infection and cellular transformation. In this review, we summarize a series of hematologic malignancies with derivations from and associations with infectious organisms. Among these are a variety of lymphomas, including Hodgkin's lymphoma (Hodgkin's disease), Burkitt lymphoma, and a host of other non-Hodgkin's lymphomas. Through innovative and ground-breaking studies, some of these malignancies have been directly linked to viral infection, such as the Epstein-Barr virus (EBV), while others have been merely associated with infection through epidemiologic studies and case-reports. Some malignancies have been demonstrated to be caused by viral infection, such as adult T-cell leukemia and lymphoma (ATLL), which is caused by the human T cell lymphotropic virus type I (HTLV-I), in certain endemic area. In the future, additional malignant states may be found to be associated with infectious etiology, which could allow for novel approaches to prevention and treatment. PMID:23272694

Sadrzadeh, Hossein; Abtahi, Seyed M; Fathi, Amir T

2012-12-01

325

["Malignant" ARDS].  

PubMed

Acute respiratory failure and the "acute respiratory distress syndrome" (ARDS) are frequent medical conditions in critically ill patients. Various causes can potentially result in the development of ARDS. Two cases are presented, in which malignant diseases were identified as causes of the respiratory failure. The first patient was diagnosed with an acute myeloic leukemia M5 (FAB). In the second patient, lung histology revealed an adenocarcinoma of the lung. These case reports show that in addition to the classical causes of ARDS, specific disease entities can mimic this form of respiratory failure. Beside solid cancers and lymphomas, acute and progressive forms of inflammatory, parenchymal lung diseases (such as acute interstitial pneumonitis, acute eosinophilic pneumonia, diffuse alveolar hemorrhagia, and acute hypersensitivity pneumonitis) can manifest with this picture. As a consequence, the diagnostic workup of respiratory failure of unknown cause should include these entities. PMID:19562262

Metzelder, S K; Reinke, C; Walthers, E M; Barth, P; Vogelmeier, C; Neubauer, A; Bals, R

2009-10-01

326

Treatment Options for Malignant Mesothelioma  

MedlinePLUS

... Dictionary Search for Clinical Trials NCI Publications Español Malignant Mesothelioma Treatment (PDQ®) Treatment Options for Malignant Mesothelioma Localized Malignant Mesothelioma (Stage I) If malignant ...

327

The effects of ponatinib, a multi-targeted tyrosine kinase inhibitor, against human U87 malignant glioblastoma cells  

PubMed Central

Glioblastoma is one of the most common malignant tumors in the nervous system in both adult and pediatric patients. Studies suggest that abnormal activation of receptor tyrosine kinases contributes to pathological development of glioblastoma. However, current therapies targeting tyrosine kinase receptors have poor therapeutic outcomes. Here, we examined anticancer effects of ponatinib, a multi-targeted tyrosine kinase inhibitor, on glioblastoma cells both in the U87MG cell line and in the mouse xenograft model. We showed that ponatinib treatment reduced cell viability and induced cell apoptosis in a dose-dependent manner in U87MG cells. In addition, ponatinib suppressed migration and invasion of U87MG cells effectively. Furthermore, ponatinib-treated tumors showed an obvious reduction of tumor volume and an increase of apoptosis as compared with vehicle-treated tumors in the mouse xenograft model. These findings support a potential application of ponatinib as a chemotherapeutic option against glioblastoma cells. PMID:25378936

Zhang, Junxia; Zhou, Qiang; Gao, Ge; Wang, Yanfen; Fang, Zhihui; Li, Guanlin; Yu, Mengfei; Kong, Lingfei; Xing, Ying; Gao, Xiaoqun

2014-01-01

328

The effects of ponatinib, a multi-targeted tyrosine kinase inhibitor, against human U87 malignant glioblastoma cells.  

PubMed

Glioblastoma is one of the most common malignant tumors in the nervous system in both adult and pediatric patients. Studies suggest that abnormal activation of receptor tyrosine kinases contributes to pathological development of glioblastoma. However, current therapies targeting tyrosine kinase receptors have poor therapeutic outcomes. Here, we examined anticancer effects of ponatinib, a multi-targeted tyrosine kinase inhibitor, on glioblastoma cells both in the U87MG cell line and in the mouse xenograft model. We showed that ponatinib treatment reduced cell viability and induced cell apoptosis in a dose-dependent manner in U87MG cells. In addition, ponatinib suppressed migration and invasion of U87MG cells effectively. Furthermore, ponatinib-treated tumors showed an obvious reduction of tumor volume and an increase of apoptosis as compared with vehicle-treated tumors in the mouse xenograft model. These findings support a potential application of ponatinib as a chemotherapeutic option against glioblastoma cells. PMID:25378936

Zhang, Junxia; Zhou, Qiang; Gao, Ge; Wang, Yanfen; Fang, Zhihui; Li, Guanlin; Yu, Mengfei; Kong, Lingfei; Xing, Ying; Gao, Xiaoqun

2014-01-01

329

Down-regulation of GnT-V enhances nasopharyngeal carcinoma cell CNE-2 radiosensitivity in vitro and in vivo  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer First investigated the role of GnT-V on the radiosensitivity of NPC cells in vitro and in vivo. Black-Right-Pointing-Pointer The mechanisms of the changing radiosensitivity were also investigated. Black-Right-Pointing-Pointer In this study, more than one experiment methods were used to investigate a problem. -- Abstract: The purpose of this study was to investigate the role of GnT-V on radiosensitivity in human nasopharyngeal carcinoma (NPC) both in vitro and in vivo, and the possible mechanism. The GnT-V stably suppressed cell line CNE-2 GnT-V/2224 was constructed from CNE-2 by transfection. The radiosensitivity of the cells was studied by CCK-8 assay, flow-cytometry, caspases-3 activity analysis and tumor xenografts model. The expression of Bcl-2, Bax and Bcl-xl was analyzed with or without radiation. The results showed that down-regulation of GnT-V enhanced CNE-2 radiosensitivity. The underlying mechanisms may be link to the cell cycle G2-M arrest and the reduction of Bcl-2/Bax ratio. The results suggest that GnT-V may be a potential target for predicting NPC response to radiotherapy.

Zhuo, Enqing; He, Jiao; Wei, Ting; Zhu, Weiliang; Meng, Hui; Li, Yan [Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou (China)] [Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou (China); Guo, Linlang, E-mail: linlangg@yahoo.com [Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou (China)] [Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou (China); Zhang, Jian, E-mail: 13925091863@139.com [Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou (China)] [Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou (China)

2012-08-03

330

Immunohistochemical evidence of ubiquitous distribution of the metalloendoprotease insulin-degrading enzyme (IDE; insulysin) in human non-malignant tissues and tumor cell lines.  

PubMed

Immunohistochemical evidence of ubiquitous distribution of the metalloprotease insulin-degrading enzyme (IDE; insulysin) in human non-malignant tissues and tumor cells is presented. Immunohistochemical staining was performed on a multi-organ tissue microarray (pancreas, lung, kidney, central/peripheral nervous system, liver, breast, placenta, myocardium, striated muscle, bone marrow, thymus, and spleen) and on a cell microarray of 31 tumor cell lines of different origin, as well as trophoblast cells and normal blood lymphocytes and granulocytes. IDE protein was expressed in all the tissues assessed and all the tumor cell lines except for Raji and HL-60. Trophoblast cells and granulocytes, but not normal lymphocytes, were also IDE-positive. PMID:18783335

Weirich, Gregor; Mengele, Karin; Yfanti, Christina; Gkazepis, Apostolos; Hellmann, Daniela; Welk, Anita; Giersig, Cecylia; Kuo, Wen-Liang; Rosner, Marsha Rich; Tang, Wei-Jen; Schmitt, Manfred

2008-11-01

331

The advent of precision therapy in gastrointestinal malignancies: Targeting the human epidermal growth factor receptor family in colorectal and esophagogastric cancer  

PubMed Central

Until recently, systemic therapy for gastrointestinal malignancies was restricted to relatively noncancer-specific cytotoxic chemotherapy. Over the last 15 years targeted therapies have become available, most notably bevacizumab in the case of advanced colorectal cancer. Unfortunately, there are no predictive biomarkers to guide the use of this agent. In this review article, we describe the advent of “Precision Medicine” (in part, the use of patient-specific molecular markers to inform treatment) in gastrointestinal cancers: The use of monoclonal antibodies targeting epidermal growth factor receptor in advanced colorectal cancer, and human epidermal growth factor receptor 2-neu in advanced esophagogastric cancer. In both instances, biomarkers help in selecting appropriate patients for such treatment. PMID:25525412

Desautels, Danielle; Harlos, Craig; Czaykowski, Piotr

2014-01-01

332

Activity of the Human Blood Group ABO, Se, H, Le, and X Gene-encoded Glycosyltransferases in Normal and Malignant Bladder Urothelium1  

Microsoft Academic Search

Immunohistochemistry has led to the finding of an expression of ABO- related blood group antigens in normal and malignant bladder urothelium which is different from that found on erythrocytes from the same individ ual. This includes a loss of blood group ABO expression in malignant urothelium, and the expression of Leb antigens in normal and malignant cells from individuals with

Torben F. Ã; Hans Wolf; Winifred M. Watkins

333

Isolation and fine mapping of 16 novel human zinc finger-encoding cDNAs identify putative candidate genes for developmental and malignant disorders  

SciTech Connect

The authors have isolated and chromosomally fine-mapped 16 novel genes belonging to the human zinc finger Krueppel family (ZNF131-140, 142, 143, 148, 151, 154, and 155), including 1 of the GLI type (ZNF143) and 3 containing a KRAB (Krueppel-associated box) segment (ZNF133, 136, and 140). Based on their map position, several of these ZNF genes are putative candidate genes for both developmental and malignant disorders: ZNF138, ZNF139, and ZNF143 were localized to 7q11.2, 7q21.3-q22.1, and 11p15.3-p15.4, regions involved in deletions and/or translocations associated with Williams syndrome, split hand and foot disease (SHFD1), and Beckwith-Wiedemann syndrome, respectively. ZNF133 was localized to 20p11.2, close to, but probably distinct from, the region deleted in Alagille syndrome. Zinc finger genes mapping to regions commonly deleted in solid tumors included ZNF132, 134, 135, 137, 154, and 155, all located on 19q13 (thyroid adenoma), and ZNF151, at 1p36.1-p36.2 (neuroblastoma, colon cancer, and other tumors). In addition, several of the ZNFs mapped to regions implicated in recurrent chromosomal rearrangements in hematological malignancies (ZNF139, 7q21.3-q22.1; ZNF148, 3q21-q22; ZNF151, 1p36.1-p36.2). The study indicates that the number of ZNF genes in human is large and that systematic isolation and mapping of ZNF genes is a straightforward approach for the identification of novel candidate disease genes. 47 refs., 2 figs., 1 tab.

Tommerup, N. [John F. Kennedy Institute, Glostrup (Denmark)] [John F. Kennedy Institute, Glostrup (Denmark); Vissing, H. [Novo Nordisk, Bagsvaerd (Denmark)] [Novo Nordisk, Bagsvaerd (Denmark)

1995-05-20

334

Exposure to the polyester PET precursor—terephthalic acid induces and perpetuates DNA damage-harboring non-malignant human breast cells  

PubMed Central

Identification of early perturbations induced in cells from non-cancerous breast tissue is critical for understanding possible breast cancer risk from chemical exposure. We have demonstrated previously that exposure to the ubiquitous xenoestrogens, bisphenol A (BPA) and methyl paraben, promotes the hallmarks of cancer in non-malignant human high-risk donor breast epithelial cells (HRBECs) isolated from several donors. Here we show that terephthalic acid (TPA), a major chemical precursor of polyethylene terephthalate (PET) containers used for the storage of food and beverages, increased the ER?: ER? ratio in multiple HRBEC samples, suggesting an estrogenic effect. Although, like BPA and methyl paraben, TPA also promoted resistance to tamoxifen-induced apoptosis, unlike these chemicals instead of inducing an increased S-phase fraction, TPA treatment arrested cell proliferation. DNA-PK, ATM and members of the MRN complex, known to be involved in DNA damage sensor and effector proteins, were elevated indicating induction of DNA strand breaks. Early DNA damage checkpoint response, mediated through p53/p21, led to G1 arrest in TPA-exposed cells. Removal of TPA from the growth medium resulted in the rapid induction of BCL2, increasing the ratio of anti-: pro-apoptotic proteins, together with overexpression of Cyclin A/CDK2 proteins. Consequently, despite elevated p53pSer15 and H2AXpSer139, indicating sustained DNA damage, TPA exposed cells resumed robust growth rates seen prior to TPA exposure. The propensity for the perpetuation of DNA aberrations that activate DNA damage pathways in non-malignant breast cells justifies careful consideration of human exposure to TPA, particularly at vulnerable life stages. PMID:25411358

Luciani-Torres, Maria Gloria; Moore, Dan H.; Dairkee, Shanaz H.

2015-01-01

335

Exposure to the polyester PET precursor--terephthalic acid induces and perpetuates DNA damage-harboring non-malignant human breast cells.  

PubMed

Identification of early perturbations induced in cells from non-cancerous breast tissue is critical for understanding possible breast cancer risk from chemical exposure. We have demonstrated previously that exposure to the ubiquitous xenoestrogens, bisphenol A (BPA) and methyl paraben, promotes the hallmarks of cancer in non-malignant human high-risk donor breast epithelial cells (HRBECs) isolated from several donors. Here we show that terephthalic acid (TPA), a major chemical precursor of polyethylene terephthalate (PET) containers used for the storage of food and beverages, increased the ER?: ER? ratio in multiple HRBEC samples, suggesting an estrogenic effect. Although, like BPA and methyl paraben, TPA also promoted resistance to tamoxifen-induced apoptosis, unlike these chemicals instead of inducing an increased S-phase fraction, TPA treatment arrested cell proliferation. DNA-PK, ATM and members of the MRN complex, known to be involved in DNA damage sensor and effector proteins, were elevated indicating induction of DNA strand breaks. Early DNA damage checkpoint response, mediated through p53/p21, led to G1 arrest in TPA-exposed cells. Removal of TPA from the growth medium resulted in the rapid induction of BCL2, increasing the ratio of anti-: pro-apoptotic proteins, together with overexpression of Cyclin A/CDK2 proteins. Consequently, despite elevated p53(pSer15) and H2AX(pSer139), indicating sustained DNA damage, TPA exposed cells resumed robust growth rates seen prior to TPA exposure. The propensity for the perpetuation of DNA aberrations that activate DNA damage pathways in non-malignant breast cells justifies careful consideration of human exposure to TPA, particularly at vulnerable life stages. PMID:25411358

Luciani-Torres, Maria Gloria; Moore, Dan H; Goodson, William H; Dairkee, Shanaz H

2015-01-01

336

Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways.  

PubMed

Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5?M) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1?, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1?, IL-6, IL-8, TNF-?) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-?B, COX-2, STAT-3, iNOS, TNF-?) and angiogenesis (HIF-1?, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis. PMID:25448439

Pratheeshkumar, Poyil; Son, Young-Ok; Divya, Sasidharan Padmaja; Roy, Ram Vinod; Hitron, John Andrew; Wang, Lei; Kim, Donghern; Dai, Jin; Asha, Padmaja; Zhang, Zhuo; Wang, Yitao; Shi, Xianglin

2014-12-01

337

Establishment of a new human pleomorphic malignant fibrous histiocytoma cell line, FU-MFH-2: molecular cytogenetic characterization by multicolor fluorescence in situ hybridization and comparative genomic hybridization  

PubMed Central

Background Pleomorphic malignant fibrous histiocytoma (MFH) is one of the most frequent malignant soft tissue tumors in adults. Despite the considerable amount of research on MFH cell lines, their characterization at a molecular cytogenetic level has not been extensively analyzed. Methods and results We established a new permanent human cell line, FU-MFH-2, from a metastatic pleomorphic MFH of a 72-year-old Japanese man, and applied multicolor fluorescence in situ hybridization (M-FISH), Urovysion™ FISH, and comparative genomic hybridization (CGH) for the characterization of chromosomal aberrations. FU-MFH-2 cells were spindle or polygonal in shape with oval nuclei, and were successfully maintained in vitro for over 80 passages. The histological features of heterotransplanted tumors in severe combined immunodeficiency mice were essentially the same as those of the original tumor. Cytogenetic and M-FISH analyses displayed a hypotriploid karyotype with numerous structural aberrations. Urovysion™ FISH revealed a homozygous deletion of the p16INK4A locus on chromosome band 9p21. CGH analysis showed a high-level amplification of 9q31-q34, gains of 1p12-p34.3, 2p21, 2q11.2-q21, 3p, 4p, 6q22-qter, 8p11.2, 8q11.2-q21.1, 9q21-qter, 11q13, 12q24, 15q21-qter, 16p13, 17, 20, and X, and losses of 1q43-qter, 4q32-qter, 5q14-q23, 7q32-qter, 8p21-pter, 8q23, 9p21-pter, 10p11.2-p13, and 10q11.2-q22. Conclusion The FU-MFH-2 cell line will be a particularly useful model for studying molecular pathogenesis of human pleomorphic MFH. PMID:21092322

2010-01-01

338

Comparison of microwave and magnetic nanoparticle hyperthermia radiosensitization in murine breast tumors  

Microsoft Academic Search

Hyperthermia has been shown to be an effective radiosensitizer. Its utility as a clinical modality has been limited by a minimally selective tumor sensitivity and the inability to be delivered in a tumor-specific manner. Recent in vivo studies (rodent and human) have shown that cancer cell-specific cytotoxicity can be effectively and safely delivered via iron oxide magnetic nanoparticles (mNP) and

Andrew J. Giustini; Alicia A. Petryk; Paul J. Hoopes

2011-01-01

339

Asbestos-related malignancy  

SciTech Connect

Asbestos-associated malignancies have received significant attention in the lay and medical literature because of the increasing frequency of two asbestos-associated tumors, lung carcinoma and mesothelioma; the wide distribution of asbestos; its status as a prototype environmental carcinogen; and the many recent legal compensation proceedings, for which medical testimony has been required. The understanding of asbestos-associated carcinogenesis has increased through study of animal models, human epidemiology, and, recently, the application of modern molecular biological techniques. However, the detailed mechanisms of carcinogenesis remain unknown. A wide variety of malignancies have been associated with asbestos, although the strongest evidence for a causal association is confined to lung cancer and mesothelioma. Epidemiological studies have provided evidence that both the type of asbestos fiber and the industry in which the exposure occurs may affect the rates of asbestos-associated cancers. It has been shown that asbestos exerts a carcinogenic effect independent of exposure to cigarette smoking that, for lung cancers, is synergistically enhanced by smoking. Other questions remain controversial, such as whether pulmonary fibrosis necessarily precedes asbestos-associated lung cancer and whether some threshold level of exposure to asbestos (including low-dose exposures that may occur in asbestos-associated public buildings) may be safe. Mesothelioma, the most closely asbestos-associated malignancy, has a dismal natural history and has been highly resistant to therapy. However, investigational multi-modality therapy may offer benefit to some patients. 179 references.

Talcott, J.A.; Antman, K.H.

1988-05-01

340

C-Kit Expression, Angiogenesis, and Grading in Canine Mast Cell Tumour: A Unique Model to Study C-Kit Driven Human Malignancies  

PubMed Central

Canine cutaneous mast cell tumour (CMCT) is a c-Kit driven tumour sharing similar c-Kit aberrations found in human gastrointestinal stromal tumour. CMCT is classified into three forms: well- (G1), intermediately (G2) (more benign diseases), and poorly (G3) differentiated (malignant) forms. We assess a correlation between c-Kit status, grading, and angiogenesis in CMCTs to explore their potential significance in humans. C-Kit receptor (c-KitR) expression, microvascular density (MVD), and mast cell granulated and degranulated status density (MCGD and MCDD, resp.) were analyzed in 97 CMCTs, by means of histochemistry, immunohistochemistry double staining, and image analysis system. Data showed that predominantly diffuse cytoplasmic- and predominantly focal paranuclear- (Golgi-like) c-Kit protein (PDC-c-Kit and PFP-c-Kit, resp.) expression correlate with high MVD, G3 histopathological grade, and MCDD. Moreover, predominant cell membrane-c-KitR (PCM-c-KitR) expression status correlates with low MVD, G1-G2 histopathological grade, and MCGD. These findings underline the key role of c-Kit in the biopathology of canine MCTs, indicating a link between aberrant c-Kit expression, increased angiogenesis, and higher histopathological grade. CMCT seems to be a model to study contributions of c-Kit activated MCs in tumour angiogenesis and to evaluate the inhibition of MCs activation by means of c-Kit tyrosine kinase inhibitors, currently translated in humans. PMID:24900982

Patruno, Rosa; Marech, Ilaria; Zizzo, Nicola; Nardulli, Patrizia; Introna, Marcello; Capriuolo, Gennaro; Rubini, Rosa Angela; Ribatti, Domenico; Gadaleta, Cosmo Damiano

2014-01-01

341

Enhanced cellular radiosensitivity induced by cofilin-1 over-expression is associated with reduced DNA repair capacity  

PubMed Central

Purpose A previous report has indicated that over-expression of cofilin-1 (CFL-1), a member of the actin depolymerizing factor (ADF)/cofilin protein family, enhances cellular radiosensitivity. This study explores, the involvement of various DNA damage responses and repair systems in the enhanced cellular radiosensitivity as well as assessing the role of CFL-1 phosphorylation in radiosensitivity. Materials and Methods Human non-small lung cancer H1299 cells harboring a tet-on gene expression system were used to induce exogenous expression of wild-type CFL-1. Colony formation assays were used to determine cell survival after ?-ray exposure. DNA damage levels were determined by comet assay. DNA repair capacity was assessed by fluorescence-based DNA repair analysis and antibody detection of various repair proteins. The effects of CFL-1 phosphorylation on radiation responses were explored using two mutant CFL-1 proteins, S3D and S3A. Finally, endogenous CFL-1 phosphorylation levels were investigated using latrunculin A (LA), cytochalasin B (CB) and Y27632. Results When phosphorylatable CFL-1 was expressed, radiosensitivity was enhanced after exposure to ?-rays and this was accompanied by DNA damage. Phosphorylated histone H2AX (?-H2AX) and p53-binding protein-1 (53BP1) foci, as well as Chk1/2 phosphorylation, were apparently suppressed, although ataxia telangiectasia mutated (ATM) kinase activation was apparently unaffected. In addition, two radiation induced double strand break (DSB) repair, systems, namely homologous recombination repair (HRR) and non-homologous end joining (NHEJ), were suppressed. Moreover, over-expression of CFL-1 S3D and CFL-1 S3A both enhanced radiosensitivity. However, enhanced radiosensitivity and reduced ?-H2AX expression were only detected in cells treated with LA which increased endogenous phospho-CFL-1, and not in cells treated with Y27632, which dephosphorylates CFL-1. Conclusion CFL-1 over-expression enhances radiosensitivity and this is associated with reduced DNA repair capacity. Although phosphorylated CFL-1 seems to be involved in radiosensitivity, further studies are required to address the importance of CFL-1 activity to the regulation of radiosensitivity. PMID:23362981

Leu, Jyh-Der; Chiu, Yu-Wen; Lo, Chia-Chien; Chiang, Pei-Hsun; Chiu, Su-Jun; Tsai, Cheng-Han; Hwang, Jeng-Jong; Chen, Ran-Chou; Gorbunova, Vera; Lee, Yi-Jang

2013-01-01

342

[Malignant hyperthermia].  

PubMed

Malignant hyperthermia (MH) is a rare hereditary, mostly subclinical myopathy. Trigger substances, such as volatile anesthetic agents and the depolarizing muscle relaxant succinylcholine can induce a potentially fatal metabolic increase in predisposed patients caused by a dysregulation of the myoplasmic calcium (Ca) concentration. Mutations in the dihydropyridine ryanodine receptor complex in combination with the trigger substances are responsible for an uncontrolled release of Ca from the sarcoplasmic reticulum. This leads to activation of the contractile apparatus and a massive increase in cellular energy production. Exhaustion of the cellular energy reserves ultimately results in local muscle cell destruction and subsequent cardiovascular failure. The clinical picture of MH episodes is very variable. Early symptoms are hypoxia, hypercapnia and cardiac arrhythmia whereas the body temperature rise, after which MH is named, often occurs later. Decisive for the course of MH episodes is a timely targeted therapy. Following introduction of the hydantoin derivative dantrolene, the previously high mortality of fulminant MH episodes could be reduced to well under 10?%. An MH predisposition can be detected using the invasive in vitro contracture test (IVCT) or mutation analysis. Few elaborate diagnostic procedures are in the developmental stage. PMID:25384957

Metterlein, T; Schuster, F; Graf, B M; Anetseder, M

2014-12-01

343

Differential ?2-adrenergic receptor expression defines the phenotype of non-tumorigenic and malignant human breast cell lines  

PubMed Central

Breast cancer is the most frequent malignancy in women. Several reports demonstrated that adrenergic receptors (ARs) are involved in breast cancer. Here we observed that epinephrine (Epi), an endogenous AR agonist, caused opposite effects in non-tumorigenic (MCF-10A and HBL-100) and tumor cells (MCF-7 and MDA-MB-231). Thus, Epi, in non-tumor breast cells, as well as isoproterenol (?-agonist), in all cell lines, maintained a benign phenotype, decreasing cell proliferation and migration, and stimulating cell adhesion. ?-AR expression and cAMP levels were higher in MCF-10A than in MCF-7 cells. ?2-AR knock-down caused a significant increase of cell proliferation and migration, and a decrease of cell adhesion both in basal and in Iso-stimulated conditions. Coincidently, ?2-AR over-expression induced a significant decrease of cell proliferation and migration, and an increase of cell adhesion. Therefore, ?2-AR is implied in cell phenotype and its agonists or antagonists could eventually complement cancer therapy. PMID:25375203

Rivero, Ezequiel M.; Galés, Céline; Sénard, Jean-Michel; Lüthy, Isabel A.

2014-01-01

344

Identification of a seven glycopeptide signature for malignant pleural mesothelioma in human serum by selected reaction monitoring  

PubMed Central

Background Serum biomarkers can improve diagnosis and treatment of malignant pleural mesothelioma (MPM). However, the evaluation of potential new serum biomarker candidates is hampered by a lack of assay technologies for their clinical evaluation. Here we followed a hypothesis-driven targeted proteomics strategy for the identification and clinical evaluation of MPM candidate biomarkers in serum of patient cohorts. Results Based on the hypothesis that cell surface exposed glycoproteins are prone to be released from tumor-cells to the circulatory system, we screened the surfaceome of model cell lines for potential MPM candidate biomarkers. Selected Reaction Monitoring (SRM) assay technology allowed for the direct evaluation of the newly identified candidates in serum. Our evaluation of 51 candidate biomarkers in the context of a training and an independent validation set revealed a reproducible glycopeptide signature of MPM in serum which complemented the MPM biomarker mesothelin. Conclusions Our study shows that SRM assay technology enables the direct clinical evaluation of protein-derived candidate biomarker panels for which clinically reliable ELISA’s currently do not exist. PMID:24207061

2013-01-01

345

Differential ??-adrenergic receptor expression defines the phenotype of non-tumorigenic and malignant human breast cell lines.  

PubMed

Breast cancer is the most frequent malignancy in women. Several reports demonstrated that adrenergic receptors (ARs) are involved in breast cancer. Here we observed that epinephrine (Epi), an endogenous AR agonist, caused opposite effects in non-tumorigenic (MCF-10A and HBL-100) and tumor cells (MCF-7 and MDA-MB-231). Thus, Epi, in non-tumor breast cells, as well as isoproterenol (?-agonist), in all cell lines, maintained a benign phenotype, decreasing cell proliferation and migration, and stimulating cell adhesion. ?-AR expression and cAMP levels were higher in MCF-10A than in MCF-7 cells. ??-AR knock-down caused a significant increase of cell proliferation and migration, and a decrease of cell adhesion both in basal and in Iso-stimulated conditions. Coincidently, ??-AR over-expression induced a significant decrease of cell proliferation and migration, and an increase of cell adhesion. Therefore, ??-AR is implied in cell phenotype and its agonists or antagonists could eventually complement cancer therapy. PMID:25375203

Gargiulo, Lucía; Copsel, Sabrina; Rivero, Ezequiel M; Galés, Céline; Sénard, Jean-Michel; Lüthy, Isabel A; Davio, Carlos; Bruzzone, Ariana

2014-10-30

346

Targeting Mcl-1 for Radiosensitization of Pancreatic Cancers12  

PubMed Central

In order to identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer, we previously conducted an RNAi library screen of 8,800 genes. We identified Mcl-1 (myeloid cell leukemia-1), an anti-apoptotic member of the Bcl-2 family, as a target for sensitizing pancreatic cancer cells to chemoradiation. In the present study we investigated Mcl-1 inhibition by either genetic or pharmacological approaches as a radiosensitizing strategy in pancreatic cancer cells. Mcl-1 depletion by siRNA produced significant radiosensitization in BxPC-3 and Panc-1 cells in association with Caspase-3 activation and PARP cleavage, but only minimal radiosensitization in MiaPaCa-2 cells. We next tested the ability of the recently identified, selective, small molecule inhibitor of Mcl-1, UMI77, to radiosensitize in pancreatic cancer cells. UMI77 caused dissociation of Mcl-1 from the pro-apoptotic protein Bak and produced significant radiosensitization in BxPC-3 and Panc-1 cells, but minimal radiosensitization in MiaPaCa-2 cells. Radiosensitization by UMI77 was associated with Caspase-3 activation and PARP cleavage. Importantly, UMI77 did not radiosensitize normal small intestinal cells. In contrast, ABT-737, an established inhibitor of Bcl-2, Bcl-XL, and Bcl-w, failed to radiosensitize pancreatic cancer cells suggesting the unique importance of Mcl-1 relative to other Bcl-2 family members to radiation survival in pancreatic cancer cells. Taken together, these results validate Mcl-1 as a target for radiosensitization of pancreatic cancer cells and demonstrate the ability of small molecules which bind the canonical BH3 groove of Mcl-1, causing displacement of Mcl-1 from Bak, to selectively radiosensitize pancreatic cancer cells. PMID:25749177

Wei, Dongping; Zhang, Qiang; Schreiber, Jason S.; Parsels, Leslie A.; Abulwerdi, Fardokht A.; Kausar, Tasneem; Lawrence, Theodore S.; Sun, Yi; Nikolovska-Coleska, Zaneta; Morgan, Meredith A.

2015-01-01

347

Targeting mcl-1 for radiosensitization of pancreatic cancers.  

PubMed

In order to identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer, we previously conducted an RNAi library screen of 8,800 genes. We identified Mcl-1 (myeloid cell leukemia-1), an anti-apoptotic member of the Bcl-2 family, as a target for sensitizing pancreatic cancer cells to chemoradiation. In the present study we investigated Mcl-1 inhibition by either genetic or pharmacological approaches as a radiosensitizing strategy in pancreatic cancer cells. Mcl-1 depletion by siRNA produced significant radiosensitization in BxPC-3 and Panc-1 cells in association with Caspase-3 activation and PARP cleavage, but only minimal radiosensitization in MiaPaCa-2 cells. We next tested the ability of the recently identified, selective, small molecule inhibitor of Mcl-1, UMI77, to radiosensitize in pancreatic cancer cells. UMI77 caused dissociation of Mcl-1 from the pro-apoptotic protein Bak and produced significant radiosensitization in BxPC-3 and Panc-1 cells, but minimal radiosensitization in MiaPaCa-2 cells. Radiosensitization by UMI77 was associated with Caspase-3 activation and PARP cleavage. Importantly, UMI77 did not radiosensitize normal small intestinal cells. In contrast, ABT-737, an established inhibitor of Bcl-2, Bcl-XL, and Bcl-w, failed to radiosensitize pancreatic cancer cells suggesting the unique importance of Mcl-1 relative to other Bcl-2 family members to radiation survival in pancreatic cancer cells. Taken together, these results validate Mcl-1 as a target for radiosensitization of pancreatic cancer cells and demonstrate the ability of small molecules which bind the canonical BH3 groove of Mcl-1, causing displacement of Mcl-1 from Bak, to selectively radiosensitize pancreatic cancer cells. PMID:25749177

Wei, Dongping; Zhang, Qiang; Schreiber, Jason S; Parsels, Leslie A; Abulwerdi, Fardokht A; Kausar, Tasneem; Lawrence, Theodore S; Sun, Yi; Nikolovska-Coleska, Zaneta; Morgan, Meredith A

2015-02-01

348

Establishment of the epithelial-specific transcriptome of normal and malignant human breast cells based on MPSS and array expression data  

PubMed Central

Introduction Diverse microarray and sequencing technologies have been widely used to characterise the molecular changes in malignant epithelial cells in breast cancers. Such gene expression studies to identify markers and targets in tumour cells are, however, compromised by the cellular heterogeneity of solid breast tumours and by the lack of appropriate counterparts representing normal breast epithelial cells. Methods Malignant neoplastic epithelial cells from primary breast cancers and luminal and myoepithelial cells isolated from normal human breast tissue were isolated by immunomagnetic separation methods. Pools of RNA from highly enriched preparations of these cell types were subjected to expression profiling using massively parallel signature sequencing (MPSS) and four different genome wide microarray platforms. Functional related transcripts of the differential tumour epithelial transcriptome were used for gene set enrichment analysis to identify enrichment of luminal and myoepithelial type genes. Clinical pathological validation of a small number of genes was performed on tissue microarrays. Results MPSS identified 6,553 differentially expressed genes between the pool of normal luminal cells and that of primary tumours substantially enriched for epithelial cells, of which 98% were represented and 60% were confirmed by microarray profiling. Significant expression level changes between these two samples detected only by microarray technology were shown by 4,149 transcripts, resulting in a combined differential tumour epithelial transcriptome of 8,051 genes. Microarray gene signatures identified a comprehensive list of 907 and 955 transcripts whose expression differed between luminal epithelial cells and myoepithelial cells, respectively. Functional annotation and gene set enrichment analysis highlighted a group of genes related to skeletal development that were associated with the myoepithelial/basal cells and upregulated in the tumour sample. One of the most highly overexpressed genes in this category, that encoding periostin, was analysed immunohistochemically on breast cancer tissue microarrays and its expression in neoplastic cells correlated with poor outcome in a cohort of poor prognosis estrogen receptor-positive tumours. Conclusion Using highly enriched cell populations in combination with multiplatform gene expression profiling studies, a comprehensive analysis of molecular changes between the normal and malignant breast tissue was established. This study provides a basis for the identification of novel and potentially important targets for diagnosis, prognosis and therapy in breast cancer. PMID:17014703

Grigoriadis, Anita; Mackay, Alan; Reis-Filho, Jorge S; Steele, Dawn; Iseli, Christian; Stevenson, Brian J; Jongeneel, C Victor; Valgeirsson, Haukur; Fenwick, Kerry; Iravani, Marjan; Leao, Maria; Simpson, Andrew JG; Strausberg, Robert L; Jat, Parmjit S; Ashworth, Alan; Neville, A Munro; O'Hare, Michael J

2006-01-01

349

Expression of basic fibroblast growth factor, FGFR1 and FGFR2 in normal and malignant human breast, and comparison with other normal tissues.  

PubMed

The expression of basic fibroblast growth factor (bFGF) and two of its receptors, FGFR1 and FGFR2, was detected using the polymerase chain reaction, and quantified by comparison to the relative amount of product obtained following co-amplification of the ubiquitous glyceraldehyde phosphate dehydrogenase transcript. Varying levels were found in the vast majority of both cancer and non-malignant breast biopsies as well as in samples of several other normal human tissues. Significantly less bFGF was present in cancers (P less than 0.0001). Similarly, FGFR2 product was also much less in cancer tissues (P = 0.0078), as was FGFR1 (P = 0.002). FGFR1 levels in cancers tended to be higher in those which were oestrogen receptor positive (P less than 0.06). Amplification of different coding regions showed evidence of variant forms of FGFR1 RNA. Cancers appeared to have a significantly greater proportion of PCR product corresponding to the region between the third immunoglobulin like domain and the tyrosine kinase domain (P = 0.046). Differential expression was observed in breast cell lines, with bFGF in the normal derived HBL100, HBR SV1.6.1 and 184A1 but little or none in ZR-75-1, MCF-7, T47D and MDA-MB-231. FGFR1 was present in most of these but FGFR2 was absent from T47D, MDA-MB-231 and HBL100. ZR-75-1 cells had a marked preponderance of FGFR1 variants lacking part of the coding sequence. Aberrant receptor processing may provide clues concerning the role of FGF's and their potential involvement in malignancy. PMID:1380281

Luqmani, Y A; Graham, M; Coombes, R C

1992-08-01

350

Tumor Suppressor Gene Inactivation during Cadmium-Induced Malignant Transformation of Human Prostate Cells Correlates with Overexpression of de Novo DNA Methyltransferase  

PubMed Central

Background Aberrant DNA methylation is common in carcinogenesis. The typical pattern appears to involve reduced expression of maintenance DNA methyltransferase, DNMT1, inducing genomic hypomethylation, whereas increased expression of de novo DNMT3a or 3b causes gene-specific hypermethylation. Objectives During cadmium-induced malignant transformation, an unusual pattern of genomic hypermethylation occurred that we studied to provide insight into the roles of specific DNMTs in oncogenesis. Methods Gene expression and DNA methylation were assessed in control and chronic cadmium-transformed prostate epithelial cells (CTPE) using reverse transcription–polymerase chain reaction (RT-PCR), Western blot analysis, methylation-specific PCR, and methyl acceptance assay. Results During the 10-weeks of cadmium exposure that induced malignant transformation, progressive increases in generalized DNMT enzymatic activity occurred that were associated with over-expression of DNMT3b without changes in DNMT1 expression. Increased DNMT3b expression preceded increased DNMT enzymatic activity. Procainamide, a specific DNMT1 inhibitor, reversed cadmium-induced genomic DNA hypermethylation. Reduced expression of the tumor suppressor genes, RASSF1A and p16, began about the time DNMT3b overexpression first occurred and progressively decreased thereafter. RASSF1A and p16 promoter regions were heavily methylated in CTPE cells, indicating silencing by hypermethylation, while the DNA demethylating agent, 5-aza-2?-deoxycytidine, reversed this silencing. DNMT1 inhibition only modestly increased RASSF1A and p16 expression in CTPE cells and did not completely reverse silencing. Conclusions These data indicate that DNMT3b overexpression can result in generalized DNA hypermethylation and gene silencing but that DNMT1 is required to maintain these effects. The pattern of genomic DNA hypermethylation together with up-regulation of DNMT3b may provide a unique set of biomarkers to specifically identify cadmium-induced human prostate cancers. PMID:17938735

Benbrahim-Tallaa, Lamia; Waterland, Robert A.; Dill, Anna L.; Webber, Mukta M.; Waalkes, Michael P.

2007-01-01

351

Wnt activation affects proliferation, invasiveness and radiosensitivity in medulloblastoma.  

PubMed

Medulloblastomas (MBs) associated with the Wnt activation represent a subgroup with a favorable prognosis, but it remains unclear whether Wnt activation confers a less aggressive phenotype and/or enhances radiosensitivity. To investigate this issue, we evaluated the biological behavior of an MB cell line, UW228-1, stably transfected with human ?-catenin cDNA encoding a nondegradable form of ?-catenin (UW-B) in standard culture conditions and after radiation treatment. We evaluated the expression, transcriptional activity, and localization of ?-catenin in the stably transfected cells using immunofluorescence and WB. We performed morphological analysis using light and electron microscopy. We then analyzed changes in the invasiveness, growth, and mortality in standard culture conditions and after radiation. We demonstrated that (A) Wnt activation inhibited 97 % of the invasion capability of the cells, (B) the growth of the UW-B cells was statistically significantly lower than that of all the other control cells (p < 0.01), (C) the mortality of irradiated UW-B cells was statistically significantly higher than that of the controls and their nonirradiated counterparts (p < 0.05), and (D) morphological features of neuronal differentiation were observed in the Wnt-activated cells. In tissue samples, the Ki-67 labeling index (LI) was lower in ?-catenin-positive samples compared to non-?-catenin positive ones. The Ki-67 LI median (LI = 40) of the nuclear ?-catenin-positive tumor samples was lower than that of non-nuclear ?-catenin-positive samples (LI = 50), but the difference was not statistically significant. Overall, our data suggest that activation of the Wnt pathway reduces the proliferation and invasion of MBs and increases the tumor's radiosensitivity. PMID:25261924

Salaroli, Roberta; Ronchi, Alice; Buttarelli, Francesca Romana; Cortesi, Filippo; Marchese, Valeria; Della Bella, Elena; Renna, Cristiano; Baldi, Caterina; Giangaspero, Felice; Cenacchi, Giovanna

2015-01-01

352

Expression of hPNAS-4 Radiosensitizes Lewis Lung Cancer  

SciTech Connect

Purpose: This study aimed to transfer the hPNAS-4 gene, a novel apoptosis-related human gene, into Lewis lung cancer (LL2) and observe its radiosensitive effect on radiation therapy in vitro and in vivo. Methods and Materials: The hPNAS-4 gene was transfected into LL2 cells, and its expression was detected via western blot. Colony formation assay and flow cytometry were used to detect the growth and apoptosis of cells treated with irradiation/PNAS-4 in vitro. The hPNAS-4 gene was transferred into LL2-bearing mice through tail vein injection of the liposome/gene complex. The tumor volumes were recorded after radiation therapy. Proliferating cell nuclear antigen (PCNA) immunohistochemistry staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed to detect the tumor cell growth and apoptosis in vivo. Results: The hPNAS-4 gene was successfully transferred into LL2 cells and tumor tissue, and its overexpressions were confirmed via western blot analysis. Compared with the control, empty plasmid, hPNAS-4, radiation, and empty plasmid plus radiation groups, the hPNAS-4 plus radiation group more significantly inhibited growth and enhanced apoptosis of LL2 cells in vitro and in vivo (P<.05). Conclusions: The hPNAS-4 gene was successfully transferred into LL2 cells and tumor tissue and was expressed in both LL2 cell and tumor tissue. The hPNAS-4 gene therapy significantly enhanced growth inhibition and apoptosis of LL2 tumor cells by radiation therapy in vitro and in vivo. Therefore, it may be a potential radiosensitive treatment of radiation therapy for lung cancer.

Zeng Hui [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China)] [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Yuan Zhu [State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China)] [State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Zhu Hong [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China)] [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Li Lei; Shi Huashan [State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China)] [State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Wang Zi; Fan Yu; Deng Qian; Zeng Jianshuang; He Yinbo [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China)] [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Xiao Jianghong [State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China)] [State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Li Zhiping, E-mail: lizhiping620312@yahoo.com.cn [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China)

2012-11-15

353

Immune checkpoint blockade in malignant mesothelioma  

PubMed Central

Monoclonal antibodies that target immune checkpoints are undoubtedly changing the therapeutic landscape of different human malignancies. Here we comment on the effects of blocking cytotoxic T lymphocyte-associated protein 4 (CTLA4) by means of the monoclonal antibody tremelimumab in patients with refractory malignant mesothelioma, a deadly disease with no effective therapeutic options. PMID:24734215

Calabrò, Luana; Maio, Michele

2014-01-01

354

Transgenic mouse model for skin malignant melanoma  

Microsoft Academic Search

We report here on a novel metallothionein-I (MT)\\/ret transgenic mouse line in which skin melanosis, benign melanocytic tumor and malignant melanoma metastasizing to distant organs develop stepwise. The process of tumor development and its malignant transformation in this line may resemble that of the human giant congenital melanocytic nevus that is present at birth and that frequently gives rise to

Masashi Kato; Masahide Takahashi; Anwarul A Akhand; Wei Liu; Yan Dai; Satoru Shimizu; Takashi Iwamoto; Haruhiko Suzuki; Izumi Nakashima

1998-01-01

355

Prognostic Role of MicroRNA-221 in Various Human Malignant Neoplasms: A Meta-Analysis of 20 Related Studies  

PubMed Central

Background MicroRNA-221 (miR-221) has been shown to play an important role in cancer prognosis. In order to evaluate the predictive value of miR-221, we compiled the evidence from 20 eligible studies to perform a meta-analysis. Design All of relevant studies were identified by searching PubMed, Embase, and Web of Science, and were assessed by further quality evaluation. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of total and stratified analyses, for overall survival (OS) and recurrence-free survival (RFS), were calculated to investigate the association between high miR-221 expression and cancer prognosis. Results We found that high miR-221 expression can predict a poor OS in malignant tumors (pooled HR?=?1.55, P?=?0.017) but has no significant association with RFS (pooled HR?=?1.02, P?=?0.942). Further in stratified analyses, high miR-221 expression was significantly associated with a poor OS in Asians (pooled HR?=?2.04, P?=?0.010) or serum/ plasma subgroup (pooled HR?=?2.28, P<0.001), and even showed significantly poor OS (pooled HR?=?1.80, P<0.001) and RFS (pooled HR?=?2.43, P?=?0.010) in hepatocellular carcinoma (HCC) subgroup, but was correlated to a favorable RFS in prostate cancer subgroup (pooled HR?=?0.51, P?=?0.004). Conclusions Our findings demonstrate that miR-221 is more suitable to predict cancer prognosis in Asians, and it is a promising prognostic biomarker for HCC. The detection of miR-221 in serum or plasma samples may make it become an effective method for monitoring patients' prognosis and assessing therapeutic efficacy in the future. PMID:24475314

Xu, Yang; Song, Ning-hong; Yin, Chang-jun

2014-01-01

356

A new treatment for human malignant melanoma targeting L-type amino acid transporter 1 (LAT1): A pilot study in a canine model  

SciTech Connect

Highlights: •LAT1 is highly expressed in tumors but at low levels in normal tissues. •We examine LAT1 expression and function in malignant melanoma (MM). •LAT1 expression in MM tissues and cell lines is higher than those in normal tissues. •LAT1 selective inhibitors inhibit amino acid uptake and cell growth in MM cells. •New chemotherapeutic protocols including LAT1 inhibitors are effective for treatment. -- Abstract: L-type amino acid transporter 1 (LAT1), an isoform of amino acid transport system L, transports branched or aromatic amino acids essential for fundamental cellular activities such as cellular growth, proliferation and maintenance. This amino acid transporter recently has received attention because of its preferential and up-regulated expression in a variety of human tumors in contrast to its limited distribution and low-level expression in normal tissues. In this study, we explored the feasibility of using LAT1 inhibitor as a new therapeutic agent for human malignant melanomas (MM) using canine spontaneous MM as a model for human MM. A comparative study of LAT expression was performed in 48 normal tissues, 25 MM tissues and five cell lines established from MM. The study observed LAT1 mRNA levels from MM tissues and cell lines that were significantly (P < 0.01) higher than in normal tissues. Additionally, MM with distant metastasis showed a higher expression than those without distant metastasis. Functional analysis of LAT1 was performed on one of the five cell lines, CMeC-1. [{sup 3}H]L-Leucine uptake and cellular growth activities in CMeC-1 were inhibited in a dose-dependent manner by selective LAT1 inhibitors (2-amino-2-norbornane-carboxylic acid, BCH and melphalan, LPM). Inhibitory growth activities of various conventional anti-cancer drugs, including carboplatin, cyclophosphamide, dacarbazine, doxorubicin, mitoxantrone, nimustine, vinblastine and vincristine, were significantly (P < 0.05) enhanced by combination use with BCH or LPM. These findings suggest that LAT1 could be a new therapeutic target for MM.

Fukumoto, Shinya; Hanazono, Kiwamu [Veterinary Internal Medicine, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan)] [Veterinary Internal Medicine, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan); Fu, Dah-Renn; Endo, Yoshifumi; Kadosawa, Tsuyoshi [Veterinary Oncology, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan)] [Veterinary Oncology, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan); Iwano, Hidetomo [Veterinary Biochemistry, Department of Basic Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan)] [Veterinary Biochemistry, Department of Basic Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan); Uchide, Tsuyoshi, E-mail: uchide@rakuno.ac.jp [Veterinary Internal Medicine, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan)] [Veterinary Internal Medicine, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan)

2013-09-13

357

Advances in radiation biology: Relative radiation sensitivities of human organ systems. Volume 12  

SciTech Connect

This volume is a thematically focused issue of Advances in Radiation Biology. The topic surveyed is relative radiosensitivity of human organ systems. Topics considered include relative radiosensitivities of the thymus, spleen, and lymphohemopoietic systems; relative radiosensitivities of the small and large intestine; relative rediosensitivities of the oral cavity, larynx, pharynx, and esophagus; relative radiation sensitivity of the integumentary system; dose response of the epidermal; microvascular, and dermal populations; relative radiosensitivity of the human lung; relative radiosensitivity of fetal tissues; and tolerance of the central and peripheral nervous system to therapeutic irradiation.

Lett, J.T.; Altman, K.I.; Ehmann, U.K.; Cox, A.B.

1987-01-01

358

Design and Synthesis of a MAO-B-Selectively Activated Prodrug Based on MPTP: A Mitochondria-Targeting Chemotherapeutic Agent for Treatment of Human Malignant Gliomas.  

PubMed

Malignant gliomas, including glioblastomas, are extremely difficult to treat. The median survival for glioblastoma patients with optimal therapeutic intervention is 15 months. We developed a novel MAO-B-selectively activated prodrug, N,N-bis(2-chloroethyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)propanamide (MP-MUS), for the treatment of gliomas based on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The design of neutral MP-MUS involved the use of a seeker molecule capable of binding to mitochondrial MAO-B, which is up-regulated ?fourfold in glioma cells. Once the binding occurs, MP-MUS is converted into a positively charged moiety, P(+) -MUS, which accumulates inside mitochondria at a theoretical maximal value of 1000:1 gradient. The LD50 of MP-MUS against glioma cells is 75??M, which is two- to threefold more potent than temozolomide, a primary drug for gliomas. Importantly, MP-MUS was found to be selectively toxic toward glioma cells. In the concentration range of 150-180??M MP-MUS killed 90-95?% of glioma cells, but stimulated the growth of normal human astrocytes. Moreover, maturation of MP-MUS is highly dependent on MAO-B, and inhibition of MAO-B activity with selegiline protected human glioma cells from apoptosis. PMID:25677185

Sharpe, Martyn A; Han, Junyan; Baskin, Alexandra M; Baskin, David S

2015-04-01

359

Radiation chemistry in the clinic: Hypoxic cell radiosensitizers for radiotherapy  

NASA Astrophysics Data System (ADS)

There is much clinical interest in increasing the radiosensitivity of radioresistant hypoxic tumour cells by developing drugs which will take part in radiation-chemical reactions to increase cell killing. This article discusses several aspects of radiosensitization by electron affinic nitroaryl compounds. The problem of correlating radiobiological effects with reactions of a particular radical by means of relative rate constants is illustrated, and chemical models of the radiosensitization phenomena discussed in this context. The implications of free-energy relationships between biological responses or rate constants of radical reactions are stressed, as is the need to characterise the competitive, protective reaction with thiols. The importance of phase-distribution relationships in controlling pharmacological properties is noted, and the application of these principles to improving the therapeutic ratio of radiosensitizers explained. A brief outline is presented of the current status of clinical trials of radiosensitizers, and future prospects for the improvement of the efficacy of radiotherapy by modifying radiation-chemical reactions are discussed.

Wardman, Peter

360

Nitroheterocyclic compounds as hypoxic cell radiosensitizers. Oncology overview  

SciTech Connect

Oncology Overviews are a service of the International Cancer Research Data Bank (ICRDB) Program of the National Cancer Institute, intended to facilitate and promote the exchange of information between cancer scientists by keeping them aware of literature related to their research being published by other laboratories throughout the world. Each Oncology Overview represents a survey of the literature associated w