Osthole promotes anti-tumor immune responses in tumor-bearing mice with hepatocellular carcinoma.

PubMed

Zhang, Lurong; Jiang, Guorong; Yao, Fei; Liang, Guoqiang; Wang, Fei; Xu, Heng; Wu, Yan; Yu, Xiao; Liu, Haiyan

2015-06-01

Osthole, a natural coumarin derivative, has been shown to have anti-tumor and anti-inflammatory activity. However, the effect of osthole on anti-tumor immune responses in tumor-bearing mice has not yet been reported. In the present study, osthole treatment did not affect the weight and the coefficient of thymus and spleen in tumor-bearing mice with hepatocellular carcinoma (HCC). However, osthole administration significantly elevated the proportion and number of the splenic CD8(+) T cells, the proportion of CD4(+) T and CD8(+) T cells in tumor tissues, and the levels of IL-2 and TNF-α in the serum of HCC tumor-bearing mice. Our results suggested that osthole could promote the activation of the tumor-infiltrating CD4(+) T and CD8(+) T cells, and elevate the proportion of CD4(+) and CD8(+) effector T cells. Osthole treatment also significantly decreased the proportion of CD4(+)CD25(+)Foxp3(+) regulatory T cells in the spleen. Taken together, osthole could enhance the T cell mediated anti-tumor immune responses in the tumor-bearing mice with HCC.

Tumor-specific pH-responsive peptide-modified pH-sensitive liposomes containing doxorubicin for enhancing glioma targeting and anti-tumor activity.

PubMed

Zhao, Yang; Ren, Wei; Zhong, Ting; Zhang, Shuang; Huang, Dan; Guo, Yang; Yao, Xin; Wang, Chao; Zhang, Wei-Qiang; Zhang, Xuan; Zhang, Qiang

2016-01-28

The pH environment in gliomas is acidic. Therefore, in the present research, we selected our previously reported tumor-specific pH-responsive peptide H7K(R2)2 as a targeting ligand, which could respond to the acidic pH environment in gliomas, possessing CPP characteristics. The pH-sensitive liposomes were selected as carriers which could also respond to the acidic pH environment in gliomas triggering encapsulated drug release from these pH-sensitive liposomes. The H7K(R2)2-modified pH-sensitive liposomes containing doxorubicin (DOX-PSL-H7K(R2)2) were designed and prepared in order to evaluate their potential targeting of glioma tumor cells and their anti-tumor activity in mice with glioma tumor cells. DOX-PSL-H7K(R2)2 was prepared by the thin-film hydration method followed by remote loading using an ammonium sulfate gradient method. The in vitro release of DOX from pH-sensitive liposomes was tested and the in vitro targeting characteristics of H7K(R2)2-modified liposomes regarding C6 (rat C6 glioma cells) and U87-MG (human glioblastoma cells) were evaluated. The in vivo anti-tumor activity of DOX-PSL-H7K(R2)2 was also investigated in C6 tumor-bearing mice and in U87-MG orthotopic tumor-bearing nude mice. A specific targeting effect triggered by an acidic pH was observed in our in vitro experiments in C6 and U87-MG glioma cells. The pH-triggered DOX release from the pH-sensitive liposomes under acidic conditions was also confirmed in our in vitro experiment. Anti-tumor activity of DOX-PSL-H7K(R2)2 was found in C6 tumor-bearing mice and U87-MG orthotopic tumor-bearing nude mice in in vivo experiments. The antiangiogenic activity of DOX-PSL-H7K(R2)2 was confirmed in C6 tumor-bearing mice in the in vivo experiment. These H7K(R2)2-modified pH-sensitive liposomes containing anti-tumor drugs developed in this study are a promising delivery system involving the response stimuli at the acidic pH in the glioma tumor microenvironment and are suitable for anti-tumor therapy

Anti-tumor activity of calcitriol: pre-clinical and clinical studies.

PubMed

Trump, Donald L; Hershberger, Pamela A; Bernardi, Ronald J; Ahmed, Sharmilla; Muindi, Josephia; Fakih, Marwan; Yu, Wei-Dong; Johnson, Candace S

2004-05-01

1,25-Dihydroxycholecalciferol (calcitriol) is recognized widely for its effects on bone and mineral metabolism. Epidemiological data suggest that low Vitamin D levels may play a role in the genesis of prostate cancer and perhaps other tumors. Calcitriol is a potent anti-proliferative agent in a wide variety of malignant cell types. In prostate, breast, colorectal, head/neck and lung cancer as well as lymphoma, leukemia and myeloma model systems calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol effects are associated with an increase in G0/G1 arrest, induction of apoptosis and differentiation, modulation of expression of growth factor receptors. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. Calcitriol potentiates the antitumor effects of many cytotoxic agents and inhibits motility and invasiveness of tumor cells and formation of new blood vessels. Phase I and II trials of calcitriol either alone or in combination with carboplatin, taxanes or dexamethasone have been initiated in patients with androgen dependent and independent prostate cancer and advanced cancer. Data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered and optimal dose and schedule are being delineated. Clinical responses have been seen with the combination of high dose calcitriol+dexamethasone in androgen independent prostate cancer (AIPC) and apparent potentiation of the antitumor effects of docetaxel have been seen in AIPC. These results demonstrate that high intermittent doses of calcitriol can be administered to patients without toxicity, that the MTD is yet to be determined and that calcitriol has potential as an anti-cancer agent.

In vitro and in vivo anti-tumor activities of a gemcitabine derivative carried by nanoparticles

PubMed Central

Sloat, Brian R.; Sandoval, Michael A.; Li, Dong; Chung, Woon-Gye; Lansakara-P., Dharmika S. P.; Proteau, Philip J.; Kiguchi, Kaoru; DiGiovanni, John; Cui, Zhengrong

2011-01-01

Gemcitabine (Gemzar®) is the first line treatment for pancreatic cancer and often used in combination therapy for non-small cell lung, ovarian, and metastatic breast cancers. Although extremely toxic to a variety of tumor cells in culture, the clinical outcome of gemcitabine treatment still needs improvement. In the present study, a new gemcitabine nanoparticle formulation was developed by incorporating a previously reported stearic acid amide derivative of gemcitabine into nanoparticles prepared from lecithin/glyceryl monostearate-in-water emulsions. The stearoyl gemcitabine nanoparticles were cytotoxic to tumor cells in culture, although it took a longer time for the gemcitabine in the nanoparticles to kill tumor cells than for free gemcitabine. In mice with pre-established model mouse or human tumors, the stearoyl gemcitabine nanoparticles were significantly more effective than free gemcitabine in controlling the tumor growth. PEGylation of the gemcitabine nanoparticles with polyethylene glycol (2000) prolonged the circulation of the nanoparticles in blood and increased the accumulation of the nanoparticles in tumor tissues (> 6-fold), but the PEGylated and un-PEGylated gemcitabine nanoparticles showed similar anti-tumor activity in mice. Nevertheless, the nanoparticle formulation was critical for the stearoyl gemcitabine to show a strong anti-tumor activity. It is concluded that for the gemcitabine derivate-containing nanoparticles, cytotoxicity data in culture may not be used to predict their in vivo anti-tumor activity, and this novel gemcitabine nanoparticle formulation has the potential to improve the clinical outcome of gemcitabine treatment. PMID:21371545

Oligodeoxynucleotides Expressing Polyguanosine Motifs Promote Anti-Tumor Activity through the Up-Regulation of IL-2

PubMed Central

Kobayashi, Nobuaki; Hong, Choongman; Klinman, Dennis M.; Shirota, Hidekazu

2012-01-01

The primary goal of cancer immunotherapy is to elicit an immune response capable of eliminating the tumor. One approach towards accomplishing that goal utilizes general (rather than tumor-specific) immunomodulatory agents to boost the number and activity of pre-existing cytotoxic T lymphocytes. We find that the intra-tumoral injection of poly-G ODN has such an effect, boosting anti-tumor immunity and promoting tumor regression. The anti-tumor activity of polyguanosine (poly-G) oligonucleotides (ODN) was mediated through CD8 T cells in a TLR9 independent manner. Mechanistically, poly-G ODN directly induced the phosphorylation of Lck (an essential element of the T cell signaling pathway), thereby enhancing the production of IL-2 and CD8 T cell proliferation. These findings establish poly-G ODN as a novel type of cancer immunotherapy. PMID:23296706

Tumor-derived inducible heat-shock protein 70 (HSP70) is an essential component of anti-tumor immunity.

PubMed

Dodd, K; Nance, S; Quezada, M; Janke, L; Morrison, J B; Williams, R T; Beere, H M

2015-03-05

The anti-apoptotic function and tumor-associated expression of heat-shock protein 70 (HSP70) is consistent with HSP70 functioning as a survival factor to promote tumorigenesis. However, its immunomodulatory activities to induce anti-tumor immunity predict the suppression of tumor growth. Using the Hsp70.1/3(-/-)(Hsp70(-/-)) mouse model, we observed that tumor-derived HSP70 was neither required for cellular transformation nor for in vivo tumor growth. Hsp70(-/-) murine embryonic fibroblasts (MEFs) were transformed by E1A/Ras and generated tumors in immunodeficient hosts as efficiently as wild-type (WT) transformants. Comparison of Bcr-Abl-mediated transformation of WT and Hsp70(-/-) bone marrow and progression of B-cell leukemogenesis in vivo revealed no differences in disease onset or survival rates, and Eμ-Myc-driven lymphoma in Hsp70(-/-) mice was phenotypically indistinguishable from that in WT Eμ-Myc mice. However, Hsp70(-/-) E1A/Ras MEFs generated significantly larger tumors than their WT counterparts in C57BL/6 J immune-competent hosts. Concurrent with this was a reduction in intra-tumoral infiltration of innate and adaptive immune cells, including macrophages and CD8(+) T cells. Evaluation of several potential mechanisms revealed an HSP70-chemokine-like activity to promote cellular migration. These observations support a role for tumor-derived HSP70 in facilitating anti-tumor immunity to limit tumor growth and highlight the potential consequences of anti-HSP70 therapy as an efficacious anti-cancer strategy.

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peters, Diane E.; Program of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA; Hoover, Benjamin

2014-09-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6more » syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. - Highlights: • Toxicity and

Anti- and pro-tumor functions of autophagy.

PubMed

Morselli, Eugenia; Galluzzi, Lorenzo; Kepp, Oliver; Vicencio, José-Miguel; Criollo, Alfredo; Maiuri, Maria Chiara; Kroemer, Guido

2009-09-01

Autophagy constitutes one of the major responses to stress in eukaryotic cells, and is regulated by a complex network of signaling cascades. Not surprisingly, autophagy is implicated in multiple pathological processes, including infection by pathogens, inflammatory bowel disease, neurodegeneration and cancer. Both oncogenesis and tumor survival are influenced by perturbations of the molecular machinery that controls autophagy. Numerous oncoproteins, including phosphatidylinositol 3-kinase, Akt1 and anti-apoptotic members of the Bcl-2 family suppress autophagy. Conversely, several tumor suppressor proteins (e.g., Atg4c; beclin 1; Bif-1; BH3-only proteins; death-associated protein kinase 1; LKB1/STK11; PTEN; UVRAG) promote the autophagic pathway. This does not entirely apply to p53, one of the most important tumor suppressor proteins, which regulates autophagy in an ambiguous fashion, depending on its subcellular localization. Irrespective of the controversial role of p53, basal levels of autophagy appear to inhibit tumor development. On the contrary, chemotherapy- and metabolic stress-induced activation of the autophagic pathway reportedly contribute to the survival of formed tumors, thereby favoring resistance. In this context, autophagy inhibition would represent a major therapeutic target for chemosensitization. Here, we will review the current knowledge on the dual role of autophagy as an anti- and pro-tumor mechanism.

Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models.

PubMed

Baker, Amanda F; Hanke, Neale T; Sands, Barbara J; Carbajal, Liliana; Anderl, Janet L; Garland, Linda L

2014-12-31

Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models. A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ. CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC50 values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC50 values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP). CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC.

Anti-cancer, anti-inflammatory and anti-microbial activities of plant extracts used against hematological tumors in traditional medicine of Jordan.

PubMed

Assaf, Areej M; Haddadin, Randa N; Aldouri, Nedhal A; Alabbassi, Reem; Mashallah, Sundus; Mohammad, Mohammad; Bustanji, Yasser

2013-02-13

Mercurialis annua L., Bongardia chrysogonum L., and Viscum cruciatum Sieb have been traditionally used by local herbalists in Jordan for the treatment of hematopoietic neoplasms. To determine the anti-cancer, anti-inflammatory and anti-microbial potentials of the three extracts against two of the most common hematopoietic malignancies in the Jordanian populations; Burkitt's lymphoma and Multiple myeloma. The anti-cancer activity was tested against the two cell lines (BJAB Burkitt's lymphoma and U266 multiple myeloma) using the MTT and trypan blue assays. The agar dilution assay was used to study the anti-microbial activity against Gram-positive bacteria, Gram-negative bacteria, anaerobic bacteria and yeast. The pro-inflammatory cytokines interleukin (IL) -1β, IL-8 and tumor necrosis factor-α (TNF-α) were measured in the pretreated cell lines using ELISA assay to determine the anti-inflammatory activity of Viscum cruciatum Sieb against the two cell lines. The results show no evidence of stimulation of tumor growth by any of the three extracts comprising cell lines from hematological malignancies, but Viscum cruciatum Sieb showed a selective anticancer activity against BJAB cells, with IC(50) value of 14.21μg/ml. The antimicrobial effect was only noticed with Viscum cruciatum extract by inhibiting Staphylococcus aureus, Candida albicans and Propionibacterium acne, but not Pseudomonas aeruginosa at MIC of 1.25, 1.25, 0.625 and <5mg/ml, respectively. The highest activity was against the anaerobic bacteria Propionibacterium acne. Viscum cruciatum Sieb extract showed an inhibitory effect on the pro-inflammatory cytokine IL-8, but it increased TNF-α and IL-1β secretions in BJAB cells. Whereas, it had an inhibitory effect on TNF-α and IL-1β cytokines while it enhanced IL-8 secretions in U266 cells. Among the three tested herbal extracts used in the traditional medicine in Jordan, only Viscum cruciatum Sieb showed high anti-cancer and anti-microbial potentials. They

Enhancement of hypoxia-activated prodrug TH-302 anti-tumor activity by Chk1 inhibition.

PubMed

Meng, Fanying; Bhupathi, Deepthi; Sun, Jessica D; Liu, Qian; Ahluwalia, Dharmendra; Wang, Yan; Matteucci, Mark D; Hart, Charles P

2015-05-21

The hypoxia-activated prodrug TH-302 is reduced at its nitroimidazole group and selectively under hypoxic conditions releases the DNA cross-linker bromo-isophosphoramide mustard (Br-IPM). Here, we have explored the effect of Chk1 inhibition on TH-302-mediated pharmacological activities. We employed in vitro cell viability, DNA damage, cellular signaling assays and the in vivo HT29 human tumor xenograft model to study the effect of Chk1inhibition on TH-302 antitumor activities. TH-302 cytotoxicity is greatly enhanced by Chk1 inhibition in p53-deficient but not in p53-proficient human cancer cell lines. Chk1 inhibitors reduced TH-302-induced cell cycle arrest via blocking TH-302-induced decrease of phosphorylation of histone H3 and increasing Cdc2-Y15 phosphorylation. Employing the single-cell gel electrophoresis (comet) assay, we observed a potentiation of the TH-302 dependent tail moment. TH-302 induced γH2AX and apoptosis were also increased upon the addition of Chk1 inhibitor. Potentiation of TH-302 cytotoxicity by Chk1 inhibitor was only observed in cell lines proficient in, but not deficient in homology-directed DNA repair. We also show that combination treatment led to lowering of Rad51 expression levels as compared to either agent alone. In vivo data demonstrate that Chk1 inhibitor enhances TH-302 anti-tumor activity in p53 mutant HT-29 human tumor xenografts, supporting the hypothesis that these in vitro results can translate to enhanced in vivo efficacy of the combination. TH-302-mediated in vitro and in vivo anti-tumor activities were greatly enhanced by the addition of Chk1 inhibitors. The preclinical data presented in this study support a new approach for the treatment of p53-deficient hypoxic cancers by combining Chk1 inhibitors with the hypoxia-activated prodrug TH-302.

Rottlerin exerts its anti-tumor activity through inhibition of Skp2 in breast cancer cells.

PubMed

Yin, Xuyuan; Zhang, Yu; Su, Jingna; Hou, Yingying; Wang, Lixia; Ye, Xiantao; Zhao, Zhe; Zhou, Xiuxia; Li, Yali; Wang, Zhiwei

2016-10-11

Studies have investigated the tumor suppressive role of rottlerin in carcinogenesis. However, the molecular mechanisms of rottlerin-induced anti-tumor activity are largely unclear. Skp2 (S-phase kinase associated protein 2) has been validated to play an oncogenic role in a variety of human malignancies. Therefore, inactivation of Skp2 could be helpful for the treatment of human cancers. In the current study, we explore whether rottlerin could inhibit Skp2 expression, leading to inhibition of cell growth, migration and invasion in breast cancer cells. We found that rottlerin treatment inhibited cell growth, induced apoptosis and cell cycle arrest. We also revealed that rottlerin suppressed cell migration and invasion in breast cancer cells. Mechanically, we observed that rottlerin significantly down-regulated the expression of Skp2 in breast cancer cells. Importantly, overexpression of Skp2 abrogated rottlerin-mediated tumor suppressive activity, whereas down-regulation of Skp2 enhanced rottlerin-triggered anti-tumor function. Strikingly, we identified that rottlerin exhibited its anti-tumor potential partly through inactivation of Skp2 in breast cancer. Our findings indicate that rottlerin could be a potential safe agent for the treatment of breast cancer.

Apigenin sensitizes colon cancer cells to anti-tumor activity of ABT-263

PubMed Central

Shao, Huanjie; Jing, Kai; Mahmoud, Esraa; Huang, Haihong; Fang, Xianjun; Yu, Chunrong

2013-01-01

Apigenin is an edible plant-derived flavonoid that shows modest anti-tumor activities in vitro and in vivo. Apigenin treatment resulted in cell growth arrest and apoptosis in various types of tumors by modulating several signaling pathways. In the present study, we evaluated interactions between apigenin and ABT-263 in colon cancer cells. We observed a synergistic effect between apigenin and ABT-263 on apoptosis of colon cancer cells. ABT-263 alone induced limited cell death while upregulating expression of Mcl-1, a potential mechanism for the acquired resistance to ABT-263. The presence of apigenin antagonized ABT-263-induced Mcl-1 upregulation and dramatically enhanced ABT-263-induced cell death. Meanwhile, apigenin suppressed AKT and ERK activation. Inactivation of either AKT or ERK by lentivirus-transduced shRNA or treatment with specific small molecule inhibitors of these pathways enhanced ABT-263-induced cell death, mirroring the effect of apigenin. Moreover, the combination response was associated with upregulation of Bim and activation of Bax. Downregulation of Bax eliminated the synergistic effect of apigenin and ABT-263 on cell death. Xenograft studies in SCID mice showed that the combined treatment with apigenin and ABT-263 inhibited tumor growth by up to 70% without obvious adverse effects, while either agent only inhibited around 30%. Our results demonstrate a novel strategy to enhance ABT-263 induced anti-tumor activity in human colon cancer cells by apigenin via inhibition of the Mcl-1, AKT and ERK pro-survival regulators. PMID:24126433

Metronomic chemotherapy: An attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance

DOE PAGES

Kareva, Irina; Waxman, David J.; Klement, Giannoula Lakka

2014-12-23

The administration of chemotherapy at reduced doses given at regular, frequent time intervals, termed ‘metronomic’ chemotherapy, presents an alternative to standard maximal tolerated dose (MTD) chemotherapy. The primary target of metronomic chemotherapy was originally identified as endothelial cells supporting the tumor vasculature, and not the tumor cells themselves, consistent with the emerging concept of cancer as a systemic disease involving both tumor cells and their microenvironment. While anti-angiogenesis is an important mechanism of action of metronomic chemotherapy, other mechanisms, including activation of anti-tumor immunity and a decrease in acquired therapeutic resistance, have also been identified. In this paper, we presentmore » evidence supporting a mechanistic explanation for the improved activity of cancer chemotherapy when administered on a metronomic, rather than an MTD schedule and discuss the implications of these findings for further translation into the clinic.« less

Utility of Clostridium difficile toxin B for inducing anti-tumor immunity.

PubMed

Huang, Tuxiong; Li, Shan; Li, Guangchao; Tian, Yuan; Wang, Haiying; Shi, Lianfa; Perez-Cordon, Gregorio; Mao, Li; Wang, Xiaoning; Wang, Jufang; Feng, Hanping

2014-01-01

Clostridium difficile toxin B (TcdB) is a key virulence factor of bacterium and induces intestinal inflammatory disease. Because of its potent cytotoxic and proinflammatory activities, we investigated the utility of TcdB in developing anti-tumor immunity. TcdB induced cell death in mouse colorectal cancer CT26 cells, and the intoxicated cells stimulated the activation of mouse bone marrow-derived dendritic cells and subsequent T cell activation in vitro. Immunization of BALB/c mice with toxin-treated CT26 cells elicited potent anti-tumor immunity that protected mice from a lethal challenge of the same tumor cells and rejected pre-injected tumors. The anti-tumor immunity generated was cell-mediated, long-term, and tumor-specific. Further experiments demonstrated that the intact cell bodies were important for the immunogenicity since lysing the toxin-treated tumor cells reduced their ability to induce antitumor immunity. Finally, we showed that TcdB is able to induce potent anti-tumor immunity in B16-F10 melanoma model. Taken together, these data demonstrate the utility of C. difficile toxin B for developing anti-tumor immunity.

Aqueous extract of Carica papaya leaves exhibits anti-tumor activity and immunomodulatory effects.

PubMed

Otsuki, Noriko; Dang, Nam H; Kumagai, Emi; Kondo, Akira; Iwata, Satoshi; Morimoto, Chikao

2010-02-17

Various parts of Carica papaya Linn. (CP) have been traditionally used as ethnomedicine for a number of disorders, including cancer. There have been anecdotes of patients with advanced cancers achieving remission following consumption of tea extract made from CP leaves. However, the precise cellular mechanism of action of CP tea extracts remains unclear. The aim of the present study is to examine the effect of aqueous-extracted CP leaf fraction on the growth of various tumor cell lines and on the anti-tumor effect of human lymphocytes. In addition, we attempted to identify the functional molecular weight fraction in the CP leaf extract. The effect of CP extract on the proliferative responses of tumor cell lines and human peripheral blood mononuclear cells (PBMC), and cytotoxic activities of PBMC were assessed by [(3)H]-thymidine incorporation. Flow cytometric analysis and measurement of caspase-3/7 activities were performed to confirm the induction of apoptosis on tumor cells. Cytokine productions by PBMC were measured by ELISA. Gene profiling of the effect of CP extract treatment was performed by microarray analysis and real-time RT-PCR. We observed significant growth inhibitory activity of the CP extract on tumor cell lines. In PBMC, the production of IL-2 and IL-4 was reduced following the addition of CP extract, whereas that of IL-12p40, IL-12p70, IFN-gamma and TNF-alpha was enhanced without growth inhibition. In addition, cytotoxicity of activated PBMC against K562 was enhanced by the addition of CP extract. Moreover, microarray analyses showed that the expression of 23 immunomodulatory genes, classified by gene ontology analysis, was enhanced by the addition of CP extract. In this regard, CCL2, CCL7, CCL8 and SERPINB2 were representative of these upregulated genes, and thus may serve as index markers of the immunomodulatory effects of CP extract. Finally, we identified the active components of CP extract, which inhibits tumor cell growth and stimulates anti-tumor

Metronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance.

PubMed

Kareva, Irina; Waxman, David J; Lakka Klement, Giannoula

2015-03-28

The administration of chemotherapy at reduced doses given at regular, frequent time intervals, termed 'metronomic' chemotherapy, presents an alternative to standard maximal tolerated dose (MTD) chemotherapy. The primary target of metronomic chemotherapy was originally identified as endothelial cells supporting the tumor vasculature, and not the tumor cells themselves, consistent with the emerging concept of cancer as a systemic disease involving both tumor cells and their microenvironment. While anti-angiogenesis is an important mechanism of action of metronomic chemotherapy, other mechanisms, including activation of anti-tumor immunity and a decrease in acquired therapeutic resistance, have also been identified. Here we present evidence supporting a mechanistic explanation for the improved activity of cancer chemotherapy when administered on a metronomic, rather than an MTD schedule and discuss the implications of these findings for further translation into the clinic. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Increased Tumor Oxygenation and Drug Uptake During Anti-Angiogenic Weekly Low Dose Cyclophosphamide Enhances the Anti-Tumor Effect of Weekly Tirapazamine

PubMed Central

Doloff, J.C.; Khan, N.; Ma, J.; Demidenko, E.; Swartz, H.M.; Jounaidi, Y.

2010-01-01

Metronomic cyclophosphamide treatment is associated with anti-angiogenic activity and is anticipated to generate exploitable hypoxia using hypoxia-activated prodrugs. Weekly administration of tirapazamine (TPZ; 5 mg/kg body weight i.p.) failed to inhibit the growth of 9L gliosarcoma tumors grown s.c. in scid mice. However, the anti-tumor effect of weekly cyclophosphamide (CPA) treatment (140 mg/kg BW i.p.) was substantially enhanced by weekly TPZ administration. An extended tumor free period and increased frequency of tumor eradication without overt toxicity were observed when TPZ was given 3, 4 or 5 days after each weekly CPA treatment. Following the 2nd CPA injection, Electron Paramagnetic Resonance (EPR) Oximetry indicated significant increases in tumor pO2, starting at 48 hr, which further increased after the 3rd CPA injection. pO2 levels were, however, stable in growing untreated tumors. A strong negative correlation (−0.81) between tumor pO2 and tumor volume during 21 days of weekly CPA chemotherapy was observed, indicating increasing tumor pO2 with decreasing tumor volume. Furthermore, CPA treatment resulted in increased tumor uptake of activated CPA. CPA induced increases in VEGF RNA, which reached a maximum on day 1, and in PLGF RNA which was sustained throughout the treatment, while anti-angiogenic host thrombospondin-1 increased dramatically through day 7 post-CPA treatment. Weekly cyclophosphamide treatment was anticipated to generate exploitable hypoxia. However, our findings suggest that weekly CPA treatment induces a functional improvement of tumor vasculature, which is characterized by increased tumor oxygenation and drug uptake in tumors, thus counter-intuitively, benefiting intratumoral activation of TPZ and perhaps other bioreductive drugs. PMID:19754361

Immune-system-dependent anti-tumor activity of a plant-derived polyphenol rich fraction in a melanoma mouse model

PubMed Central

Gomez-Cadena, A; Urueña, C; Prieto, K; Martinez-Usatorre, A; Donda, A; Barreto, A; Romero, P; Fiorentino, S

2016-01-01

Recent findings suggest that part of the anti-tumor effects of several chemotherapeutic agents require an intact immune system. This is in part due to the induction of immunogenic cell death. We have identified a gallotannin-rich fraction, obtained from Caesalpinia spinosa (P2Et) as an anti-tumor agent in both breast carcinoma and melanoma. Here, we report that P2Et treatment results in activation of caspase 3 and 9, mobilization of cytochrome c and externalization of annexin V in tumor cells, thus suggesting the induction of apoptosis. This was preceded by the onset of autophagy and the expression of immunogenic cell death markers. We further demonstrate that P2Et-treated tumor cells are highly immunogenic in vaccinated mice and induce immune system activation, clearly shown by the generation of interferon gamma (IFN-γ) producing tyrosine-related protein 2 antigen-specific CD8+ T cells. Moreover, the tumor protective effects of P2Et treatment were abolished in immunodeficient mice, and partially lost after CD4 and CD8 depletion, indicating that P2Et's anti-tumor activity is highly dependent on immune system and at least in part of T cells. Altogether, these results support the hypothesis that the gallotannin-rich fraction P2Et's anti-tumor effects are mediated to a great extent by the endogenous immune response following to the exposure to immunogenic dying tumor cells. PMID:27253407

Novel anti-Sialyl-Tn monoclonal antibodies and antibody-drug conjugates demonstrate tumor specificity and anti-tumor activity.

PubMed

Prendergast, Jillian M; Galvao da Silva, Ana Paula; Eavarone, David A; Ghaderi, Darius; Zhang, Mai; Brady, Dane; Wicks, Joan; DeSander, Julie; Behrens, Jeff; Rueda, Bo R

Targeted therapeutics that can differentiate between normal and malignant tumor cells represent the ideal standard for the development of a successful anti-cancer strategy. The Sialyl-Thomsen-nouveau antigen (STn or Sialyl-Tn, also known as CD175s) is rarely seen in normal adult tissues, but it is abundantly expressed in many types of human epithelial cancers. We have identified novel antibodies that specifically target with high affinity the STn glycan independent of its carrier protein, affording the potential to recognize a wider array of cancer-specific sialylated proteins. A panel of murine monoclonal anti-STn therapeutic antibodies were generated and their binding specificity and efficacy were characterized in vitro and in in vivo murine cancer models. A subset of these antibodies were conjugated to monomethyl auristatin E (MMAE) to generate antibody-drug conjugates (ADCs). These ADCs demonstrated in vitro efficacy in STn-expressing cell lines and significant tumor growth inhibition in STn-expressing tumor xenograft cancer models with no evidence of overt toxicity.

Anti-tumor and anti-metastasis activities of honey bee larvae powder by suppressing the expression of EZH2.

PubMed

Kageyama, Masakatsu; Li, Kejuan; Sun, Shuang; Xing, Guoqing; Gao, Ran; Lei, Zhongfang; Zhang, Zhenya

2018-06-12

Honey bee larvae products have been widely used as traditional daily supplements and complementary medicine for health promotion. However, there is little scientific evidence about their bioactivities. This study was designed to examine the anti-tumor and anti-metastasis effects of honey bee larvae powder (HLP) and explore the underlying mechanism. A subcutaneous transplantation model (murine breast cancer cell 4T1-LUC) and lung metastasis model (murine melanoma cell B16-F10) were established to evaluate the anti-tumor and anti-metastasis effects of HLP. Honey bee larvae powder extract (HLE) was obtained by 70% ethanol extraction, and its chemical composition was determined according to physiochemical methods. Cell Counting Kit-8 assay was performed to test the cytotoxicity of HLE, and qRT-PCR assays were conducted to examine the mRNA levels of tumor marker EZH2 in HLE-treated tumor cells. In vivo xenograft tumor assays in BALB/c mice revealed dose-dependent suppression of tumor growth and lung metastasis showing an inhibition rate of 37.5% and 70.4% at 6 g/kg HLP-administered group with no toxicity to the animals. In vitro studies indicated that HLE showed no cytotoxicity to cancer cells at doses up to 1000 μg/mL, however, it significantly decreased EZH2 mRNA levels in HLE (1000 μg/mL)-treated B10-F10 cells (28.49%) and 4T1-LUC cells (26.75%). Further studies to elucidate the mechanisms involved and to isolate the active components of honey bee larva may provide more valuable information for its development and application in cancer treatment. Copyright © 2018. Published by Elsevier Masson SAS.

Canine parvovirus NS1 protein exhibits anti-tumor activity in a mouse mammary tumor model.

PubMed

Gupta, Shishir Kumar; Yadav, Pavan Kumar; Gandham, Ravi Kumar; Sahoo, A P; Harish, D R; Singh, Arvind Kumar; Tiwari, A K

2016-02-02

Many viral proteins have the ability to kill tumor cells specifically without harming the normal cells. These proteins, on ectopic expression, cause lysis or induction of apoptosis in the target tumor cells. Parvovirus NS1 is one of such proteins, which is known to kill high proliferating tumor cells. In the present study, we assessed the apoptosis inducing ability of canine parvovirus type 2 NS1 protein (CPV2.NS1) in vitro in 4T1 cells, and found it to cause significant cell death due to induction of apoptosis through intrinsic or mitochondrial pathway. Further, we also evaluated the oncolytic activity of CPV2.NS1 protein in a mouse mammary tumor model. The results suggested that CPV2.NS1 was able to inhibit the growth of 4T1 induced mouse mammary tumor as indicated by significantly reduced tumor volume, mitotic, AgNOR and PCNA indices. Further, inhibition of tumor growth was found to be because of induction of apoptosis in the tumor cells, which was evident by a significant increase in the number of TUNEL positive cells. Further, CPV2.NS1 was also able to stimulate the immune cells against the tumor antigens as indicated by the increased CD4+ and CD8+ counts in the blood of CVP2.NS1 treated mice. Further optimization of the delivery of NS1 protein and use of an adjuvant may further enhance its anti-tumor activity. Copyright © 2015 Elsevier B.V. All rights reserved.

TH9 cells in anti-tumor immunity.

PubMed

Rivera Vargas, Thaiz; Humblin, Etienne; Végran, Frédérique; Ghiringhelli, François; Apetoh, Lionel

2017-01-01

IL-9 was initially identified as a T cell growth factor with a potential oncogenic activity. Accordingly, IL-9 drives tumor growth in most hematological cancers. However, the links between IL-9 and cancer progression have been recently revisited following the discovery of T H 9 cells. T H 9 cells, which have been characterized in 2008 as a proinflammatory CD4 T cell subset that promotes protection against parasites and drives tissue inflammation in colitis, actually harbor potent IL-9-dependent anti-cancer properties in solid tumors and especially melanoma. While the molecular mechanisms underlying these observations are still being investigated, T H 9 cells were demonstrated to activate both innate and adaptive immune responses, thereby favoring anti-cancer immunity and tumor elimination. Human T H 9 cells have also been identified in cancer tissues, but their functions remain elusive. The present review aims to discuss the anti-cancer potential of T H 9 cells and their possible clinical relevance for cancer immunotherapy.

Oral JS-38, a metabolite from Xenorhabdus sp., has both anti-tumor activity and the ability to elevate peripheral neutrophils.

PubMed

Liu, Min-Yu; Xiao, Lin; Chen, Geng-Hui; Wang, Yong-Xiang; Xiong, Wei-Xia; Li, Fei; Liu, Ying; Huang, Xiao-Ling; Deng, Yi-Fang; Zhang, Zhen; Sun, Hai-Yan; Liu, Quan-Hai; Yin, Ming

2014-10-01

JS-38 (mitothiolore), a synthetic version of a metabolite isolated from Xenorhabdus sp., was evaluated for its anti-tumor and white blood cell (WBC) elevating activities. These anti-proliferative activities were assessed in vitro using a panel of ten cell lines. The anti-tumor activities were tested in vivo using B16 allograft mouse models and xenograft models of A549 human lung carcinoma and QGY human hepatoma in nude mice. The anti-tumor interactions of JS-38 and cyclophosphamide (CTX) or 5-fluorouracil (5-Fu) were studied in a S180 sarcoma model in ICR mice. Specific stimulatory effects were determined on peripheral neutrophils in normal and CTX- and 5-Fu-induced neutropenic mice. The IC50 values ranged from 0.1 to 2.0 μmol·L(-1). JS-38 (1 μmol·L(-1)) caused an increase in A549 tumor cell apoptosis. Multi-daily gavage of JS-38 (15, 30, and 60 mg·kg(-1)·d(-1)) inhibited in vivo tumor progression without a significant effect on body weight. JS-38 additively enhanced the in vivo anti-tumor effects of CTX or 5-Fu. JS-38 increased peripheral neutrophil counts and neutrophil rates in normal BALB/c mice almost as effectively as granulocyte colony-stimulating factor (G-CSF). In mice with neutropenia induced by CTX or 5-Fu, JS-38 rapidly restored neutrophil counts. These results suggest that JS-38 has anti-tumor activity, and also has the ability to increase peripheral blood neutrophils. Copyright © 2014 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Alpha-tocopherol attenuates the anti-tumor activity of crizotinib against cells transformed by NPM-ALK

PubMed Central

Uchihara, Yuki; Ueda, Fumihito; Tago, Kenji; Nakazawa, Yosuke; Ohe, Tomoyuki; Mashino, Tadahiko; Yokota, Shigenobu; Kasahara, Tadashi; Tamura, Hiroomi

2017-01-01

Anaplastic large cell lymphomas (ALCL) are mainly characterized by harboring the fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The ALK inhibitor, crizotinib specifically induced apoptosis in Ba/F3 cells expressing NPM-ALK by inhibiting the activation of NPM-ALK and its downstream molecule, signal transducer and activator of transcription factor 3 (STAT3). We found that α-tocopherol, a major component of vitamin E, attenuated the effects of crizotinib independently of its anti-oxidant properties. Although α-tocopherol suppressed the inhibitory effects of crizotinib on the signaling axis including NPM-ALK and STAT3, it had no influence on the intake of crizotinib into cells. Crizotinib also directly inhibited the kinase activity of NPM-ALK; however, this inhibitory effect was not altered by the co-treatment with α-tocopherol. Whereas the nuclear localization of NPM-ALK was disappeared by the treatment with crizotinib, the co-treatment with α-tocopherol swept the effect of crizotinib and caused the localization of NPM-ALK in nucleus. The administration of α-tocopherol attenuated the anti-tumor activity of crizotinib against NPM-ALK-provoked tumorigenesis in vivo. Furthermore, the α-tocopherol-induced inhibition of crizotinib-caused apoptosis was also observed in NPM-ALK-positive cells derived from ALCL patients, namely, SUDHL-1 and Ki-JK. Collectively, these results not only revealed the novel mechanism underlying crizotinib-induced apoptosis in NPM-ALK-positive cells, but also suggest that the anti-tumor effects of crizotinib are attenuated when it is taken in combination with vitamin E. PMID:28806414

Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Ping; Fu, Shilong; Cao, Zhifei

Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressivemore » ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy. - Highlights: • Oroxin B selectively induces tumor-suppressive ER stress in B-lymphoma cells. • Oroxin B significantly prolonged overall survival of lymphoma-xenografted mice

CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response.

PubMed

Chatterjee, Shilpak; Daenthanasanmak, Anusara; Chakraborty, Paramita; Wyatt, Megan W; Dhar, Payal; Selvam, Shanmugam Panneer; Fu, Jianing; Zhang, Jinyu; Nguyen, Hung; Kang, Inhong; Toth, Kyle; Al-Homrani, Mazen; Husain, Mahvash; Beeson, Gyda; Ball, Lauren; Helke, Kristi; Husain, Shahid; Garrett-Mayer, Elizabeth; Hardiman, Gary; Mehrotra, Meenal; Nishimura, Michael I; Beeson, Craig C; Bupp, Melanie Gubbels; Wu, Jennifer; Ogretmen, Besim; Paulos, Chrystal M; Rathmell, Jeffery; Yu, Xue-Zhong; Mehrotra, Shikhar

2018-01-09

Heightened effector function and prolonged persistence, the key attributes of Th1 and Th17 cells, respectively, are key features of potent anti-tumor T cells. Here, we established ex vivo culture conditions to generate hybrid Th1/17 cells, which persisted long-term in vivo while maintaining their effector function. Using transcriptomics and metabolic profiling approaches, we showed that the enhanced anti-tumor property of Th1/17 cells was dependent on the increased NAD + -dependent activity of the histone deacetylase Sirt1. Pharmacological or genetic inhibition of Sirt1 activity impaired the anti-tumor potential of Th1/17 cells. Importantly, T cells with reduced surface expression of the NADase CD38 exhibited intrinsically higher NAD + , enhanced oxidative phosphorylation, higher glutaminolysis, and altered mitochondrial dynamics that vastly improved tumor control. Lastly, blocking CD38 expression improved tumor control even when using Th0 anti-tumor T cells. Thus, strategies targeting the CD38-NAD + axis could increase the efficacy of anti-tumor adoptive T cell therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

Tivantinib (ARQ-197) exhibits anti-tumor activity with down-regulation of FAK in oral squamous cell carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xi, Wei-Hong; Yang, Li-Yun; Cao, Zhong-Yi, E-mail: m18070383032@163.com

Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide and the 5 years survival rate of the patients is about 60% in the USA, due to acquired chemotherapeutic resistance and metastasis of the disease. In this study, we found that tivantinib, a selective MET inhibitor, suppresses OCSS cell proliferation and colony formation, however, anti-tumor activities induced by tivantinib are independent of the inhibition of MET signaling pathway. In addition, tivantinib cause G2/M cell cycle arrest and caspases-dependent apoptosis in OSCC cell lines. We also found that tivantinib dose-dependently suppressed the activation and expression of FAK. Inmore » all, these data suggested that tivantinib may be developed as a chemotherapeutic agent to effectively treat certain cancers including OSCC. - Highlights: • Tivantinib suppresses OSCC cell growth independent of the inhibition of HGF/MET signaling pathway. • Tivantinib blocks cell cycle and induces caspases-mediated apoptosis. • Tivantinib elicits its anti-tumor activity with the inhibition of FAK signaling pathway.« less

Necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy

PubMed Central

Wu, Zhi-Qiang; Shi, Yang-Yang; Zaorsky, Nicholas G.; Deng, Lei; Yuan, Zhi-Yong; Lu, You; Wang, Ping

2016-01-01

While the mechanisms underlying apoptosis and autophagy have been well characterized over recent decades, another regulated cell death event, necroptosis, remains poorly understood. Elucidating the signaling networks involved in the regulation of necroptosis may allow this form of regulated cell death to be exploited for diagnosis and treatment of cancer, and will contribute to the understanding of the complex tumor microenvironment. In this review, we have summarized the mechanisms and regulation of necroptosis, the converging and diverging features of necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy, as well as attempts to exploit this newly gained knowledge to provide therapeutics for cancer. PMID:27429198

Evaluation of anti-tumorigenic activity of BP3B against colon cancer with patient-derived tumor xenograft model.

PubMed

Kim, Hye-Youn; Kim, Jinhee; Ha Thi, Huyen Trang; Bang, Ok-Sun; Lee, Won-Suk; Hong, Suntaek

2016-11-18

KIOM-CRC#BP3B (BP3B) is a novel herbal prescription that is composed of three plant extracts. Our preliminary study identified that BP3B exhibited potent anti-proliferative activity against various types of cancer cell lines in vitro. Because the in vivo anti-tumor effect of BP3B is not evaluated before clinical trial, we want to test it using patient's samples. To confirm the in vivo anti-cancer effect of BP3B, we used genetically characterized patient-derived colon tumor xenograft (PDTX) mouse model. Anti-cancer activity was evaluated with apoptosis, proliferation, angiogenesis and histological analysis. Oral administration of BP3B significantly inhibited the tumor growth in two PDTX models. Furthermore, TUNEL assay showed that BP3B induced apoptosis of tumor tissues, which was associated with degradation of PARP and Caspase 8 and activation of Caspase 3. We also observed that BP3B inhibited cancer cell proliferation by down-regulation of Cyclin D1 and induction of p27 proteins. Inhibition of angiogenesis in BP3B-treated group was observed with immunofluorescence staining using CD31 and Tie-2 antibodies. These findings indicated that BP3B has a strong growth-inhibitory activity against colon cancer in in vivo model and will be a good therapeutic candidate for treatment of refractory colon cancer.

Non-thermal atmospheric pressure plasma activates lactate in Ringer’s solution for anti-tumor effects

NASA Astrophysics Data System (ADS)

Tanaka, Hiromasa; Nakamura, Kae; Mizuno, Masaaki; Ishikawa, Kenji; Takeda, Keigo; Kajiyama, Hiroaki; Utsumi, Fumi; Kikkawa, Fumitaka; Hori, Masaru

2016-11-01

Non-thermal atmospheric pressure plasma is a novel approach for wound healing, blood coagulation, and cancer therapy. A recent discovery in the field of plasma medicine is that non-thermal atmospheric pressure plasma not only directly but also indirectly affects cells via plasma-treated liquids. This discovery has led to the use of non-thermal atmospheric pressure plasma as a novel chemotherapy. We refer to these plasma-treated liquids as plasma-activated liquids. We chose Ringer’s solutions to produce plasma-activated liquids for clinical applications. In vitro and in vivo experiments demonstrated that plasma-activated Ringer’s lactate solution has anti-tumor effects, but of the four components in Ringer’s lactate solution, only lactate exhibited anti-tumor effects through activation by non-thermal plasma. Nuclear magnetic resonance analyses indicate that plasma irradiation generates acetyl and pyruvic acid-like groups in Ringer’s lactate solution. Overall, these results suggest that plasma-activated Ringer’s lactate solution is promising for chemotherapy.

Anti-angiogenic and anti-metastatic activity of JAK inhibitor AZD1480

PubMed Central

Xin, Hong; Herrmann, Andreas; Reckamp, Karen; Zhang, Wang; Pal, Sumanta; Hedvat, Michael; Zhang, Chunyan; Liang, Wei; Scuto, Anna; Weng, Shaobu; Morosini, Deborah; Cao, Zhu A.; Zinda, Michael; Figlin, Robert; Huszar, Dennis; Jove, Richard; Yu, Hua

2011-01-01

STAT3 has important functions in both tumor cells and the tumor microenvironment to facilitate cancer progression. The STAT regulatory kinase JAK has been strongly implicated in promoting oncogenesis of various solid tumors, including through the use of JAK kinase inhibitors such as AZD1480. However, direct evidence that JAK drives STAT3 function and cancer pathogenesis at the level of the tumor microenvironment has yet to be established clearly. In this study, we show that AZD1480 inhibits STAT3 in tumor-associated myeloid cells, reducing their number and inhibiting tumor metastasis. Myeloid cell-mediated angiogenesis was also diminished by AZD1480, with additional direct inhibition of endothelial cell function in vitro and in vivo. AZD1480 blocked lung infiltration of myeloid cells and formation of pulmonary metastases in both mouse syngeneic experimental and spontaneous metastatic models. Furthermore, AZD1480 reduced angiogenesis and metastasis in a human xenograft tumor model. Although the effects of AZD1480 on the tumor microenvironment were important for the observed anti-angiogenic activity, constitutive activation of STAT3 in tumor cells themselves could block these anti-angiogenic effects demonstrating the complexity of the JAK/STAT signaling network in tumor progression. Together, our results indicated that AZD1480 can effectively inhibit tumor angiogenesis and metastasis mediated by STAT3 in stromal cells as well as tumor cells. PMID:21920898

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer.

PubMed

Telli, M L; Stover, D G; Loi, S; Aparicio, S; Carey, L A; Domchek, S M; Newman, L; Sledge, G W; Winer, E P

2018-05-07

Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit. We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection. Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise. HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of 'immune cold' TNBCs.

A Novel Immunomodulatory Hemocyanin from the Limpet Fissurella latimarginata Promotes Potent Anti-Tumor Activity in Melanoma

PubMed Central

Arancibia, Sergio; Espinoza, Cecilia; Salazar, Fabián; Del Campo, Miguel; Tampe, Ricardo; Zhong, Ta-Ying; De Ioannes, Pablo; Moltedo, Bruno; Ferreira, Jorge; Lavelle, Ed C.; Manubens, Augusto; De Ioannes, Alfredo E.; Becker, María Inés

2014-01-01

Hemocyanins, the huge oxygen-transporting glycoproteins of some mollusks, are used as immunomodulatory proteins with proven anti-cancer properties. The biodiversity of hemocyanins has promoted interest in identifying new anti-cancer candidates with improved immunological properties. Hemocyanins promote Th1 responses without known side effects, which make them ideal for long-term sustained treatment of cancer. In this study, we evaluated a novel hemocyanin from the limpet/gastropod Fissurella latimarginata (FLH). This protein has the typical hollow, cylindrical structure of other known hemocyanins, such as the keyhole limpet hemocyanin (KLH) and the Concholepas hemocyanin (CCH). FLH, like the KLH isoforms, is composed of a single type of polypeptide with exposed N- and O-linked oligosaccharides. However, its immunogenicity was significantly greater than that of KLH and CCH, as FLH induced a stronger humoral immune response and had more potent anti-tumor activity, delaying tumor growth and increasing the survival of mice challenged with B16F10 melanoma cells, in prophylactic and therapeutic settings. Additionally, FLH-treated mice demonstrated increased IFN-γ production and higher numbers of tumor-infiltrating CD4+ lymphocytes. Furthermore, in vitro assays demonstrated that FLH, but not CCH or KLH, stimulated the rapid production of pro-inflammatory cytokines (IL-6, IL-12, IL-23 and TNF-α) by dendritic cells, triggering a pro-inflammatory milieu that may explain its enhanced immunological activity. Moreover, this effect was abolished when deglycosylated FLH was used, suggesting that carbohydrates play a crucial role in the innate immune recognition of this protein. Altogether, our data demonstrate that FLH possesses increased anti-tumor activity in part because it activates a more potent innate immune response in comparison to other known hemocyanins. In conclusion, FLH is a potential new marine adjuvant for immunization and possible cancer immunotherapy. PMID

A novel immunomodulatory hemocyanin from the limpet Fissurella latimarginata promotes potent anti-tumor activity in melanoma.

PubMed

Arancibia, Sergio; Espinoza, Cecilia; Salazar, Fabián; Del Campo, Miguel; Tampe, Ricardo; Zhong, Ta-Ying; De Ioannes, Pablo; Moltedo, Bruno; Ferreira, Jorge; Lavelle, Ed C; Manubens, Augusto; De Ioannes, Alfredo E; Becker, María Inés

2014-01-01

Hemocyanins, the huge oxygen-transporting glycoproteins of some mollusks, are used as immunomodulatory proteins with proven anti-cancer properties. The biodiversity of hemocyanins has promoted interest in identifying new anti-cancer candidates with improved immunological properties. Hemocyanins promote Th1 responses without known side effects, which make them ideal for long-term sustained treatment of cancer. In this study, we evaluated a novel hemocyanin from the limpet/gastropod Fissurella latimarginata (FLH). This protein has the typical hollow, cylindrical structure of other known hemocyanins, such as the keyhole limpet hemocyanin (KLH) and the Concholepas hemocyanin (CCH). FLH, like the KLH isoforms, is composed of a single type of polypeptide with exposed N- and O-linked oligosaccharides. However, its immunogenicity was significantly greater than that of KLH and CCH, as FLH induced a stronger humoral immune response and had more potent anti-tumor activity, delaying tumor growth and increasing the survival of mice challenged with B16F10 melanoma cells, in prophylactic and therapeutic settings. Additionally, FLH-treated mice demonstrated increased IFN-γ production and higher numbers of tumor-infiltrating CD4(+) lymphocytes. Furthermore, in vitro assays demonstrated that FLH, but not CCH or KLH, stimulated the rapid production of pro-inflammatory cytokines (IL-6, IL-12, IL-23 and TNF-α) by dendritic cells, triggering a pro-inflammatory milieu that may explain its enhanced immunological activity. Moreover, this effect was abolished when deglycosylated FLH was used, suggesting that carbohydrates play a crucial role in the innate immune recognition of this protein. Altogether, our data demonstrate that FLH possesses increased anti-tumor activity in part because it activates a more potent innate immune response in comparison to other known hemocyanins. In conclusion, FLH is a potential new marine adjuvant for immunization and possible cancer immunotherapy.

Chimeric antigen receptors with human scFvs preferentially induce T cell anti-tumor activity against tumors with high B7H6 expression.

PubMed

Gacerez, Albert T; Hua, Casey K; Ackerman, Margaret E; Sentman, Charles L

2018-05-01

B7H6 is emerging as a promising tumor antigen that is known to be expressed on a wide array of tumors and is reported to stimulate anti-tumor responses from the immune system. As such, B7H6 presents a good target for tumor-specific immunotherapies. B7H6-specific chimeric antigen receptors (CAR) based on a murine antibody showed successful targeting and elimination of tumors expressing B7H6. However, mouse single chain variable fragments (scFvs) have the potential to induce host anti-CAR responses that may limit efficacy, so human scFvs specific for B7H6 were selected by yeast surface display. In this study, we validate the functionality of these human scFvs when formatted into chimeric antigen receptors. The data indicate that T cells expressing these B7H6-specific human scFvs as CARs induced potent anti-tumor activity in vitro and in vivo against tumors expressing high amounts of B7H6. Importantly, these human scFv-based CARs are sensitive to changes in B7H6 expression which may potentially spare non-tumor cells that express B7H6 and provides the foundation for future clinical development.

Macrophage PPARγ inhibits Gpr132 to mediate the anti-tumor effects of rosiglitazone

PubMed Central

Cheng, Wing Yin; Huynh, HoangDinh; Chen, Peiwen; Peña-Llopis, Samuel; Wan, Yihong

2016-01-01

Tumor-associated macrophage (TAM) significantly contributes to cancer progression. Human cancer is enhanced by PPARγ loss-of-function mutations, but inhibited by PPARγ agonists such as TZD diabetes drugs including rosiglitazone. However, it remains enigmatic whether and how macrophage contributes to PPARγ tumor-suppressive functions. Here we report that macrophage PPARγ deletion in mice not only exacerbates mammary tumor development but also impairs the anti-tumor effects of rosiglitazone. Mechanistically, we identify Gpr132 as a novel direct PPARγ target in macrophage whose expression is enhanced by PPARγ loss but repressed by PPARγ activation. Functionally, macrophage Gpr132 is pro-inflammatory and pro-tumor. Genetic Gpr132 deletion not only retards inflammation and cancer growth but also abrogates the anti-tumor effects of PPARγ and rosiglitazone. Pharmacological Gpr132 inhibition significantly impedes mammary tumor malignancy. These findings uncover macrophage PPARγ and Gpr132 as critical TAM modulators, new cancer therapeutic targets, and essential mediators of TZD anti-cancer effects. DOI: http://dx.doi.org/10.7554/eLife.18501.001 PMID:27692066

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities.

PubMed

Peters, Diane E; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A; Leppla, Stephen H; Bugge, Thomas H

2014-09-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5-3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. Published by Elsevier Inc.

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

PubMed Central

Peters, Diane E.; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A.; Leppla, Stephen H.; Bugge, Thomas H.

2014-01-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; Mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA- activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32%–87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. PMID:24971906

Porritoxins, metabolites of Alternaria porri, as anti-tumor-promoting active compounds.

PubMed

Horiuchi, Masayuki; Tokuda, Harukuni; Ohnishi, Keiichiro; Yamashita, Masakazu; Nishino, Hoyoku; Maoka, Takashi

2006-02-01

To search for possible cancer chemopreventive agents from natural sources, we performed primary screening of metabolites of Alternaria porri by examining their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. The ethyl acetate extract of A. porri showed the inhibitory effect on EBV-EA activation. Three porritoxins (1-3) were obtained as inhibitory active compounds for EBV-EA from ethyl acetate extract. 6-(3',3'-Dimethylallyloxy)-4-methoxy-5-methylphthalide (2) showed the strongest activity among them. Inhibitory effect of porritoxin (1) and (2) was superior to that of beta-carotene, a well-known anti-tumor promoter. Furthermore, the structure-activity correlation of porritoxins and their related compounds were discussed.

Phenformin Inhibits Myeloid-Derived Suppressor Cells and Enhances the Anti-Tumor Activity of PD-1 Blockade in Melanoma.

PubMed

Kim, Sun Hye; Li, Man; Trousil, Sebastian; Zhang, Yaqing; Pasca di Magliano, Marina; Swanson, Kenneth D; Zheng, Bin

2017-08-01

Biguanides, such as the diabetes therapeutics metformin and phenformin, have shown antitumor activity both in vitro and in vivo. However, their potential effects on the tumor microenvironment are largely unknown. Here we report that phenformin selectively inhibits granulocytic myeloid-derived suppressor cells in spleens of tumor-bearing mice and ex vivo. Phenformin induces production of reactive oxygen species in granulocytic myeloid-derived suppressor cells, whereas the antioxidant N-acetylcysteine attenuates the inhibitory effects of phenformin. Co-treatment of phenformin enhances the effect of anti-PD-1 antibody therapy on inhibiting tumor growth in the BRAF V600E/PTEN-null melanoma mouse model. Combination of phenformin and anti PD-1 cooperatively induces CD8 + T-cell infiltration and decreases levels of proteins that are critical for immune suppressive activities of myeloid-derived suppressor cells. Our findings show a selective, inhibitory effect of phenformin on granulocytic myeloid-derived suppressor cell-driven immune suppression and support that phenformin improves the anti-tumor activity of PD-1 blockade immunotherapy in melanoma. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Anti-tumor activities of peptides corresponding to conserved complementary determining regions from different immunoglobulins.

PubMed

Figueiredo, Carlos R; Matsuo, Alisson L; Massaoka, Mariana H; Polonelli, Luciano; Travassos, Luiz R

2014-09-01

Short synthetic peptides corresponding to sequences of complementarity-determining regions (CDRs) from different immunoglobulin families have been shown to induce antimicrobial, antiviral and antitumor activities regardless of the specificity of the original monoclonal antibody (mAb). Presently, we studied the in vitro and in vivo antitumor activity of synthetic peptides derived from conserved CDR sequences of different immunoglobulins against human tumor cell lines and murine B16F10-Nex2 melanoma aiming at the discovery of candidate molecules for cancer therapy. Four light- and heavy-chain CDR peptide sequences from different antibodies (C36-L1, HA9-H2, 1-H2 and Mg16-H2) showed cytotoxic activity against murine melanoma and a panel of human tumor cell lineages in vitro. Importantly, they also exerted anti-metastatic activity using a syngeneic melanoma model in mice. Other peptides (D07-H3, MN20v1, MS2-H3) were also protective against metastatic melanoma, without showing significant cytotoxicity against tumor cells in vitro. In this case, we suggest that these peptides may act as immune adjuvants in vivo. As observed, peptides induced nitric oxide production in bone-marrow macrophages showing that innate immune cells can also be modulated by these CDR peptides. The present screening supports the search in immunoglobulins of rather frequent CDR sequences that are endowed with specific antitumor properties and may be candidates to be developed as anti-cancer drugs. Copyright © 2014 Elsevier Inc. All rights reserved.

Synthesis and anti-tumor evaluation of panaxadiol halogen-derivatives.

PubMed

Xiao, Shengnan; Chen, Shuai; Sun, Yuanyuan; Zhou, Wuxi; Piao, Huri; Zhao, Yuqing

2017-09-01

In the current work, 13 novel panaxadiol (PD) derivatives were synthesized by reacting with chloroacetyl chloride and bromoacetyl bromide. Their in vitro antitumor activities were evaluated on three human tumor cell lines (HCT-116, BGC-823, SW-480) and three normal cells (human gastric epithelial cell line-GES-1, hair follicle dermal papilla cell line-HHDPC and rat myocardial cell line-H9C2) by MTT assay. Compared with PD, the results demonstrated that compound 1e, 2d, 2e showed significant anti-tumor activity against three tumor cell lines, the IC50 value of compound 2d against HCT-116 was the lowest (3.836μM). The anti-tumor activity of open-ring compounds are significantly better than the compounds of C-25 cyclization. Compound 1f, 2f, 2g showed the strong anti-tumor activity. The IC50 value of compound 2g against BGC-823 and SW-480 were the lowest (0.6μM and 0.1μM, respectively). Combined with cytotoxicity test, the IC50 value of compound 1e, 2d, 2e are greater than 100. the open-ring compounds (1f, 2f, 2g) showed a strong toxicity. The toxicity of 1f is lower than 2f and 2g. These compounds may be useful for the development of novel antiproliferative agents. Copyright © 2017. Published by Elsevier Ltd.

Nanosuspension delivery of paclitaxel to xenograft mice can alter drug disposition and anti-tumor activity

NASA Astrophysics Data System (ADS)

Chiang, Po-Chang; Gould, Stephen; Nannini, Michelle; Qin, Ann; Deng, Yuzhong; Arrazate, Alfonso; Kam, Kimberly R.; Ran, Yingqing; Wong, Harvey

2014-04-01

Paclitaxel is a common chemotherapeutic agent that is effective against various cancers. The poor aqueous solubility of paclitaxel necessitates a large percentage of Cremophor EL:ethanol (USP) in its commercial formulation which leads to hypersensitivity reactions in patients. We evaluate the use of a crystalline nanosuspension versus the USP formulation to deliver paclitaxel to tumor-bearing xenograft mice. Anti-tumor efficacy was assessed following intravenous administration of three 20 mg/kg doses of paclitaxel. Paclitaxel pharmacokinetics and tissue distribution were evaluated, and differences were observed between the two formulations. Plasma clearance and tissue to plasma ratio of mice that were dosed with the nanosuspension are approximately 33- and 11-fold higher compared to those of mice that were given the USP formulation. Despite a higher tumor to plasma ratio for the nanosuspension treatment group, absolute paclitaxel tumor exposure was higher for the USP group. Accordingly, a higher anti-tumor effect was observed in the xenograft mice that were dosed with the USP formulation (90% versus 42% tumor growth inhibition). This reduction in activity of nanoparticle formulation appeared to result from a slower than anticipated dissolution in vivo. This study illustrates a need for careful consideration of both dose and systemic solubility prior utilizing nanosuspension as a mode of intravenous delivery.

Design, synthesis, anti-lung cancer activity, and chemosensitization of tumor-selective MCACs based on ROS-mediated JNK pathway activation and NF-κB pathway inhibition.

PubMed

Chen, Liping; Li, Qian; Weng, Bixia; Wang, Jiabing; Zhou, Yangyang; Cheng, Dezhi; Sirirak, Thanchanok; Qiu, Peihong; Wu, Jianzhang

2018-05-10

EF24 and F35 both were effective monocarbonyl curcumin analogues (MCACs) with excellent anti-tumor activity, however, drug defect such as toxicity may limit their further development. To get anti-lung cancer drugs with high efficiency, low toxicity and chemosensitization, a series of analogues based on EF24 and F35 were designed and synthesized. A number of compounds were found to exhibit cytotoxic activities selectively towards lung cancer cells compared to normal cells. Among these compounds, 5B was considered as an optimal anti-tumor agent for lung cancer cells with IC 50 values ranging from 1.0 to 1.7 μM, selectivity index (SI, as a logarithm of a ratio of IC 50 value for normal and cancer cells) were all above 1.1, while the SI of EF24 and F35 were less than 0.8. Consistent with selectivity in vitro, 5B was observed to show lower toxicity in acute toxicity experiment than EF24 and F35 respectively. Further, 5B was found to exert anti-tumor effects through ROS-mediated activation of JNK pathway and inhibition of NF-κB pathway. 5B could significantly enhance the sensitivity of A549 cells to cisplatin or 5-Fu. These findings suggested that 5B was an effective and less toxic MCAC and provided a promising candidate for anti-tumor drugs. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Correlation between anti-PD-L1 tumor concentrations and tumor-specific and nonspecific biomarkers in a melanoma mouse model

PubMed Central

Contreras, Ana M.; Merino, María; Vasquez, Marcos; Trocóniz, Iñaki F.

2016-01-01

Blockade of PD-L1 with specific monoclonal antibodies (anti-PD-L1) represents a therapeutic strategy to increase the capability of the immune system to modulate the tumor immune-resistance. The relationship between anti-PD-L1 tumor exposition and anti-tumor effect represents a challenge that has been addressed in this work through the identification of certain biomarkers implicated in the antibody's mechanism of action, using a syngeneic melanoma mouse model. The development of an in-vitro/in-vivo platform has allowed us to investigate the PD-L1 behavior after its blockage with anti-PD-L1 at cellular level and in animals. In-vitro studies showed that the complex PD-L1/anti-PD-L1 was retained mainly at the cell surface. The antibody concentration and time exposure affected directly the recycling or ligand turnover. In-vivo studies showed that anti-PD-L1 was therapeutically active at all stage of the disease, with a rapid onset, a low but durable efficacy and non-relevant toxic effect. This efficacy measured as tumor shrinkage correlated with tumor-specific infiltrating lymphocytes (TILs), which increased as antibody tumor concentrations increased. Both, TILS and antibody concentrations followed similar kinetic patterns, justifying the observed anti-PD-L1 rapid onset. Interestingly, peripheral lymphocytes (PBLs) behave as infiltrating lymphocytes, suggesting that these PBLs might be considered as a possible biomarker for antibody activity. PMID:27764774

YAP is essential for Treg mediated suppression of anti-tumor immunity.

PubMed

Ni, Xuhao; Tao, Jinhui; Barbi, Joseph; Chen, Qian; Park, Benjamin V; Li, Zhiguang; Zhang, Nailing; Lebid, Andriana; Ramaswamy, Anjali; Wei, Ping; Zheng, Ying; Zhang, Xuehong; Wu, Xingmei; Vignali, Paolo D A; Yang, Cuiping; Li, Huabin; Pardoll, Drew; Lu, Ling; Pan, Duojia; Pan, Fan

2018-06-15

Regulatory T cells (Tregs) are critical for maintaining self-tolerance and immune homeostasis, but their suppressive function can impede effective anti-tumor immune responses. Foxp3 is a transcription factor expressed in Tregs that is required for their function. However, the pathways and microenvironmental cues governing Foxp3 expression and Treg function are not completely understood. Herein, we report that Yes-associated protein (YAP), a co-activator of the Hippo pathway, is highly expressed in Tregs and bolsters Foxp3 expression and Treg function in vitro and in vivo. This potentiation stemmed from YAP-dependent upregulation of Activin signaling which amplifies TGFβ/SMAD activation in Tregs. YAP-deficiency resulted in dysfunctional Tregs unable to suppress anti-tumor immunity or promote tumor growth in mice. Chemical YAP antagonism and knockout or blockade of the YAP-regulated Activin Receptor similarly improved anti-tumor immunity. Thus we identify YAP as an unexpected amplifier of a Treg-reinforcing pathway with significant potential as an anti-cancer immunotherapeutic target. Copyright ©2018, American Association for Cancer Research.

Pyruvate induces transient tumor hypoxia by enhancing mitochondrial oxygen consumption and potentiates the anti-tumor effect of a hypoxia-activated prodrug TH-302.

PubMed

Takakusagi, Yoichi; Matsumoto, Shingo; Saito, Keita; Matsuo, Masayuki; Kishimoto, Shun; Wojtkowiak, Jonathan W; DeGraff, William; Kesarwala, Aparna H; Choudhuri, Rajani; Devasahayam, Nallathamby; Subramanian, Sankaran; Munasinghe, Jeeva P; Gillies, Robert J; Mitchell, James B; Hart, Charles P; Krishna, Murali C

2014-01-01

TH-302 is a hypoxia-activated prodrug (HAP) of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302. The hypoxia-dependent cytotoxicity of TH-302 was evaluated by a viability assay in murine SCCVII and human HT29 cells. Modulation in cellular oxygen consumption and in vivo tumor oxygenation by the pyruvate treatment was monitored by extracellular flux analysis and electron paramagnetic resonance (EPR) oxygen imaging, respectively. The enhancement of the anti-tumor effect of TH-302 by pyruvate treatment was evaluated by monitoring the growth suppression of the tumor xenografts inoculated subcutaneously in mice. TH-302 preferentially inhibited the growth of both SCCVII and HT29 cells under hypoxic conditions (0.1% O2), with minimal effect under aerobic conditions (21% O2). Basal oxygen consumption rates increased after the pyruvate treatment in SCCVII cells in a concentration-dependent manner, suggesting that pyruvate enhances the mitochondrial respiration to consume excess cellular oxygen. In vivo EPR oxygen imaging showed that the intravenous administration of pyruvate globally induced the transient hypoxia 30 min after the injection in SCCVII and HT29 tumors at the size of 500-1500 mm(3). Pretreatment of SCCVII tumor bearing mice with pyruvate 30 min prior to TH-302 administration, initiated with small tumors (∼ 550 mm(3)), significantly delayed tumor growth. Our in vitro and in vivo studies showed that pyruvate induces transient hypoxia by enhancing mitochondrial oxygen consumption in tumor cells. TH-302 therapy can be potentiated by pyruvate pretreatment if started at the appropriate tumor size and oxygen concentration.

Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs.

PubMed

Murray, Michael; Hraiki, Adam; Bebawy, Mary; Pazderka, Curtis; Rawling, Tristan

2015-06-01

Lipids have the potential for development as anticancer agents. Endogenous membrane lipids, such as ceramides and certain saturated fatty acids, have been found to modulate the viability of tumor cells. In addition, many tumors over-express cyclooxygenase, lipoxygenase or cytochrome P450 enzymes that mediate the biotransformation of ω-6 polyunsaturated fatty acids (PUFAs) to potent eicosanoid regulators of tumor cell proliferation and cell death. In contrast, several analogous products from the biotransformation of ω-3 PUFAs impair particular tumorigenic pathways. For example, the ω-3 17,18-epoxide of eicosapentaenoic acid activates anti-proliferative and proapoptotic signaling cascades in tumor cells and the lipoxygenase-derived resolvins are effective inhibitors of inflammatory pathways that may drive tumor expansion. However, the development of potential anti-cancer drugs based on these molecules is complex, with in vivo stability a major issue. Nevertheless, recent successes with the antitumor alkyl phospholipids, which are synthetic analogues of naturally-occurring membrane phospholipid esters, have provided the impetus for development of further molecules. The alkyl phospholipids have been tested against a range of cancers and show considerable activity against skin cancers and certain leukemias. Very recently, it has been shown that combination strategies, in which alkyl phospholipids are used in conjunction with established anticancer agents, are promising new therapeutic approaches. In future, the evaluation of new lipid-based molecules in single-agent and combination treatments may also be assessed. This could provide a range of important treatment options in the management of advanced and metastatic cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling.

PubMed

Su, Rui; Dong, Lei; Li, Chenying; Nachtergaele, Sigrid; Wunderlich, Mark; Qing, Ying; Deng, Xiaolan; Wang, Yungui; Weng, Xiaocheng; Hu, Chao; Yu, Mengxia; Skibbe, Jennifer; Dai, Qing; Zou, Dongling; Wu, Tong; Yu, Kangkang; Weng, Hengyou; Huang, Huilin; Ferchen, Kyle; Qin, Xi; Zhang, Bin; Qi, Jun; Sasaki, Atsuo T; Plas, David R; Bradner, James E; Wei, Minjie; Marcucci, Guido; Jiang, Xi; Mulloy, James C; Jin, Jie; He, Chuan; Chen, Jianjun

2018-01-11

R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, was reported as an oncometabolite. We show here that R-2HG also exerts a broad anti-leukemic activity in vitro and in vivo by inhibiting leukemia cell proliferation/viability and by promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits fat mass and obesity-associated protein (FTO) activity, thereby increasing global N 6 -methyladenosine (m 6 A) RNA modification in R-2HG-sensitive leukemia cells, which in turn decreases the stability of MYC/CEBPA transcripts, leading to the suppression of relevant pathways. Ectopically expressed mutant IDH1 and S-2HG recapitulate the effects of R-2HG. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. Collectively, while R-2HG accumulated in IDH1/2 mutant cancers contributes to cancer initiation, our work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m 6 A/MYC/CEBPA signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

Enhancement of anti-tumor activity of hybrid peptide in conjugation with carboxymethyl dextran via disulfide linkers.

PubMed

Gaowa, Arong; Horibe, Tomohisa; Kohno, Masayuki; Tabata, Yasuhiko; Harada, Hiroshi; Hiraoka, Masahiro; Kawakami, Koji

2015-05-01

To improve the anti-tumor activity of EGFR2R-lytic hybrid peptide, we prepared peptide-modified dextran conjugates with the disulfide bonds between thiolated carboxymethyl dextran (CMD-Cys) and cysteine-conjugated peptide (EGFR2R-lytic-Cys). In vitro release studies showed that the peptide was released from the CMD-s-s-peptide conjugate in a concentration-dependent manner in the presence of glutathione (GSH, 2μM-2mM). The CMD-s-s-peptide conjugate exhibited a similar cytotoxic activity with free peptide alone against human pancreatic cancer BxPC-3 cells in vitro. Furthermore, it was shown that the CMD-s-s-peptide conjugates were highly accumulated in tumor tissue in a mouse xenograft model using BxPC-3 cells, and the anti-tumor activity of the conjugate was more effective than that of the free peptide. In addition, the plasma concentrations of peptide were moderately increased and the elimination half-life of the peptide was prolonged after intravenous injection of CMD-s-s-peptide conjugates. These results demonstrated that the conjugate based on thiolated CMD polymer would be potentially useful carriers for the sustained release of the hybrid peptide in vivo. Copyright © 2015 Elsevier B.V. All rights reserved.

Anti-cancer activity of Annexin V in murine melanoma model by suppressing tumor angiogenesis.

PubMed

Zhang, Xuerui; Huo, Lina; Jin, Haibo; Han, Yuheng; Wang, Jie; Zhang, Yanjun; Lai, Xinghuan; Le, Ziwei; Zhang, Jing; Hua, Zichun

2017-06-27

Annexin V, a protein with high affinity to phosphatidylserine (PS) in a calcium dependent manner, has been widely used to probe apoptosis. Annexin V in inhibiting engulfment of apoptotic cells by macrophages had been reported to increase the immunogenicity of tumor cells undergoing apoptosis. However, far less is known about its multiple properties, especially in cancer therapies. Here we found that Annexin V had a good anti-tumor activity in murine melanomaxenograft model. Treatment with Annexin V showed significant reduction in tumor size and remarkable tumor necrosis areas. The serum level of VEGF was downregualted by Annexin V both in normal mice and mice bearing tumor, suggesting that its new role on impeding tumor angiogenesis. In Silico analysis using Oncomine database, we also found the negative correlation of AnnexinV and VEGF both in skin and melanoma. The decreased Annexin V expression shows linearity relation with the elevated VEGF expression. These data provided a possibility that Annexin V can be used as a novel angiogenesis inhibitor in tumor therapy.

Anti-tumor effects of an engineered 'killer' transfer RNA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Dong-hui; Lee, Jiyoung; Frankenberger, Casey

2012-10-12

Highlights: Black-Right-Pointing-Pointer tRNA with anti-cancer effects. Black-Right-Pointing-Pointer tRNA induced protein misfolding. Black-Right-Pointing-Pointer tRNA as anti-tumor agent. -- Abstract: A hallmark of cancer cells is their ability to continuously divide; and rapid proliferation requires increased protein translation. Elevating levels of misfolded proteins can elicit growth arrest due to ER stress and decreased global translation. Failure to correct prolonged ER stress eventually results in cell death via apoptosis. tRNA{sup Ser}(AAU) is an engineered human tRNA{sup Ser} with an anticodon coding for isoleucine. Here we test the possibility that tRNA{sup Ser}(AAU) can be an effective killing agent of breast cancer cells and canmore » effectively inhibit tumor-formation in mice. We found that tRNA{sup Ser}(AAU) exert strong effects on breast cancer translation activity, cell viability, and tumor formation. Translation is strongly inhibited by tRNA{sup Ser}(AAU) in both tumorigenic and non-tumorigenic cells. tRNA{sup Ser}(AAU) significantly decreased the number of viable cells over time. A short time treatment with tRNA{sup Ser}(AAU) was sufficient to eliminate breast tumor formation in a xenograft mouse model. Our results indicate that tRNA{sup Ser}(AAU) can inhibit breast cancer metabolism, growth and tumor formation. This RNA has strong anti-cancer effects and presents an opportunity for its development into an anti-tumor agent. Because tRNA{sup Ser}(AAU) corrupts the protein synthesis mechanism that is an integral component of the cell, it would be extremely difficult for tumor cells to evolve and develop resistance against this anti-tumor agent.« less

The natural product chitosan enhances the anti-tumor activity of natural killer cells by activating dendritic cells.

PubMed

Li, Xinxin; Dong, Wenjuan; Nalin, Ansel P; Wang, Yufeng; Pan, Pan; Xu, Bo; Zhang, Yibo; Tun, Steven; Zhang, Jianying; Wang, Li-Shu; He, Xiaoming; Caligiuri, Michael A; Yu, Jianhua

2018-01-01

Natural products comprise an important class of biologically active molecules. Many of these compounds derived from natural sources exhibit specific physiologic or biochemical effects. An example of a natural product is chitosan, which is enriched in the shells of certain seafood that are frequently consumed worldwide. Like other natural products, chitosan has the potential for applications in clinical medicine and perhaps in cancer therapy. Toward this end, the immunomodulatory or anti-cancer properties of chitosan have yet to be reported. In this study, we discovered that chitosan enhanced the anti-tumor activity of natural killer (NK) cells by activating dendritic cells (DCs). In the presence of DCs, chitosan augmented IFN-γ production by human NK cells. Mechanistically, chitosan activated DCs to express pro-inflammatory cytokines such as interleukin (IL)-12 and IL-15, which in turn activated the STAT4 and NF-κB signaling pathways, respectively, in NK cells. Moreover, chitosan promoted NK cell survival, and also enhanced NK cell cytotoxicity against leukemia cells. Finally, a related in vivo study demonstrated that chitosan activated NK cells against B16F10 tumor cells in an immunocompetent syngeneic murine melanoma model. This effect was accompanied by in vivo upregulation of IL-12 and IL-15 in DCs, as well as increased IFN-γ production and cytolytic degranulation in NK cells. Collectively, our results demonstrate that chitosan activates DCs leading to enhanced capacity for immune surveillance by NK cells. We believe that our study has future clinical applications for chitosan in the prevention or treatment of cancer and infectious diseases.

Phosphatidylserine-targeting antibodies augment the anti-tumorigenic activity of anti-PD-1 therapy by enhancing immune activation and downregulating pro-oncogenic factors induced by T-cell checkpoint inhibition in murine triple-negative breast cancers.

PubMed

Gray, Michael J; Gong, Jian; Hatch, Michaela M S; Nguyen, Van; Hughes, Christopher C W; Hutchins, Jeff T; Freimark, Bruce D

2016-05-11

The purpose of this study was to investigate the potential of antibody-directed immunotherapy targeting the aminophospholipid phosphatidylserine, which promotes immunosuppression when exposed in the tumor microenvironment, alone and in combination with antibody treatment towards the T-cell checkpoint inhibitor PD-1 in breast carcinomas, including triple-negative breast cancers. Immune-competent mice bearing syngeneic EMT-6 or E0771 tumors were subjected to treatments comprising of a phosphatidylserine-targeting and an anti-PD-1 antibody either as single or combinational treatments. Anti-tumor effects were determined by tumor growth inhibition and changes in overall survival accompanying each treatment. The generation of a tumor-specific immune response in animals undergoing complete tumor regression was assessed by secondary tumor cell challenge and splenocyte-produced IFNγ in the presence or absence of irradiated tumor cells. Changes in the presence of tumor-infiltrating lymphocytes were assessed by flow cytometry, while mRNA-based immune profiling was determined using NanoString PanCancer Immune Profiling Panel analysis. Treatment by a phosphatidylserine-targeting antibody inhibits in-vivo growth and significantly enhances the anti-tumor activity of antibody-mediated PD-1 therapy, including providing a distinct survival advantage over treatment by either single agent. Animals in which complete tumor regression occurred with combination treatments were resistant to secondary tumor challenge and presented heightened expression levels of splenocyte-produced IFNγ. Combinational treatment by a phosphatidylserine-targeting antibody with anti-PD-1 therapy increased the number of tumor-infiltrating lymphocytes more than that observed with single-arm therapies. Finally, immunoprofiling analysis revealed that the combination of anti-phosphatidylserine targeting antibody and anti-PD-1 therapy enhanced tumor-infiltrating lymphocytes, and increased expression of pro

Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity

PubMed Central

Dahlberg, Carin I. M.; Sarhan, Dhifaf; Chrobok, Michael; Duru, Adil D.; Alici, Evren

2015-01-01

Natural killer (NK) cells were discovered 40 years ago, by their ability to recognize and kill tumor cells without the requirement of prior antigen exposure. Since then, NK cells have been seen as promising agents for cell-based cancer therapies. However, NK cells represent only a minor fraction of the human lymphocyte population. Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients. Initial NK cell-based clinical trials suggested that NK cell-infusion is safe and feasible with almost no NK cell-related toxicity, including graft-versus-host disease. Complete remission and increased disease-free survival is shown in a small number of patients with hematological malignances. Furthermore, successful adoptive NK cell-based therapies from haploidentical donors have been demonstrated. Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors. While NK cells have great potential in targeting tumor cells, the efficiency of NK cell functions in the tumor microenvironment is yet unclear. The failure of immune surveillance may in part be due to sustained immunological pressure on tumor cells resulting in the development of tumor escape variants that are invisible to the immune system. Alternatively, this could be due to the complex network of immune-suppressive compartments in the tumor microenvironment, including myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Although the negative effect of the tumor microenvironment on NK cells can be transiently reverted by ex vivo expansion and long-term activation, the aforementioned NK cell/tumor microenvironment interactions upon reinfusion are not fully elucidated. Within this context, genetic modification of NK cells

Intratumoral delivery of CpG-conjugated anti-MUC1 antibody enhances NK cell anti-tumor activity.

PubMed

Schettini, Jorge; Kidiyoor, Amritha; Besmer, Dahlia M; Tinder, Teresa L; Roy, Lopamudra Das; Lustgarten, Joseph; Gendler, Sandra J; Mukherjee, Pinku

2012-11-01

Monoclonal antibodies (mAbs) against tumor-associated antigens are useful anticancer agents. Antibody-dependent cellular cytotoxicity (ADCC) is one of the major mechanisms responsible for initiating natural killer cell (NK)-mediated killing of tumors. However, the regulation of ADCC via NK cells is poorly understood. We have investigated the cytolytic activity of NK cells against pancreatic cancer cells that were coated with an antibody directed against the human tumor antigen, Mucin-1 designated HMFG-2, either alone or conjugated to CpG oligodeoxynucleotide (CpG ODN). Conjugated antibodies were tested for their ability to elicit ADCC in vitro and in vivo against pancreatic cancer cells. NK cells cultured in the presence of immobilized CpG ODN, HMFG-2 Ab, or CpG ODN-conjugated HMFG-2 Ab were able to up-regulate perforin similarly. Interestingly, a significant higher ADCC was observed when CpG ODN-conjugated HMFG-2-coated tumor cells were co-cultured with NK cells compared to unconjugated HMFG-2 Ab or CpG ODN alone. Moreover, MyD88-deficient NK cells can perform ADCC in vitro. Furthermore, intratumoral injections of CpG ODN-conjugated HMFG-2 induced a significant reduction in tumor burden in vivo in an established model of pancreatic tumor in nude mice compared to CpG ODN or the HMFG-2 alone. Depletion of macrophages or NK cells before treatment confirmed that both cells were required for the anti-tumor response in vivo. Results also suggest that CpG ODN and HMFG-2 Ab could be sensed by NK cells on the mAb-coated tumor cells triggering enhanced ADCC in vitro and in vivo.

Intratumoral delivery of CpG-conjugated anti-MUC1 antibody enhances NK cell anti-tumor activity

PubMed Central

Schettini, Jorge; Kidiyoor, Amritha; Besmer, Dahlia M.; Tinder, Teresa L.; Roy, Lopamudra Das; Lustgarten, Joseph; Gendler, Sandra J.

2013-01-01

Monoclonal antibodies (mAbs) against tumor-associated antigens are useful anticancer agents. Antibody-dependent cellular cytotoxicity (ADCC) is one of the major mechanisms responsible for initiating natural killer cell (NK)-mediated killing of tumors. However, the regulation of ADCC via NK cells is poorly understood. We have investigated the cytolytic activity of NK cells against pancreatic cancer cells that were coated with an antibody directed against the human tumor antigen, Mucin-1 designated HMFG-2, either alone or conjugated to CpG oligodeoxynucleotide (CpG ODN). Conjugated antibodies were tested for their ability to elicit ADCC in vitro and in vivo against pancreatic cancer cells. NK cells cultured in the presence of immobilized CpG ODN, HMFG-2 Ab, or CpG ODN-conjugated HMFG-2 Ab were able to up-regulate perforin similarly. Interestingly, a significant higher ADCC was observed when CpG ODN-conjugated HMFG-2-coated tumor cells were co-cultured with NK cells compared to unconjugated HMFG-2 Ab or CpG ODN alone. Moreover, MyD88-deficient NK cells can perform ADCC in vitro. Furthermore, intratumoral injections of CpG ODN-conjugated HMFG-2 induced a significant reduction in tumor burden in vivo in an established model of pancreatic tumor in nude mice compared to CpG ODN or the HMFG-2 alone. Depletion of macrophages or NK cells before treatment confirmed that both cells were required for the anti-tumor response in vivo. Results also suggest that CpG ODN and HMFG-2 Ab could be sensed by NK cells on the mAb-coated tumor cells triggering enhanced ADCC in vitro and in vivo. PMID:22543528

Anti-Tumor Activity of Eurycoma longifolia Root Extracts against K-562 Cell Line: In Vitro and In Vivo Study

PubMed Central

Majid, Amin Malik Shah Abdul; Kit-Lam, Chan; Abdullah, Wan Zaidah; Zaki, Abdelhamid; Jamal Din, Shah Kamal Khan; Yusoff, Narazah Mohd

2014-01-01

Eurycoma longifolia Jack has been widely used in traditional medicine for its antimalarial, aphrodisiac, anti-diabetic, antimicrobial and anti-pyretic activities. Its anticancer activity has also been recently reported on different solid tumors, however no anti-leukemic activity of this plant has been reported. Thus the present study assesses the in vitro and in vivo anti-proliferative and apoptotic potentials of E. longifolia on K-562 leukemic cell line. The K-562 cells (purchased from ATCC) were isolated from patients with chronic myelocytic leukemia (CML) were treated with the various fractions (TAF273, F3 and F4) of E. longifolia root methanolic extract at various concentrations and time intervals and the anti-proliferative activity assessed by MTS assay. Flow cytometry was used to assess the apoptosis and cell cycle arrest. Nude mice injected subcutaneously with 107 K-562 cells were used to study the anti-leukemic activity of TAF273 in vivo. TAF273, F3 and F4 showed various degrees of growth inhibition with IC50 values of 19, 55 and 62 µg/ml, respectively. TAF273 induced apoptosis in a dose and time dependent manner. TAF273 arrested cell cycle at G1and S phases. Intraperitoneal administration of TAF273 (50 mg/kg) resulted in a significant growth inhibition of subcutaneous tumor in TAF273-treated mice compared with the control mice (P = 0.024). TAF273 shows potent anti-proliferative activity in vitro and in vivo models of CML and therefore, justifies further efforts to define more clearly the potential benefits of using TAF273 as a novel therapeutic strategy for CML management. PMID:24409284

Dll4 Blockade Potentiates the Anti-Tumor Effects of VEGF Inhibition in Renal Cell Carcinoma Patient-Derived Xenografts

PubMed Central

Miles, Kiersten Marie; Seshadri, Mukund; Ciamporcero, Eric; Adelaiye, Remi; Gillard, Bryan; Sotomayor, Paula; Attwood, Kristopher; Shen, Li; Conroy, Dylan; Kuhnert, Frank; Lalani, Alshad S.; Thurston, Gavin; Pili, Roberto

2014-01-01

Background The Notch ligand Delta-like 4 (Dll4) is highly expressed in vascular endothelium and has been shown to play a pivotal role in regulating tumor angiogenesis. Blockade of the Dll4-Notch pathway in preclinical cancer models has been associated with non-productive angiogenesis and reduced tumor growth. Given the cross-talk between the vascular endothelial growth factor (VEGF) and Delta-Notch pathways in tumor angiogenesis, we examined the activity of a function-blocking Dll4 antibody, REGN1035, alone and in combination with anti-VEGF therapy in renal cell carcinoma (RCC). Methods and Results Severe combined immunodeficiency (SCID) mice bearing patient-derived clear cell RCC xenografts were treated with REGN1035 and in combination with the multi-targeted tyrosine kinase inhibitor sunitinib or the VEGF blocker ziv-aflibercept. Immunohistochemical and immunofluorescent analyses were carried out, as well as magnetic resonance imaging (MRI) examinations pre and 24 hours and 2 weeks post treatment. Single agent treatment with REGN1035 resulted in significant tumor growth inhibition (36–62%) that was equivalent to or exceeded the single agent anti-tumor activity of the VEGF pathway inhibitors sunitinib (38–54%) and ziv-aflibercept (46%). Importantly, combination treatments with REGN1035 plus VEGF inhibitors resulted in enhanced anti-tumor effects (72–80% growth inhibition), including some tumor regression. Magnetic resonance imaging showed a marked decrease in tumor perfusion in all treatment groups. Interestingly, anti-tumor efficacy of the combination of REGN1035 and ziv-aflibercept was also observed in a sunitinib resistant ccRCC model. Conclusions Overall, these findings demonstrate the potent anti-tumor activity of Dll4 blockade in RCC patient-derived tumors and a combination benefit for the simultaneous targeting of the Dll4 and VEGF signaling pathways, highlighting the therapeutic potential of this treatment modality in RCC. PMID:25393540

Combination immunotherapy and active-specific tumor cell vaccination augments anti-cancer immunity in a mouse model of gastric cancer

PubMed Central

2011-01-01

Background Active-specific immunotherapy used as an adjuvant therapeutic strategy is rather unexplored for cancers with poorly characterized tumor antigens like gastric cancer. The aim of this study was to augment a therapeutic immune response to a low immunogenic tumor cell line derived from a spontaneous gastric tumor of a CEA424-SV40 large T antigen (CEA424-SV40 TAg) transgenic mouse. Methods Mice were treated with a lymphodepleting dose of cyclophosphamide prior to reconstitution with syngeneic spleen cells and vaccination with a whole tumor cell vaccine combined with GM-CSF (a treatment strategy abbreviated as LRAST). Anti-tumor activity to subcutaneous tumor challenge was examined in a prophylactic as well as a therapeutic setting and compared to corresponding controls. Results LRAST enhances tumor-specific T cell responses and efficiently inhibits growth of subsequent transplanted tumor cells. In addition, LRAST tended to slow down growth of established tumors. The improved anti-tumor immune response was accompanied by a transient decrease in the frequency and absolute number of CD4+CD25+FoxP3+ T cells (Tregs). Conclusions Our data support the concept that whole tumor cell vaccination in a lymphodepleted and reconstituted host in combination with GM-CSF induces therapeutic tumor-specific T cells. However, the long-term efficacy of the treatment may be dampened by the recurrence of Tregs. Strategies to counteract suppressive immune mechanisms are required to further evaluate this therapeutic vaccination protocol. PMID:21859450

Physalin A exerts anti-tumor activity in non-small cell lung cancer cell lines by suppressing JAK/STAT3 signaling

PubMed Central

Loo, Jacky F.C.; Xia, Dajin; Gao, Sizhi P.; Ma, Zhongjun; Chen, Zhe

2016-01-01

The signal transducers and activators of transcription 3 (STAT3) signaling pathway plays critical roles in the pathogenesis and progression of various human cancers, including non-small cell lung cancer (NSCLC). In this study, we aimed to evaluate the therapeutic potential of physalin A, a bioactive withanolide derived from Physalis alkekengi var. francheti used in traditional Chinese medicine, was evaluated in human NSCLC cells. Its and determined whether it effect oninhibited both constitutive and induced STAT3 activity, through repressing the phosphorylation levels of JAK2 and JAK3, resulting in anti-proliferation and pro-apoptotic effects on NSCLC cells was also determined, and. theThe antitumor effects of physalin A were also validated usingin an in vivo mouse xenograft models of NSCLC cells. Physalin A had anti-proliferative and pro-apoptotic effects in NSCLC cells with constitutively activated STAT3; it also suppressed both constitutive and induced STAT3 activity by modulating the phosphorylation of JAK2 and JAK3. Furthermore, physalin A abrogated the nuclear translocation and transcriptional activity of STAT3, thereby decreasing the expression levels of STAT3, its target genes, such as Bcl-2 and XIAP. Knockdown of STAT3 expression by small interfering RNA (siRNA) significantly enhanced the pro-apoptotic effects of physalin A in NSCLC cells. Moreover, physalin A significantly suppressed tumor xenograft growth. Thus, as an inhibitor of JAK2/3-STAT3 signaling, physalin A, has potent anti-tumor activities, which may facilitate the development of a therapeutic strategy for treating NSCLC. PMID:26843613

CKD-516 displays vascular disrupting properties and enhances anti-tumor activity in combination with chemotherapy in a murine tumor model.

PubMed

Moon, Chang Hoon; Lee, Seung Ju; Lee, Ho Yong; Dung, Le Thi Kim; Cho, Wha Ja; Cha, HeeJeong; Park, Jeong Woo; Min, Young Joo

2014-06-01

CKD-516 is a benzophenone analog in which the B ring is modified by replacement with a carbonyl group. The study assessed CKD-516 as a vascular disrupting agent or anti-cancer drug. To assess the effect of S516 on vascularization, we analyzed the effect on human umbilical vein endothelial cells (HUVECs). To determine the inhibition of cell proliferation of S516, we used H460 lung carcinoma cells. The alteration of microtubules was analyzed using immunoblot, RT-PCR and confocal imaging. To evaluate the anti-tumor effects of gemcitabine and/or CKD-516, H460 xenograft mice were treated with CKD-516 (2.5 mg/kg) and/or gemcitabine (40 mg/kg), and tumor growth was compared with vehicle-treated control. For histologic analysis, liver, spleen and tumor tissues from H460 xenograft mice were obtained 12 and 24 h after CKD-516 injection. Cytoskeletal changes of HUVECs treated with 10 nM S516 were assessed by immunoblot and confocal imaging. S516 disrupted tubulin assembly and resulted in microtubule dysfunction, which induced cell cycle arrest (G2/M). S516 markedly enhanced the depolymerization of microtubules, perhaps due to the vascular disrupting properties of S516. Interestingly, S516 decreased the amount of total tubulin protein in HUVECs. Especially, S516 decreased mRNA expression α-tubulin (HUVECs only) and β-tubulin (HUVECs and H460 cells) at an early time point (4 h). Immunocytochemical analysis showed that S516 changed the cellular microtubule network and inhibited the formation of polymerized microtubules. Extensive central necrosis of tumors was evident by 12 h after treatment with CKD-516 (2.5 mg/kg, i.p.). In H460 xenografts, CKD-516 combined with gemcitabine significantly delayed tumor growth up to 57 % and 36 % as compared to control and gemcitabine alone, respectively. CKD-516 is a novel agent with vascular disrupting properties and enhances anti-tumor activity in combination with chemotherapy.

Anti-neoplastic activity of Amblyomma sculptum, Amblyomma parvum and Rhipicephalus sanguineus tick saliva on breast tumor cell lines.

PubMed

Sousa, Ana Carolina Prado; Oliveira, Carlo José Freire; Szabó, Matias Pablo Juan; Silva, Marcelo José Barbosa

2018-06-15

Cancer is one of the most troubling diseases and is becoming increasingly common. Breast cancer has a high cure rate when diagnosed early, but when diagnosed late, treatment is frequently painful, devastating and unsuccessful. The search for new treatments that are more effective and less harmful has led to several substances and biomolecules from plants and animals with potential anti-tumor activity. Within this context, ticks have emerged as an excellent source of new molecules with a wide array of therapeutic properties. Various molecules in tick saliva have immunomodulatory, anticoagulant, anti-inflammatory and anti-tumor effects across different tumor cell lines. Our study evaluates the effect of saliva from three widespread and important tick species in Brazil (Amblyomma sculptum, Amblyomma parvum and Rhipicephalus sanguineus) on MCF-7, MDA-MB-231 breast cancer cell lines and on the non-neoplastic MCF-10A cell line. We found that tick saliva from all three tick species showed cytotoxicity to tumor cells (MCF-7, MDA-MB-231) but not to the non-tumor cells (MCF-10A). Morphological changes on the surface of MCF-7 and MDA-MB-231 tumor cells did not occur on the MCF-10A cells. We also demonstrated that tumor cells die by apoptosis induced by caspase-3 and caspase 7 activity, suggesting that intrinsic pathway apoptosis may be triggered by tick saliva. These changes were not observed in MCF10A cells, which remained broadly unchanged even after exposure to diverse types of saliva. These results suggest that tick saliva from these tick species is a source of molecules, or biomolecules, useful for the potential source for the development of new breast cancer drugs. Copyright © 2018 Elsevier Ltd. All rights reserved.

Regulatory T cells as suppressors of anti-tumor immunity: Role of metabolism.

PubMed

De Rosa, Veronica; Di Rella, Francesca; Di Giacomo, Antonio; Matarese, Giuseppe

2017-06-01

Novel concepts in immunometabolism support the hypothesis that glucose consumption is also used to modulate anti-tumor immune responses, favoring growth and expansion of specific cellular subsets defined in the past as suppressor T cells and currently reborn as regulatory T (Treg) cells. During the 1920s, Otto Warburg and colleagues observed that tumors consumed high amounts of glucose compared to normal tissues, even in the presence of oxygen and completely functioning mitochondria. However, the role of the Warburg Effect is still not completely understood, particularly in the context of an ongoing anti-tumor immune response. Current experimental evidence suggests that tumor-derived metabolic restrictions can drive T cell hyporesponsiveness and immune tolerance. For example, several glycolytic enzymes, deregulated in cancer, contribute to tumor progression independently from their canonical metabolic activity. Indeed, they can control apoptosis, gene expression and activation of specific intracellular pathways, thus suggesting a direct link between metabolic switches and pro-tumorigenic transcriptional programs. Focus of this review is to define the specific metabolic pathways controlling Treg cell immunobiology in the context of anti-tumor immunity and tumor progression. Copyright © 2017 Elsevier Ltd. All rights reserved.

Differential Fc-receptor engagement drives an anti-tumor vaccinal effect

PubMed Central

DiLillo, David J.; Ravetch, Jeffrey V.

2015-01-01

Summary Passively-administered anti-tumor mAbs rapidly kill tumor targets via FcγR-mediated cytotoxicity (ADCC), a short-term process. However, anti-tumor mAb treatment can also induce a vaccinal effect, in which mAb-mediated tumor death induces a long-term anti-tumor cellular immune response. To determine how such responses are generated, we utilized a murine model of an anti-tumor vaccinal effect against a model neoantigen. We demonstrate that FcγR expression by CD11c+ antigen-presenting cells is required to generate anti-tumor T cell responses upon ADCC-mediated tumor clearance. Using FcγR-humanized mice, we demonstrate that anti-tumor huIgG1 must engage hFcγRIIIA on macrophages to mediate ADCC, but also engage hFcγRIIA, the sole hFcγR expressed by human DCs, to generate a potent vaccinal effect. Thus, while next-generation anti-tumor antibodies with enhanced binding to only hFcγRIIIA are now in clinical use, ideal anti-tumor antibodies must be optimized for both cytotoxic effects as well as hFcγRIIA engagement on DCs to stimulate long-term anti-tumor cellular immunity. PMID:25976835

In vivo pharmacokinetics, biodistribution and the anti-tumor effect of cyclic RGD-modified doxorubicin-loaded polymers in tumor-bearing mice.

PubMed

Wang, Chen; Li, Yuan; Chen, Binbin; Zou, Meijuan

2016-10-01

In our previous study, we successfully produced and characterized a multifunctional drug delivery system with doxorubicin (RC/GO/DOX), which was based on graphene oxide (GO) and cyclic RGD-modified chitosan (RC). Its characteristics include: pH-responsiveness, active targeting of hepatocarcinoma cells, and efficient loading with controlled drug release. Here, we report the pharmacokinetics, biodistribution, and anti-tumor efficacy of RC/GO/DOX polymers in tumor-bearing nude mice. The objective of this study is to assess its targeting potential for tumors. Pharmacokinetic and biodistribution profiles demonstrated that tumor accumulation of RC/GO/DOX polymers was almost three times higher than the others, highlighting the efficacy of the active targeting strategy. Furthermore, the tumor inhibition rate of RC/GO/DOX polymers was 56.64%, 2.09 and 2.93 times higher than that of CS/GO/DOX polymers (without modification) and the DOX solution, respectively. Anti-tumor efficacy results indicated that the tumor growth was better controlled by RC/GO/DOX polymers than the others. Hematoxylin and eosin (H&E) staining showed remarkable changes in tumor histology. Compared with the saline group, the tumor section from the RC/GO/DOX group revealed a marked increase in the quantity of apoptotic and necrotic cells, and a reduction in the quantity of the blood vessels. Together, these studies show that this new system could be regarded as a suitable form of DOX-based treatment of the hepatocellular carcinoma. Copyright © 2016 Elsevier B.V. All rights reserved.

Supercritical-Carbon Dioxide Fluid Extract from Chrysanthemum indicum Enhances Anti-Tumor Effect and Reduces Toxicity of Bleomycin in Tumor-Bearing Mice.

PubMed

Yang, Hong-Mei; Sun, Chao-Yue; Liang, Jia-Li; Xu, Lie-Qiang; Zhang, Zhen-Biao; Luo, Dan-Dan; Chen, Han-Bin; Huang, Yong-Zhong; Wang, Qi; Lee, David Yue-Wei; Yuan, Jie; Li, Yu-Cui

2017-02-24

Bleomycin (BLM), a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum , an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CI SCFE ) have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CI SCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CI SCFE combined with BLM in the treatment of hepatoma 22 (H22) tumor-bearing mice. The results suggested that the oral administration of CI SCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6), tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CI SCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-β1 by activating the gene expression of miR-29b. Taken together, these results indicated that CI SCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future.

Supercritical-Carbon Dioxide Fluid Extract from Chrysanthemum indicum Enhances Anti-Tumor Effect and Reduces Toxicity of Bleomycin in Tumor-Bearing Mice

PubMed Central

Yang, Hong-Mei; Sun, Chao-Yue; Liang, Jia-Li; Xu, Lie-Qiang; Zhang, Zhen-Biao; Luo, Dan-Dan; Chen, Han-Bin; Huang, Yong-Zhong; Wang, Qi; Lee, David Yue-Wei; Yuan, Jie; Li, Yu-Cui

2017-01-01

Bleomycin (BLM), a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CISCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CISCFE combined with BLM in the treatment of hepatoma 22 (H22) tumor-bearing mice. The results suggested that the oral administration of CISCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6), tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CISCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-β1 by activating the gene expression of miR-29b. Taken together, these results indicated that CISCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future. PMID:28245556

Anti-tumor activity and mechanism of apoptosis of A549 induced by ruthenium complex.

PubMed

Sun, Dongdong; Mou, Zhipeng; Li, Nuan; Zhang, Weiwei; Wang, Yazhe; Yang, Endong; Wang, Weiyun

2016-12-01

Two new ruthenium (II) polypyridyl complexes [Ru(MeIm) 4 (pip)] 2+ (1) and [Ru(MeIm) 4 (4-npip)] 2+ (2) were synthesized under the guidance of computational studies (DFT). Their binding property to human telomeric G-quadruplex studied by UV-Vis absorption spectroscopy, the fluorescent resonance energy transfer (FRET) melting assay and circular dichroism (CD) spectroscopy for validating the theoretical prediction. Both of them were evaluated for their potential anti-proliferative activity against four human tumor cell lines. Complex 2 shows growth inhibition against all the cell lines tested, especially the human lung tumor cell (A549). The RTCA analysis not only validated the inhibition activity but also showed the ability of reducing A549 cells' migration. DNA-flow cytometric analysis, mitochondrial membrane potential (ΔΨm) and the scavenger measurements of reactive oxygen species (ROS) analysis carried out to investigate the mechanism of cell growth inhibition and apoptosis-inducing effect of complex 2. The results demonstrated that complex 2 induces tumor cells apoptosis by acting on both mitochondrial homeostasis destruction and death receptor signaling pathways. And those suggested that complex 2 could be a candidate for further evaluation as a chemotherapeutic agent against human tumor.

Ferulic Acid Exerts Anti-Angiogenic and Anti-Tumor Activity by Targeting Fibroblast Growth Factor Receptor 1-Mediated Angiogenesis.

PubMed

Yang, Guang-Wei; Jiang, Jin-Song; Lu, Wei-Qin

2015-10-12

Most anti-angiogenic therapies currently being evaluated target the vascular endothelial growth factor (VEGF) pathway; however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here, we identified ferulic acid as a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor and a novel agent with potential anti-angiogenic and anti-cancer activities. Ferulic acid demonstrated inhibition of endothelial cell proliferation, migration and tube formation in response to basic fibroblast growth factor 1 (FGF1). In ex vivo and in vivo angiogenesis assays, ferulic acid suppressed FGF1-induced microvessel sprouting of rat aortic rings and angiogenesis. To understand the underlying molecular basis, we examined the effects of ferulic acid on different molecular components and found that ferulic acid suppressed FGF1-triggered activation of FGFR1 and phosphatidyl inositol 3-kinase (PI3K)-protein kinase B (Akt) signaling. Moreover, ferulic acid directly inhibited proliferation and blocked the PI3K-Akt pathway in melanoma cell. In vivo, using a melanoma xenograft model, ferulic acid showed growth-inhibitory activity associated with inhibition of angiogenesis. Taken together, our results indicate that ferulic acid targets the FGFR1-mediated PI3K-Akt signaling pathway, leading to the suppression of melanoma growth and angiogenesis.

Antisecretory Factor-mediated Inhibition of Cell Volume Dynamics Produces Anti-tumor Activity in Glioblastoma. | Office of Cancer Genomics

Cancer.gov

Interstitial fluid pressure (IFP) presents a barrier to drug uptake in solid tumors, including the aggressive primary brain tumor glioblastoma multiforme (GBM). It remains unclear how fluid dynamics impacts tumor progression and can be targeted therapeutically. To address this issue, a novel telemetry-based approach was developed to measure changes in IFP during progression of GBM xenografts. Antisecretory factor (AF) is an endogenous protein that displays anti-secretory effects in animals and patients.

Enhanced anti-tumor activity and safety profile of targeted nano-scaled HPMA copolymer-alendronate-TNP-470 conjugate in the treatment of bone malignances

PubMed Central

Segal, Ehud; Pan, Huaizhong; Benayoun, Liat; Kopečková, Pavla; Shaked, Yuval; Kopeček, Jindčrich; Satchi-Fainaro, Ronit

2015-01-01

Bone neoplasms, such as osteosarcoma, exhibit a propensity for systemic metastases resulting in adverse clinical outcome. Traditional treatment consisting of aggressive chemotherapy combined with surgical resection, has been the mainstay of these malignances. Therefore, bone-targeted non-toxic therapies are required. We previously conjugated the aminobisphosphonate alendronate (ALN), and the potent anti-angiogenic agent TNP-470 with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. HPMA copolymer-ALN-TNP-470 conjugate exhibited improved anti-angiogenic and anti-tumor activity compared with the combination of free ALN and TNP-470 when evaluated in a xenogeneic model of human osteosarcoma. The immune system has major effect on toxicology studies and on tumor progression. Therefore, in this manuscript we examined the safety and efficacy profiles of the conjugate using murine osteosarcoma syngeneic model. Toxicity and efficacy evaluation revealed superior anti-tumor activity and decreased organ-related toxicities of the conjugate compared with the combination of free ALN plus TNP-470. Finally, comparative anti-angiogenic activity and specificity studies, using surrogate biomarkers of circulating endothelial cells (CEC), highlighted the advantage of the conjugate over the free agents. The therapeutic platform described here may have clinical translational relevance for the treatment of bone-related angiogenesis-dependent malignances. PMID:21429572

Complimentary mechanisms of dual checkpoint blockade expand unique T-cell repertoires and activate adaptive anti-tumor immunity in triple-negative breast tumors

PubMed Central

Wei, Junping; Yang, Xiao Yi; Lei, Gangjun; Wang, Tao; Liu, Cong-Xiao; Morse, Michael A.; Gouin, Kenneth; Knott, Simon R. V.; Hartman, Zachary C.

2018-01-01

ABSTRACT Triple-negative breast cancer (TNBC) is an aggressive and molecularly diverse breast cancer subtype typified by the presence of p53 mutations (∼80%), elevated immune gene signatures and neoantigen expression, as well as the presence of tumor infiltrating lymphocytes (TILs). As these factors are hypothesized to be strong immunologic prerequisites for the use of immune checkpoint blockade (ICB) antibodies, multiple clinical trials testing single ICBs have advanced to Phase III, with early indications of heterogeneous response rates of <20% to anti-PD1 and anti-PDL1 ICB. While promising, these modest response rates highlight the need for mechanistic studies to understand how different ICBs function, how their combination impacts functionality and efficacy, as well as what immunologic parameters predict efficacy to different ICBs regimens in TNBC. To address these issues, we tested anti-PD1 and anti-CTLA4 in multiple models of TNBC and found that their combination profoundly enhanced the efficacy of either treatment alone. We demonstrate that this efficacy is due to anti-CTLA4-driven expansion of an individually unique T-cell receptor (TCR) repertoire whose functionality is enhanced by both intratumoral Treg suppression and anti-PD1 blockade of tumor expressed PDL1. Notably, the individuality of the TCR repertoire was observed regardless of whether the tumor cells expressed a nonself antigen (ovalbumin) or if tumor-specific transgenic T-cells were transferred prior to sequencing. However, responsiveness was strongly correlated with systemic measures of tumor-specific T-cell and B-cell responses, which along with systemic assessment of TCR expansion, may serve as the most useful predictors for clinical responsiveness in future clinical trials of TNBC utilizing anti-PD1/anti-CTLA4 ICB. PMID:29721371

Complimentary mechanisms of dual checkpoint blockade expand unique T-cell repertoires and activate adaptive anti-tumor immunity in triple-negative breast tumors.

PubMed

Crosby, Erika J; Wei, Junping; Yang, Xiao Yi; Lei, Gangjun; Wang, Tao; Liu, Cong-Xiao; Agarwal, Pankaj; Korman, Alan J; Morse, Michael A; Gouin, Kenneth; Knott, Simon R V; Lyerly, H Kim; Hartman, Zachary C

2018-01-01

Triple-negative breast cancer (TNBC) is an aggressive and molecularly diverse breast cancer subtype typified by the presence of p53 mutations (∼80%), elevated immune gene signatures and neoantigen expression, as well as the presence of tumor infiltrating lymphocytes (TILs). As these factors are hypothesized to be strong immunologic prerequisites for the use of immune checkpoint blockade (ICB) antibodies, multiple clinical trials testing single ICBs have advanced to Phase III, with early indications of heterogeneous response rates of <20% to anti-PD1 and anti-PDL1 ICB. While promising, these modest response rates highlight the need for mechanistic studies to understand how different ICBs function, how their combination impacts functionality and efficacy, as well as what immunologic parameters predict efficacy to different ICBs regimens in TNBC. To address these issues, we tested anti-PD1 and anti-CTLA4 in multiple models of TNBC and found that their combination profoundly enhanced the efficacy of either treatment alone. We demonstrate that this efficacy is due to anti-CTLA4-driven expansion of an individually unique T-cell receptor (TCR) repertoire whose functionality is enhanced by both intratumoral Treg suppression and anti-PD1 blockade of tumor expressed PDL1. Notably, the individuality of the TCR repertoire was observed regardless of whether the tumor cells expressed a nonself antigen (ovalbumin) or if tumor-specific transgenic T-cells were transferred prior to sequencing. However, responsiveness was strongly correlated with systemic measures of tumor-specific T-cell and B-cell responses, which along with systemic assessment of TCR expansion, may serve as the most useful predictors for clinical responsiveness in future clinical trials of TNBC utilizing anti-PD1/anti-CTLA4 ICB.

Redox-responsive mesoporous selenium delivery of doxorubicin targets MCF-7 cells and synergistically enhances its anti-tumor activity.

PubMed

Zhao, Shuang; Yu, Qianqian; Pan, Jiali; Zhou, Yanhui; Cao, Chengwen; Ouyang, Jian-Ming; Liu, Jie

2017-05-01

To reduce the side effects and enhance the anti-tumor activities of anticancer drugs in the clinic, the use of nano mesoporous materials, with mesoporous silica (MSN) being the best-studied, has become an effective method of drug delivery. In this study, we successfully synthesized mesoporous selenium (MSe) nanoparticles and first introduced them to the field of drug delivery. Loading MSe with doxorubicin (DOX) is mainly driven by the physical adsorption mechanism of the mesopores, and our results demonstrated that MSe could synergistically enhance the antitumor activity of DOX. Coating the surface of MSe@DOX with Human serum albumin (HSA) generated a unique redox-responsive nanoparticle (HSA-MSe@DOX) that demonstrated glutathione-dependent drug release, increased tumor-targeting effects and enhanced cellular uptake throug nanoparticle interact with SPARC in MCF-7 cells. In vitro, HSA-MSe@DOX prominently induced cancer cell toxicity by synergistically enhancing the effects of MSe and DOX. Moreover, HSA-MSe@DOX possessed tumor-targeting abilities in tumor-bearing nude mice and not only decreased the side effects associated with DOX, but also enhanced its antitumor activity. Therefore, HSA-MSe@DOX is a promising new drug that warrants further evaluation in the treatments of tumors. To reduce the side effects and enhance the anti-tumor activities of anticancer drugs, we successfully synthesized mesoporous selenium (MSe) nanoparticles and first introduced them to the field of drug delivery. Loading MSe with doxorubicin (DOX) is mainly driven by the physical adsorption mechanism of the mesopores. Coating the surface of MSe@DOX with Human serum albumin (HSA) generated a unique redox-responsive nanoparticle (HSA-MSe@DOX) that demonstrated glutathione-dependent drug release, increased tumor-targeting effects and enhanced cellular uptake throug nanoparticle interact with SPARC in MCF-7 cells. In vitro and in vivo, HSA-MSe@DOX possessed tumor-targeting abilities and not only

Assessment of anti-angiogenic and anti-tumoral potentials of Origanum onites L. essential oil.

PubMed

Bostancıoğlu, Rakibe Beklem; Kürkçüoğlu, Mine; Başer, Kemal Hüsnü Can; Koparal, Ayşe Tansu

2012-06-01

Medicinal plants and culinary herbs with anti-angiogenic and little toxicity properties have gained importance. Non-toxic anti-angiogenic phytochemicals are useful in combating cancer by preventing the formation of new blood vessels to support the tumor growth. We have investigated the essential oil of Origanum onites L. (OOEO), for a possible anti-angiogenic activity. OOEO was analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC/MS). The anti-proliferative activities (by MTT assay, 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide), anti-angiogenic activities (by tube formation assay), cell migration inhibiting capability (migration assay) and apoptotic potential (DAPI staining) of OOEO were evaluated on rat adipose tissue endothelial cells (RATECs) and 5RP7 (c-H-ras transformed rat embryonic fibroblasts) cells. Our results revealed that OOEO could markedly inhibit cell viability and induced apoptosis of 5RP7 cells and also could block in vitro tube formation and migration of RATEC. These results imply that OOEO having anti-angiogenic activity might be useful in preventing angiogenesis-related diseases and in combating cancer. Copyright © 2012 Elsevier Ltd. All rights reserved.

Gamma-irradiated bacterial preparation having anti-tumor activity

DOEpatents

Vass, Arpad A.; Tyndall, Richard L.; Terzaghi-Howe, Peggy

1999-01-01

A bacterial preparation from Pseudomonas species isolated #15 ATCC 55638 that has been exposed to gamma radiation exhibits cytotoxicity that is specific for neoplastic carcinoma cells. A method for obtaining a bacterial preparation having antitumor activity consists of suspending a bacterial isolate in media and exposing the suspension to gamma radiation. A bacterial preparation of an aged culture of an amoeba-associated bacteria exhibits anti-reverse transcriptase activity. A method for obtaining a bacterial preparation having anti-reverse transcriptase activity from an amoeba-associated bacterial isolate grown to stationary phase is disclosed.

Increased anti-tumor effects using IL2 with anti-TGFβ reveals competition between mouse NK and CD8 T cells

PubMed Central

Alvarez, Maite; Bouchlaka, Myriam N.; Sckisel, Gail D.; Sungur, Can M.; Chen, Mingyi; Murphy, William J.

2014-01-01

Due to increasing interest in the removal of immunosuppressive pathways in cancer, the combination of IL2 with antibodies to neutralize TGFβ, a potent immunosuppressive cytokine, was assessed. Combination immunotherapy resulted in significantly greater anti-tumor effects. These were correlated with significant increases in the numbers and functionality of NK cells, NK progenitors and activated CD8 T cells resulting in the observed anti-tumor effects. Combination immunotherapy was also accompanied with lesser toxicities than IL2 therapy alone. Additionally, we observed a dual competition between NK and activated CD8 T cells such that after immunotherapy, the depletion of either effector population resulted in the increased total expansion of the other population and compensatory anti-tumor effects. This study demonstrates the efficacy of this combination immunotherapeutic regimen as a promising cancer therapy and illustrates the existence of potent competitive regulatory pathways between NK and CD8 T cells in response to systemic activation. PMID:25000978

Protein Kinase C-θ (PKC-θ) in Natural Killer Cell Function and Anti-Tumor Immunity

PubMed Central

Anel, Alberto; Aguiló, Juan I.; Catalán, Elena; Garaude, Johan; Rathore, Moeez G.; Pardo, Julián; Villalba, Martín

2012-01-01

The protein kinase C-θ (PKCθ), which is essential for T cell function and survival, is also required for efficient anti-tumor immune surveillance. Natural killer (NK) cells, which express PKCθ, play a prominent role in this process, mainly by elimination of tumor cells with reduced or absent major histocompatibility complex class-I (MHC-I) expression. This justifies the increased interest of the use of activated NK cells in anti-tumor immunotherapy in the clinic. The in vivo development of MHC-I-deficient tumors is much favored in PKCθ−/− mice compared with wild-type mice. Recent data offer some clues on the mechanism that could explain the important role of PKCθ in NK cell-mediated anti-tumor immune surveillance: some studies show that PKCθ is implicated in signal transduction and anti-tumoral activity of NK cells elicited by interleukin (IL)-12 or IL-15, while others show that it is implicated in NK cell functional activation mediated by certain killer-activating receptors. Alternatively, the possibility that PKCθ is involved in NK cell degranulation is discussed, since recent data indicate that it is implicated in microtubule-organizing center polarization to the immune synapse in CD4+ T cells. The implication of PKC isoforms in degranulation has been more extensively studied in cytotoxic T lymphocyte, and these studies will be also summarized. PMID:22783260

Anti-tumor immunity of BAM-SiPc-mediated vascular photodynamic therapy in a BALB/c mouse model.

PubMed

Yeung, Hing-Yuen; Lo, Pui-Chi; Ng, Dennis K P; Fong, Wing-Ping

2017-02-01

In recent decades, accumulating evidence from both animal and clinical studies has suggested that a sufficiently activated immune system may strongly augment various types of cancer treatment, including photodynamic therapy (PDT). Through the generation of reactive oxygen species, PDT eradicates tumors by triggering localized tumor damage and inducing anti-tumor immunity. As the major component of anti-tumor immunity, the involvement of a cell-mediated immune response in PDT has been well investigated in the past decade, whereas the role of humoral immunity has remained relatively unexplored. In the present investigation, using the photosensitizer BAM-SiPc and the CT26 tumor-bearing BALB/c mouse model, it was demonstrated that both cell-mediated and humoral adaptive immune components could be involved in PDT. With a vascular PDT (VPDT) regimen, BAM-SiPc could eradicate the tumors of ∼70% of tumor-bearing mice and trigger an anti-tumor immune response that could last for more than 1 year. An elevation of Th2 cytokines was detected ex vivo after VPDT, indicating the potential involvement of a humoral response. An analysis of serum from the VPDT-cured mice also revealed elevated levels of tumor-specific antibodies. Moreover, this serum could effectively hinder tumor growth and protect the mice against further re-challenge in a T-cell-dependent manner. Taken together, these results show that the humoral components induced after BAM-SiPc-VPDT could assist the development of anti-tumor immunity.

Gamma-irradiated bacterial preparation having anti-tumor activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vass, A.A.; Tyndall, R.L.; Terzaghi-Howe, P.

1999-11-16

This application describes a bacterial preparation from Pseudomonas species isolated {number{underscore}sign}15 ATCC 55638 that has been exposed to gamma radiation exhibits cytotoxicity that is specific for neoplastic carcinoma cells. A method for obtaining a bacterial preparation having antitumor activity consists of suspending a bacterial isolate in media and exposing the suspension to gamma radiation. A bacterial preparation of an aged culture of an amoeba-associated bacteria exhibits anti-reverse transcriptase activity. A method for obtaining a bacterial preparation having anti-reverse transcriptase activity from an amoeba-associated bacterial isolate grown to stationary phase is disclosed.

Recent advances in medicinal chemistry of sulfonamides. Rational design as anti-tumoral, anti-bacterial and anti-inflammatory agents.

PubMed

Shah, Syed Shoaib Ahmad; Rivera, Gildardo; Ashfaq, Muhammad

2013-01-01

Now-a-days, cancer is becoming one of the major problems of public health in the world. Pharmacology treatment is a way to increase quality and long life. Predominantly, in last decade sulfonamide derivatives have been described as potential carbonic anhydrase inhibitors. In the present work, we describe recent advances during the last decade in medicinal chemistry of sulfonamides derivatives with some examples of rational design as anti-tumoral, antibacterial and anti-inflammatory agents. We show strategy design, structure-activity relationship, biological activity and advances of new sulfonamide compounds that have more health significance than some clinically used sulfonamides.

An Il12-Il2-Antibody Fusion Protein Targeting Hodgkin's Lymphoma Cells Potentiates Activation Of Nk And T Cells For An Anti-Tumor Attack

PubMed Central

Friedrichs, Björn; Heuser, Claudia; Guhlke, Stefan; Abken, Hinrich; Hombach, Andreas A.

2012-01-01

Successful immunotherapy of Hodgkin's disease is so far hampered by the striking unresponsiveness of lymphoma infiltrating immune cells. To mobilize both adoptive and innate immune cells for an anti-tumor attack we fused the pro-inflammatory cytokines IL2 and IL12 to an anti-CD30 scFv antibody in a dual cytokine fusion protein to accumulate both cytokines at the malignant CD30+ Hodgkin/Reed-Sternberg cells in the lymphoma lesion. The tumor-targeted IL12-IL2 fusion protein was superior in activating resting T cells to amplify and secrete pro-inflammatory cytokines compared to targeted IL2 or IL12 alone. NK cells were also activated by the dual cytokine protein to secrete IFN-γ and to lyse target cells. The tumor-targeted IL12-IL2, when applied by i.v. injection to immune-competent mice with established antigen-positive tumors, accumulated at the tumor site and induced tumor regression. Data demonstrate that simultaneous targeting of two cytokines in a spatial and temporal simultaneous fashion to pre-defined tissues is feasible by a dual-cytokine antibody fusion protein. In the case of IL12 and IL2, this produced superior anti-tumor efficacy implying the strategy to muster a broader immune cell response in the combat against cancer. PMID:23028547

Synergistic anti-tumor activity of Nimotuzumab in combination with Trastuzumab in HER2-positive breast cancer.

PubMed

Yang, Yun; Guo, Rui; Tian, Xiaoting; Zhang, Ziheng; Zhang, Pengfei; Li, Changzheng; Feng, Zhiwei

2017-08-05

Breast cancer is characterized with poor prognosis and high recurrence. HER2 is highly expressed in breast cancer and is a target for cancer therapy and prevention. Here, we investigated the anti-tumor activity of the combination of an HER2 inhibitor, trastuzumab with an EGFR-inhibitor, nimotuzumab in HER2-overexpressing breast cancer. Our data showed that a greater anti-tumor activity from the combination of trastuzumab and nimotuzumab than any alone usage of above antibody both in vitro and in vivo. Based on the combination index value, our data demonstrated that nimotuzumab synergistically enhanced trastuzumab-induced cell growth inhibition. Furthermore, we investigated the possible mechanism of this synergistic efficacy induced by trastuzumab plus nimotuzumab. Data showed that the combination was more potent in reducing the phosphorylation of HER2 and ERK1/2. We also found that the synergistic inhibition was partly attributed to the ROS generation and repression of NRF2 pathway that is known to promote cell growth. These results support the clinical development of this two-drug regimen for the treatment of HER2-amplified breast cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

Vaccination with Irradiated Tumor Cells Engineered to Secrete Murine Granulocyte-Macrophage Colony-Stimulating Factor Stimulates Potent, Specific, and Long-Lasting Anti-Tumor Immunity

NASA Astrophysics Data System (ADS)

Dranoff, Glenn; Jaffee, Elizabeth; Lazenby, Audrey; Golumbek, Paul; Levitsky, Hyam; Brose, Katja; Jackson, Valerie; Hamada, Hirofumi; Pardoll, Drew; Mulligan, Richard C.

1993-04-01

To compare the ability of different cytokines and other molecules to enhance the immunogenicity of tumor cells, we generated 10 retroviruses encoding potential immunomodulators and studied the vaccination properties of murine tumor cells transduced by the viruses. Using a B16 melanoma model, in which irradiated tumor cells alone do not stimulate significant anti-tumor immunity, we found that irradiated tumor cells expressing murine granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated potent, long-lasting, and specific anti-tumor immunity, requiring both CD4^+ and CD8^+ cells. Irradiated cells expressing interleukins 4 and 6 also stimulated detectable, but weaker, activity. In contrast to the B16 system, we found that in a number of other tumor models, the levels of anti-tumor immunity reported previously in cytokine gene transfer studies involving live, transduced cells could be achieved through the use of irradiated cells alone. Nevertheless, manipulation of the vaccine or challenge doses made it possible to demonstrate the activity of murine GM-CSF in those systems as well. Overall, our results have important implications for the clinical use of genetically modified tumor cells as therapeutic cancer vaccines.

Co-stimulation through the CD137/4-1BB pathway protects human melanoma tumor-infiltrating lymphocytes from activation-induced cell death and enhances anti-tumor effector function

PubMed Central

Hernandez-Chacon, Jessica Ann; Li, Yufeng; Wu, Richard C.; Bernatchez, Chantale; Wang, Yijun; Weber, Jeffrey; Hwu, Patrick; Radvanyi, Laszlo

2011-01-01

Adoptive T-cell therapy (ACT) using expanded tumor-infiltrating lymphocytes (TIL) with high-dose IL-2 is a promising form of immunotherapy for Stage IV melanoma having clinical response rates of 50% or more. One of the major problems preventing further success of this therapy is that the current protocols used to highly expand TIL for infusion drive CD8+ T cells to differentiate into effector cells losing key co-stimulatory molecules such as CD28 and CD27. This has been associated with a lack of persistence in vivo for reasons not entirely clear. In this study, we demonstrate that while human melanoma CD8+ TIL lost CD27 and CD28 expression during the rapid expansion for ACT, they gained expression of the alternative co-stimulatory molecule CD137/4-1BB, and to a lesser extent CD134/OX40. Post-REP TIL were found to be highly sensitive to activation-induced cell death (AICD) when re-activated through the TCR with low levels of OKT3 antibody. However, co-ligation of 4-1BB using two different agonistic anti-4-1BB antibodies potently prevented AICD of post-REP CD8+ TIL, including those specific for MART-1, and facilitated even further cell expansion. This was correlated with increased levels of bcl-2 and bcl-xL together with decreased bim expression. 4-1BB-co-stimulated post-REP TIL also expressed increased levels of the cytolytic granule proteins and exhibited enhanced CTL activity against melanoma cells. Lastly, post-REP CD8+ TIL were protected from cell death by anti-4-1BB ligation when exposed to HLA-matched melanoma cells. Our results indicate that 4-1BB co-stimulation may significantly improve TIL survival during melanoma ACT and boost anti-tumor cytolytic activity. PMID:21389874

CS2164, a novel multi-target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti-tumor potency.

PubMed

Zhou, You; Shan, Song; Li, Zhi-Bin; Xin, Li-Jun; Pan, De-Si; Yang, Qian-Jiao; Liu, Ying-Ping; Yue, Xu-Peng; Liu, Xiao-Rong; Gao, Ji-Zhou; Zhang, Jin-Wen; Ning, Zhi-Qiang; Lu, Xian-Ping

2017-03-01

Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti-cancer efficacy and acquired drug resistance demand new agents that may offer better clinical benefits. In the effort to find a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi-kinase inhibitor, CS2164. CS2164 inhibited the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα and c-Kit), mitosis-related kinase Aurora B and chronic inflammation-related kinase CSF-1R in a high potency manner with the IC 50 at a single-digit nanomolar range. Consequently, CS2164 displayed anti-angiogenic activities through suppression of VEGFR/PDGFR phosphorylation, inhibition of ligand-dependent cell proliferation and capillary tube formation, and prevention of vasculature formation in tumor tissues. CS2164 also showed induction of G2/M cell cycle arrest and suppression of cell proliferation in tumor tissues through the inhibition of Aurora B-mediated H3 phosphorylation. Furthermore, CS2164 demonstrated the inhibitory effect on CSF-1R phosphorylation that led to the suppression of ligand-stimulated monocyte-to-macrophage differentiation and reduced CSF-1R + cells in tumor tissues. The in vivo animal efficacy studies revealed that CS2164 induced remarkable regression or complete inhibition of tumor growth at well-tolerated oral doses in several human tumor xenograft models. Collectively, these results indicate that CS2164 is a highly selective multi-kinase inhibitor with potent anti-tumor activities against tumor angiogenesis, mitosis and chronic inflammation, which may provide the rationale for further clinical assessment of CS2164 as a therapeutic agent in the treatment of cancer. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Radiotherapy-Induced Anti-Tumor Immunity Contributes to the Therapeutic Efficacy of Irradiation and Can Be Augmented by CTLA-4 Blockade in a Mouse Model

PubMed Central

Yoshimoto, Yuya; Suzuki, Yoshiyuki; Mimura, Kousaku; Ando, Ken; Oike, Takahiro; Sato, Hiro; Okonogi, Noriyuki; Maruyama, Takanori; Izawa, Shinichiro; Noda, Shin-ei; Fujii, Hideki; Kono, Koji; Nakano, Takashi

2014-01-01

Purpose There is growing evidence that tumor-specific immune responses play an important role in anti-cancer therapy, including radiotherapy. Using mouse tumor models we demonstrate that irradiation-induced anti-tumor immunity is essential for the therapeutic efficacy of irradiation and can be augmented by modulation of cytotoxic T lymphocyte (CTL) activity. Methods and Materials C57BL/6 mice, syngeneic EL4 lymphoma cells, and Lewis lung carcinoma (LL/C) cells were used. Cells were injected into the right femurs of mice. Ten days after inoculation, tumors were treated with 30 Gy of local X-ray irradiation and their growth was subsequently measured. The effect of irradiation on tumor growth delay (TGD) was defined as the time (in days) for tumors to grow to 500 mm3 in the treated group minus that of the untreated group. Cytokine production and serum antibodies were measured by ELISA and flow cytometry. Results In the EL4 tumor model, tumors were locally controlled by X-ray irradiation and re-introduced EL4 cells were completely rejected. Mouse EL4-specific systemic immunity was confirmed by splenocyte cytokine production and detection of tumor-specific IgG1 antibodies. In the LL/C tumor model, X-ray irradiation also significantly delayed tumor growth (TGD: 15.4 days) and prolonged median survival time (MST) to 59 days (versus 28 days in the non-irradiated group). CD8(+) cell depletion using an anti-CD8 antibody significantly decreased the therapeutic efficacy of irradiation (TGD, 8.7 days; MST, 49 days). Next, we examined whether T cell modulation affected the efficacy of radiotherapy. An anti-CTLA-4 antibody significantly increased the anti-tumor activity of radiotherapy (TGD was prolonged from 13.1 to 19.5 days), while anti-FR4 and anti-GITR antibodies did not affect efficacy. Conclusions Our results indicate that tumor-specific immune responses play an important role in the therapeutic efficacy of irradiation. Immunomodulation, including CTLA-4 blockade, may be a

Radiotherapy-induced anti-tumor immunity contributes to the therapeutic efficacy of irradiation and can be augmented by CTLA-4 blockade in a mouse model.

PubMed

Yoshimoto, Yuya; Suzuki, Yoshiyuki; Mimura, Kousaku; Ando, Ken; Oike, Takahiro; Sato, Hiro; Okonogi, Noriyuki; Maruyama, Takanori; Izawa, Shinichiro; Noda, Shin-ei; Fujii, Hideki; Kono, Koji; Nakano, Takashi

2014-01-01

There is growing evidence that tumor-specific immune responses play an important role in anti-cancer therapy, including radiotherapy. Using mouse tumor models we demonstrate that irradiation-induced anti-tumor immunity is essential for the therapeutic efficacy of irradiation and can be augmented by modulation of cytotoxic T lymphocyte (CTL) activity. C57BL/6 mice, syngeneic EL4 lymphoma cells, and Lewis lung carcinoma (LL/C) cells were used. Cells were injected into the right femurs of mice. Ten days after inoculation, tumors were treated with 30 Gy of local X-ray irradiation and their growth was subsequently measured. The effect of irradiation on tumor growth delay (TGD) was defined as the time (in days) for tumors to grow to 500 mm3 in the treated group minus that of the untreated group. Cytokine production and serum antibodies were measured by ELISA and flow cytometry. In the EL4 tumor model, tumors were locally controlled by X-ray irradiation and re-introduced EL4 cells were completely rejected. Mouse EL4-specific systemic immunity was confirmed by splenocyte cytokine production and detection of tumor-specific IgG1 antibodies. In the LL/C tumor model, X-ray irradiation also significantly delayed tumor growth (TGD: 15.4 days) and prolonged median survival time (MST) to 59 days (versus 28 days in the non-irradiated group). CD8(+) cell depletion using an anti-CD8 antibody significantly decreased the therapeutic efficacy of irradiation (TGD, 8.7 days; MST, 49 days). Next, we examined whether T cell modulation affected the efficacy of radiotherapy. An anti-CTLA-4 antibody significantly increased the anti-tumor activity of radiotherapy (TGD was prolonged from 13.1 to 19.5 days), while anti-FR4 and anti-GITR antibodies did not affect efficacy. Our results indicate that tumor-specific immune responses play an important role in the therapeutic efficacy of irradiation. Immunomodulation, including CTLA-4 blockade, may be a promising treatment in combination with

Synergy of brief activation of CD8 T-cells in the presence of IL-12 and adoptive transfer into lymphopenic hosts promotes tumor clearance and anti-tumor memory

PubMed Central

Díaz-Montero, C Marcela; Naga, Osama; Zidan, Abdel-Aziz A; Salem, Mohamed L; Pallin, Maria; Parmigiani, Anita; Walker, Gail; Wieder, Eric; Komanduri, Krishna; Cole, David J; Montero, Alberto J; Lichtenheld, Mathias G

2011-01-01

Adoptive T-cell therapy holds great promise for the treatment of metastatic melanoma. However, prohibitive costs associated with current technology required for culture and expansion of tumor-reactive T-cells, the need for intense preconditioning regimens to induce lymphopenia, and the unpredictable anti-tumor effect of adoptively transferred T-cells remain significant impediments for its clinical implementation. Here we report a simplified combinatorial approach that involves short activation of CD8+ T cells in the presence of IL-12 followed by adoptive transfer into tumor bearing animals after a single injection of cyclophosphamide. This approach resulted in complete eradication of B16 melanoma, and the establishment of long term immunological memory capable of fully protecting mice after a second B16 melanoma challenge. The activated donor cells were unique because they simultaneously exhibited traits for cytotoxic effector function, central memory-like, homing, and senescence. After tumor eradication and within three months after transfer, CD8+ cells exhibited a conventional memory CTL phenotype. Moreover, these memory CTLs acquired functional attributes characteristic of memory stem cells, including the ability to resist chemotherapy-induced toxicity. Our results suggest that short-term T-cell receptor signaling in the presence of IL-12 promotes promiscuous qualities in naïve CTL which - upon transfer into lymphopenic hosts- are sufficient to eradicate tumors and generate life-long tumor-specific memory. PMID:21915391

Evaluation and structure-activity relationship analysis of a new series of arylnaphthalene lignans as potential anti-tumor agents.

PubMed

Luo, Jiaoyang; Hu, Yichen; Kong, Weijun; Yang, Meihua

2014-01-01

Arylnaphthalene lignan lactones have attracted considerable interest because of their anti-tumor and anti-hyperlipidimic activities. However, to our knowledge, few studies have explored the effects of these compounds on human leukemia cell lines. In this study, five arylnaphthalene lignans including 6'-hydroxy justicidin A (HJA), 6'-hydroxy justicidin B (HJB), justicidin B (JB), chinensinaphthol methyl ether (CME) and Taiwanin E methyl ether (TEME) were isolated from Justicia procumbens and their effects on the proliferation and apoptosis of the human leukemia K562 cell line were investigated then used to assess structure-activity relationships. To achieve these aims, cytotoxicity was assayed using the MTT assay, while intracellular SOD activity was detected using the SOD Activity Assay kit. Apoptosis was measured by both the using a cycle TEST PLUS DNA reagent kit as well as the FITC Annexin V apoptosis detection kit in combination with flow cytometry. Activation of caspase-mediated apoptosis was evaluated using a FITC active Caspase-3 apoptosis kit and flow cytometry. The results indicated that HJB, HJA and JB significantly inhibited the growth of K562 cells by decreasing both proliferation and SOD activity and inducing apoptosis. The sequence of anti-proliferative activity induced by the five tested arylnaphthalenes by decreasing strength was HJB > HJA > JB > CME > TEME. HJB, HJA and JB also decreased SOD activity and induced apoptosis in a dose-dependent manner. Activation of caspase-3 further indicated that HJB, HJA and JB induced caspase-dependent intrinsic and/or extrinsic apoptosis pathways. Together, these assays suggest that arylnaphthalene lignans derived from Justicia procumbens induce apoptosis to varying degrees, through a caspase-dependent pathway in human leukemia K562 cells. Furthermore, analysis of structure-activity relationships suggest that hydroxyl substitution at C-1 and C-6' significantly increased the antiproliferative activity of

Anti-tumor and Chemoprotective Effect of Bauhinia tomentosa by Regulating Growth Factors and Inflammatory Mediators.

PubMed

Kannan, Narayanan; Sakthivel, Kunnathur Murugesan; Guruvayoorappan, Chandrasekaran

2015-01-01

Cancer is a leading cause of death worldwide. Due to the toxic side effects of the commonly used chemotherapeutic drug cyclophosphamide (CTX), the use of herbal medicines with fewer side effects but having potential use as inducing anti-cancer outcomes in situ has become increasingly popular. The present study sought to investigate the effects of a methanolic extract of Bauhinia tomentosa against Dalton's ascites lymphoma (DAL) induced ascites as well as solid tumors in BALB/c mice. Specifically, B. tomentosa extract was administered intraperitonealy (IP) at 10 mg/kg. BW body weight starting just after tumor cell implantation and thereafter for 10 consecutive days. In the ascites tumor model hosts, administration of extract resulted in a 52% increase in the life span. In solid tumor models, co-administration of extract and CTX significantly reduced tumor volume (relative to in untreated hosts) by 73% compared to just by 52% when the extract alone was provided. Co-administration of the extract also mitigated CTX-induced toxicity, including decreases in WBC count, and in bone marrow cellularity and α-esterase activity. Extract treatment also attenuated any increases in serum levels of TNFα, iNOS, IL-1β, IL-6, GM-CSF, and VEGF seen in tumor-bearing hosts. This study confirmed that, the potent antitumor activity of B.tomentosa extract may be associated with immune modulatory effects by regulating anti-oxidants and cytokine levels.

Characterization and anti-tumor effects of chondroitin sulfate-chitosan nanoparticles delivery system

NASA Astrophysics Data System (ADS)

Hu, Chieh-Shen; Tang, Sung-Ling; Chiang, Chiao-Hsi; Hosseinkhani, Hossein; Hong, Po-Da; Yeh, Ming-Kung

2014-11-01

We prepared chondroitin sulfate (ChS)-chitosan (CS) nanoparticles (NPs) as a delivery carrier, and doxorubicin (Dox) was used as a model drug. The physicochemical properties and biological activities of the Dox-ChS-CS NPs including the release profile, cell cytotoxicity, cellular internalization, and in vivo anti-tumor effects were evaluated. The ChS-CS NPs and Dox-ChS-CS NPs had a mean size of 262.0 ± 15.0 and 369.4 ± 77.4 nm, and a zeta potential of 30.2 ± 0.9 and 20.6 ± 3.1 mV, respectively. In vitro release tests showed that the 50 % release time for the Dox-ChS-CS NPs was 20 h. Two hepatoma cell models, HepG2 and HuH6, were used for evaluating the cytotoxicity and cell uptake efficiency of the Dox-ChS-CS NPs. A significant difference was observed between doxorubicin solution and the Dox-ChS-CS NPs in the cellular uptake within 60 min ( p < 0.01). For the in vivo human xenograft-nude mouse model, the Dox-ChS-CS NPs were more effective with less body weight loss and anti-tumor growth suppression in comparison with the Dox solution. The prepared Dox-ChS-CS NPs offer a new effective targeting nanoparticle delivery system platform for anti-tumor therapy.

Anti-tumor effect of emodin on gynecological cancer cells.

PubMed

Wang, Yaoxian; Yu, Hui; Zhang, Jin; Ge, Xin; Gao, Jing; Zhang, Yunyan; Lou, Ge

2015-10-01

Although an anti-tumor effect of emodin has been reported before, its effect on human gynecological cancer cells has so far not been studied. Here, we assessed the effect of emodin on cervical cancer-derived (Hela), choriocarcinoma-derived (JAR) and ovarian cancer-derived (HO-8910) cells, and investigated the possible underlying molecular and cellular mechanisms. The respective cells were treated with 0, 5, 10 or 15 μM emodin for 72 h. Subsequently, MTT and Transwell in vitro migration assays revealed that emodin significantly decreased the viability and invasive capacity of the gynecological cancer-derived cells tested. We found that emodin induced apoptosis and significantly decreased mitochondrial membrane potential and ATP release in these cells. We also found that emodin may exert its apoptotic effects via regulating the activity of caspase-9 and the expression of cleaved-caspase-3. Moreover, we found that emodin induced a cell cycle arrest at the G0/G1 phase, possibly through down-regulating the key cell cycle regulators Cyclin D and Cyclin E. Interestingly, emodin also led to autophagic cell death, as revealed by increased MAP LC3 expression, a marker of the autophagosome, and decreased expression of the autophagy regulators Beclin-1 and Atg12-Atg5. Finally, we found that the protein levels of both VEGF and VEGFR-2 were significantly decreased in emodin-treated cells, suggesting an anti-angiogenic effect of emodin on gynecological cancer-derived cells. Our results suggest that emodin exhibits an anti-tumor effect on gynecological cancer-derived cells, possibly through multiple mechanisms including the induction of apoptosis and autophagy, the arrest of the cell cycle, and the inhibition of angiogenesis. Our findings may provide a basis for the design of potential emodin-based strategies for the treatment of gynecological tumors.

Triple negative breast cancer: Key role of Tumor-Associated Macrophages in regulating the activity of anti-PD-1/PD-L1 agents.

PubMed

Santoni, Matteo; Romagnoli, Emanuela; Saladino, Tiziana; Foghini, Laura; Guarino, Stefania; Capponi, Marco; Giannini, Massimo; Cognigni, Paolo Decembrini; Ferrara, Gerardo; Battelli, Nicola

2018-01-01

Triple-negative breast cancer (TNBC) is associated with a poor prognosis, due to its aggressive behaviour and lack of effective targeted therapies. Immunocheckpoint inhibitors, such as anti-programmed cell death 1 (PD-1) and anti-PD-ligand(L)1 agents, are in course of investigation in TNBC, used alone or in combination with other systemic or local approaches. However, the high cost of these drugs and the lack of validated predictive biomarkers support the development of strategies aimed to overcome resistance and optimize the efficacy of these approaches. Tumor-Associated Macrophages (TAMs) derive from peripheral blood monocytes recruited into the TNBC microenvironment and, in response to several stimuli, undergo M1 (classical) or M2 (alternative) activation. In TNBC, TAMs promote tumor growth and progression by several mechanisms that include the secretion of inhibitory cytokines, the reduction of effector functions of Tumor Infiltrating Lymphocytes (TILs) and the promotion of Regulatory T cell (Treg). Interestingly, TAMs have been shown to directly and indirectly modulate PD-1/PD-L1 expression in tumor environment. On this scenario, several TAM-centered strategies have been proposed, such as the suppression of TAM recruitment, the depletion of their number, the switch of M2 TAMs into antitumor M1 phenotype and the inhibition of TAM-associated molecules. In this review, we will illustrate the activity of TAMs and associated molecules in TNBC, focusing on their role in modulating the expression of PD-1/PD-L1 and on the emerging TAM-tailored strategies for TNBC patients. Copyright © 2017 Elsevier B.V. All rights reserved.

IDENTIFICATION OF A NOVEL CLASS OF ANTI-INFLAMMATORY COMPOUNDS WITH ANTI-TUMOR ACTIVITY IN COLORECTAL AND LUNG CANCERS

PubMed Central

Chang, Hui-Hua; Song, Zuohe; Wisner, Lee; Tripp, Tina; Gokhale, Vijay

2011-01-01

Summary Chronic inflammation is associated with 25% of all cancers. In the inflammation-cancer axis, prostaglandin E2 (PGE2) is one of the major players. PGE2 synthases (PGES) are the enzymes downstream of the cyclooxygenases (COXs) in the PGE2 biosynthesis pathway. Microsomal prostaglandin E2 synthase 1 (mPGES-1) is inducible by pro-inflammatory stimuli and constitutively expressed in a variety of cancers. The potential role for this enzyme in tumorigenesis has been reported and mPGES-1 represents a novel therapeutic target for cancers. In order to identify novel small molecule inhibitors of mPGES-1, we screened the ChemBridge library and identified 13 compounds as potential hits. These compounds were tested for their ability to bind directly to the enzyme using surface plasmon resonance spectroscopy and to decrease cytokine-stimulated PGE2 production in various cancer cell lines. We demonstrate that the compound PGE0001 (ChemBridge ID number 5654455) binds to human mPGES-1 recombinant protein with good affinity (KD = 21.3 ± 7.8 μM). PGE0001 reduces IL-1β-induced PGE2 release in human HCA-7 colon and A549 lung cancer cell lines with EC50 in the submicromolar range. Although PGE0001 may have alternative targets based on the results from in vitro assays, it shows promising effects in vivo. PGE0001 exhibits significant anti-tumor activity in SW837 rectum and A549 lung cancer xenografts in SCID mice. Single injection i.p. of PGE0001 at 100 mg/kg decreases serum PGE2 levels in mice within 5 h. In summary, our data suggest that the identified compound PGE0001 exerts anti-tumor activity via the inhibition of the PGE2 synthesis pathway. PMID:21931968

Dendritic cell activation enhances anti-PD-1 mediated immunotherapy against glioblastoma.

PubMed

Garzon-Muvdi, Tomas; Theodros, Debebe; Luksik, Andrew S; Maxwell, Russell; Kim, Eileen; Jackson, Christopher M; Belcaid, Zineb; Ganguly, Sudipto; Tyler, Betty; Brem, Henry; Pardoll, Drew M; Lim, Michael

2018-04-17

The glioblastoma (GBM) immune microenvironment is highly suppressive as it targets and hinders multiple components of the immune system. Checkpoint blockade (CB) is being evaluated for GBM patients. However, biomarker analyses suggest that CB monotherapy may be effective only in a small fraction of GBM patients. We hypothesized that activation of antigen presentation would increase the therapeutic response to PD-1 blockade. We show that activating DCs through TLR3 agonists enhances the anti-tumor immune response to CB and increases survival in GBM. Mice treated with TLR3 agonist poly(I:C) and anti-PD-1 demonstrated increased DC activation and increased T cell proliferation in tumor draining lymph nodes. We show that DCs are necessary for the improved anti-tumor immune response. This study suggests that augmenting antigen presentation is an effective multimodal immunotherapy strategy that intensifies anti-tumor responses in GBM. Specifically, these data represent an expanded role for TLR3 agonists as adjuvants to CB. Using a preclinical model of GBM, we tested the efficacy of combinatorial immunotherapy with anti-PD-1 and TLR3 agonist, poly(I:C). Characterization of the immune response in tumor infiltrating immune cells and in secondary lymphoid organs was performed. Additionally, dendritic cell (DC) depletion experiments were performed.

Inhibition of protein kinase CK2 reduces CYP24A1 expression and enhances 1,25-dihydroxyvitamin D3 anti-tumor activity in human prostate cancer cells

PubMed Central

Luo, Wei; Yu, Wei-Dong; Ma, Yingyu; Chernov, Mikhail; Trump, Donald L.; Johnson, Candace S.

2013-01-01

Vitamin D has broad range of physiological functions and anti-tumor effects. 24-hydroxylase, encoded by the CYP24A1 gene, is the key enzyme for degrading many forms of vitamin D including the most active form, 1,25D3. Inhibition of CYP24A1 enhances 1,25D3 anti-tumor activity. In order to isolate regulators of CYP24A1 expression in prostate cancer cells, we established a stable prostate cancer cell line PC3 with CYP24A1 promoter driving luciferase expression to screen a small molecular library for compounds that inhibit CYP24A1 promoter activity. From this screening, we identified, 4,5,6,7-tetrabromobenzimidazole (TBBz), a protein kinase CK2 selective inhibitor as a disruptor of CYP24A1 promoter activity. We show that TBBz inhibits CYP24A1 promoter activity induced by 1,25D3 in prostate cancer cells. In addition, TBBz downregulates endogenous CYP24A1 mRNA level in TBBz treated PC3 cells. Furthermore, siRNA-mediated CK2 knockdown reduces 1,25D3 induced CYP24A1 mRNA expression in PC3 cells. These results suggest that CK2 contributes to 1,25D3 mediated target gene expression. Lastly, inhibition of CK2 by TBBz or CK2 siRNA significantly enhanced 1,25D3 mediated anti-proliferative effect in vitro and in vivo in a xenograft model. In summary, our findings reveal that protein kinase CK2 is involved in the regulation of CYP24A1 expression by 1,25D3 and CK2 inhibitor enhances 1,25D3 mediated anti-tumor effect. PMID:23358686

A novel approach to the discovery of anti-tumor pharmaceuticals: searching for activators of liponecrosis

PubMed Central

Arlia-Ciommo, Anthony; Svistkova, Veronika; Mohtashami, Sadaf; Titorenko, Vladimir I.

2016-01-01

A recently conducted chemical genetic screen for pharmaceuticals that can extend longevity of the yeast Saccharomyces cerevisiae has identified lithocholic acid as a potent anti-aging molecule. It was found that this hydrophobic bile acid is also a selective anti-tumor chemical compound; it kills different types of cultured cancer cells if used at concentrations that do not compromise the viability of non-cancerous cells. These studies have revealed that yeast can be successfully used as a model organism for high-throughput screens aimed at the discovery of selectively acting anti-tumor small molecules. Two metabolic traits of rapidly proliferating fermenting yeast, namely aerobic glycolysis and lipogenesis, are known to be similar to those of cancer cells. The mechanisms underlying these key metabolic features of cancer cells and fermenting yeast have been established; such mechanisms are discussed in this review. We also suggest how a yeast-based chemical genetic screen can be used for the high-throughput development of selective anti-tumor pharmaceuticals that kill only cancer cells. This screen consists of searching for chemical compounds capable of increasing the abundance of membrane lipids enriched in unsaturated fatty acids that would therefore be toxic only to rapidly proliferating cells, such as cancer cells and fermenting yeast. PMID:26636650

Molecularly Characterized Solvent Extracts and Saponins from Polygonum hydropiper L. Show High Anti-Angiogenic, Anti-Tumor, Brine Shrimp, and Fibroblast NIH/3T3 Cell Line Cytotoxicity

PubMed Central

Ayaz, Muhammad; Junaid, Muhammad; Ullah, Farhat; Sadiq, Abdul; Subhan, Fazal; Khan, Mir Azam; Ahmad, Waqar; Ali, Gowhar; Imran, Muhammad; Ahmad, Sajjad

2016-01-01

Polygonum hydropiper is used as anti-cancer and anti-rheumatic agent in folk medicine. This study was designed to investigate the anti-angiogenic, anti-tumor, and cytotoxic potentials of different solvent extracts and isolated saponins. Samples were analyzed using GC, Gas Chromatography–Mass Spectrometry (GC–MS) to identify major and bioactive compounds. Quantitation of antiangiogenesis for the plant's samples including methanolic extract (Ph.Cr), its subsequent fractions; n-hexane (Ph.Hex), chloroform (Ph.Chf), ethyl acetate (Ph.EtAc), n-Butanol (Ph.Bt), aqueous (Ph.Aq), saponins (Ph.Sp) were performed using the chick embryo chorioallantoic membrane (CAM) assay. Potato disc anti-tumor assay was performed on Agrobacterium tumefaciens containing tumor inducing plasmid. Cytotoxicity was performed against Artemia salina and mouse embryonic fibroblast NIH/3T3 cell line following contact toxicity and MTT cells viability assays, respectively. The GC–MS analysis of Ph.Cr, Ph.Hex, Ph.Chf, Ph.Bt, and Ph.EtAc identified 126, 124, 153, 131, and 164 compounds, respectively. In anti-angiogenic assay, Ph.Chf, Ph.Sp, Ph.EtAc, and Ph.Cr exhibited highest activity with IC50 of 28.65, 19.21, 88.75, and 461.53 μg/ml, respectively. In anti-tumor assay, Ph.Sp, Ph.Chf, Ph.EtAc, and Ph.Cr were most potent with IC50 of 18.39, 73.81, 217.19, and 342.53 μg/ml, respectively. In MTT cells viability assay, Ph.Chf, Ph.EtAc, Ph.Sp were most active causing 79.00, 72.50, and 71.50% cytotoxicity, respectively, at 1000 μg/ml with the LD50 of 140, 160, and 175 μg/ml, respectively. In overall study, Ph.Chf and Ph.Sp have shown overwhelming results which signifies their potentials as sources of therapeutic agents against cancer. PMID:27065865

Anti-tumor bioactivities of curcumin on mice loaded with gastric carcinoma.

PubMed

Wang, Xiao-Ping; Wang, Qiao-Xia; Lin, Huan-Ping; Chang, Na

2017-09-20

Curcumin, a derivative from the dried rhizome of curcuma longa, has been proven to possess anti-tumor effects. However, the detailed molecular mechanisms have not been fully elucidated. In this study, we aimed to explore the anti-tumor mechanisms of curcumin in treating gastric cancer. BALB/C mice grafted with a mouse gastric adenocarcinoma cell line (MFC) were used as the experimental model. Mice received different doses of curcumin after grafting. Tumor size was measured and tumor weight was determined after tumor inoculation. TUNEL assay and flow cytometric analysis were applied to evaluate the apoptosis of the cancer cells. Serum cytokines IFN-γ, TNF-α, granzyme B and perforin were detected by ELISA assay. The anti-tumor effect was determined using cytotoxic T-lymphocyte (CTL) assays and in vivo tumor prevention tests. The expression of DEC1, HIF-1α, STAT3 and VEGF in tumor tissues was examined by immunostaining and analyzed using an Image J analysis system. Compared with controls, tumor growth (size and weight) was significantly inhibited by curcumin treatment (P < 0.05). The apoptotic index in gastric cancer cells was significantly increased in the curcumin treatment group. Splenocyte cells from mice treated with curcumin exhibited higher cytolytic effects on MFC cancer cells than those from mice treated with saline (P < 0.01). The expression of DEC1, HIF-1α, STAT3 and VEGF in tumor tissues was down-regulated after curcumin treatment. Our results indicate that curcumin inhibits the proliferation of gastric carcinoma by inducing the apoptosis of tumor cells, activating immune cells to secrete a large amount of cytokines, and down-regulating the DEC1, HIF-1α, VEGF and STAT3 signal transduction pathways.

Vitamin E δ-Tocotrienol Augments the Anti-tumor Activity of Gemcitabine and Suppresses Constitutive NF-κB Activation in Pancreatic Cancer

PubMed Central

Husain, Kazim; Francois, Rony A.; Yamauchi, Teruo; Perez, Marta; Sebti, Said M.; Malafa, Mokenge P.

2011-01-01

The nuclear factor-κB (NF-κB) transcription factor functions as a crucial regulator of cell survival and chemoresistance in pancreatic cancer. Recent studies suggest that tocotrienols, which are the unsaturated forms of vitamin E, are a promising class of anti-cancer compounds that inhibit the growth and survival of many cancer cells, including pancreatic cancer. Here, we show that tocotrienols inhibited NF-κB activity and the survival of human pancreatic cancer cells in vitro and in vivo. Importantly, we found the bioactivity of the 4 natural tocotrienol compounds (α-, β-, δ-, and γ-tocotrienol) to be directly related to their ability to suppress NF-κB activity in vitro and in vivo. The most bioactive tocotrienol for pancreatic cancer, δ-tocotrienol, significantly enhanced the efficacy of gemcitabine to inhibit pancreatic cancer growth and survival in vitro and in vivo. Moreover, we found that δ-tocotrienol augmentation of gemcitabine activity in pancreatic cancer cells and tumors is associated with significant suppression of NF-κB activity and the expression of NF-κB transcriptional targets [Bcl-XL, X-linked inhibitor of apoptosis (XIAP), and survivin]. Our study represents the first comprehensive pre-clinical evaluation of the activity of natural vitamin E compounds in pancreatic cancer. Given these results, we are conducting a phase I trial of δ-tocotrienol in patients with pancreatic cancer utilizing pancreatic tumor cell survival and NF-κB signaling components as intermediate biomarkers. Our data also support future clinical investigation of δ-tocotrienol to augment gemcitabine activity in pancreatic cancer. PMID:21971120

Broad-spectrum anti-tumor and anti-metastatic DNA vaccine based on p62-encoding vector

PubMed Central

Sherman, Michael Y.; Gabai, Vladimir; Kiselev, Oleg; Komissarov, Andrey; Grudinin, Mikhail; Shartukova, Maria; Romanovskaya-Romanko, Ekaterina A.; Kudryavets, Yuri; Bezdenezhnykh, Natalya; Lykhova, Oleksandra; Semesyuk, Nadiia; Concetti, Antonio; Tsyb, Anatoly; Filimonova, Marina; Makarchuk, Victoria; Yakubovsky, Raisa; Chursov, Andrey; Shcherbinina, Vita; Shneider, Alexander

2013-01-01

Autophagy plays an important role in neoplastic transformation of cells and in resistance of cancer cells to radio- and chemotherapy. p62 (SQSTM1) is a key component of autophagic machinery which is also involved in signal transduction. Although recent empirical observations demonstrated that p62 is overexpressed in variety of human tumors, a mechanism of p62 overexpression is not known. Here we report that the transformation of normal human mammary epithelial cells with diverse oncogenes (RAS, PIK3CA and Her2) causes marked accumulation of p62. Based on this result, we hypothesized that p62 may be a feasible candidate to be an anti-cancer DNA vaccine. Here we performed a preclinical study of a novel DNA vaccine encoding p62. Intramuscularly administered p62-encoding plasmid induced anti-p62 antibodies and exhibited strong antitumor activity in four models of allogeneic mouse tumors – B16 melanoma, Lewis lung carcinoma (LLC), S37 sarcoma, and Ca755 breast carcinoma. In mice challenged with Ca755 cells, p62 treatment had dual effect: inhibited tumor growth in some mice and prolonged life in those mice which developed tumor size similar to control. P62-encoding plasmid has demonstrated its potency both as a preventive and therapeutic vaccine. Importantly, p62 vaccination drastically suppressed metastasis formation: in B16 melanoma where tumor cells where injected intravenously, and in LLC and S37 sarcoma with spontaneous metastasis. Overall, we conclude that a p62-encoding vector(s) constitute(s) a novel, effective broad-spectrum antitumor and anti-metastatic vaccine feasible for further development and clinical trials. PMID:24121124

Ghrelin levels in patients with juvenile idiopathic arthritis: relation to anti-tumor necrosis factor treatment and disease activity.

PubMed

Karagiozoglou-Lampoudi, Thomais; Trachana, Maria; Agakidis, Charalampos; Pratsidou-Gertsi, Polyxeni; Taparkou, Anna; Lampoudi, Sotiria; Kanakoudi-Tsakalidou, Florentia

2011-10-01

Studies in adults with rheumatoid arthritis reported low serum ghrelin that increased following anti-tumor necrosis factor (TNF) infusion. Data on juvenile idiopathic arthritis (JIA) are lacking. The aim of this pilot study was to explore serum ghrelin levels in patients with JIA and the possible association with anti-TNF treatment, disease activity, and nutritional status. Fifty-two patients with JIA (14/52 on anti-TNF treatment) were studied. Juvenile idiopathic arthritis was inactive in 3 of 14 anti-TNF-treated patients and in 11 of 38 non-anti-TNF-treated patients. The nutritional status, energy intake/requirements, appetite, and fasting serum ghrelin levels were assessed. Ghrelin control values were obtained from 50 individuals with minor illness matched for age, sex, and body mass index. Ghrelin levels in patients with JIA were significantly lower than in controls (P < .001, confidence interval [CI] = -101 to -331). Analysis according to anti-TNF treatment and disease activity showed that ghrelin levels were comparable to control values only in 3 patients with anti-TNF-induced remission. Ghrelin in non-anti-TNF-treated patients in remission was low. Multiple regression analysis showed that disease activity (P = .002, CI = -84.16 to -20.01) and anti-TNF treatment (P = .003, CI = -82.51 to -18.33) were significant independent predictors of ghrelin after adjusting for other potential confounders. Ghrelin did not correlate with nutritional status, energy balance, and appetite. Serum ghrelin is low in patients with JIA and is restored to values similar to those in controls following anti-TNF-induced remission. Our study provides evidence that TNF blockade is independently associated with serum ghrelin, which possibly contributes to anti-TNF-induced remission. These preliminary results could form the basis for future research. Copyright © 2011 Elsevier Inc. All rights reserved.

Oligoesculin fraction induces anti-tumor effects and promotes immune responses on B16-F10 mice melanoma.

PubMed

Mokdad Bzeouich, Imen; Mustapha, Nadia; Sassi, Aicha; Ghedira, Kamel; Ghoul, Mohamed; Chebil, Latifa; Luis, José; Chekir-Ghedira, Leila

2016-08-01

Laccase was used to enzymatically polymerize esculin. Oligoesculin fraction was obtained after ultrafiltration through a 5-kDa membrane. Several studies have been carried out to prove the effectiveness of natural substances such as immunomodulators to promote the anti-cancer activity in situ. The purpose of our report was to explore whether the anti-tumor potential of the oligoesculin fraction in vitro and in vivo is linked to its immunological mechanisms in melanoma-bearing mice. We revealed that oligoesculin fraction reduced B16-F10 proliferation and migration in vitro in a dose-related manner. Moreover, melanin synthesis and tyrosinase activity were inhibited in these melanoma cells in a concentration-dependent way. The anti-tumor potential of oligoesculin fraction was also assessed in vivo. Our results showed that intraperitoneal administration of oligoesculin fraction, at 50 mg/kg body weight (b.w.) for 21 days, reduced tumor size and weight with percentages of inhibition of 94 and 87 %, respectively. Oligoesculin fraction was effective in promoting lysosomal activity and nitric oxide (NO) production by peritoneal macrophages in tumor-implanted mice. In addition, the activities of natural killer (NK), cytotoxic T lymphocytes, and macrophages were significantly enhanced by oligoesculin fraction. These findings suggested that this polymer with its anti-tumor and immunomodulatory properties could be used for the treatment of melanoma.

Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells.

PubMed

Boyerinas, Benjamin; Jochems, Caroline; Fantini, Massimo; Heery, Christopher R; Gulley, James L; Tsang, Kwong Yok; Schlom, Jeffrey

2015-10-01

Several anti-PD-1/PD-L1 monoclonal antibodies (mAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these mAbs is to inhibit PD-1 on immune cells interacting with PD-L1 on tumor cells. These mAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective mAb-mediated cancer therapies. A fully human anti-PD-L1 mAb would potentially be able to block PD-1/PD-L1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 mAb. The studies reported here demonstrate (i) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (ii) IFNγ can enhance tumor cell PD-L1 expression and, in some cases, enhance ADCC tumor cell lysis; (iii) purified NK cells are potent effectors for avelumab; (iv) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (v) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (vi) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity. ©2015 American Association for Cancer Research.

Antibody-dependent cellular cytotoxicity (ADCC) activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells

PubMed Central

Fantini, Massimo; Heery, Christopher R.; Gulley, James L.; Tsang, Kwong Yok; Schlom, Jeffrey

2015-01-01

Several anti-PD1/PD-L1 monoclonal antibodies (MAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these MAbs is to inhibit PD1 on immune cells interacting with PD-L1 on tumor cells. These MAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective MAb-mediated cancer therapies. A fully human anti-PD-L1 MAb would potentially be able to block PD-L1/PD1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 MAb. The studies reported here demonstrate (a) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (b) IFNγ can enhance tumor cell PD-L1 expression and in some cases enhance ADCC tumor cell lysis; (c) purified NK cells are potent effectors for avelumab; (d) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (e) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (f) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 MAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity. PMID:26014098

Second primary tumor in anti-Ma1/2-positive paraneoplastic limbic encephalitis.

PubMed

Leyhe, T; Schüle, R; Schwärzler, F; Gasser, T; Haarmeier, T

2006-05-01

Memory loss can be a symptom of paraneoplastic limbic encephalitis (PLE) a neuropsychiatric disorder associated mostly with small-cell lung cancer and anti-Hu antibodies or with testicular tumors and anti-Ma2 antibodies. We present the case of a patient with temporal coincidence of beginning cognitive decline and diagnosis of a carcinoma of the prostate in whom we diagnosed anti-Ma1/Ma2-positive PLE. The tumor had been completely resected but memory impairment further deteriorated. As the effective treatment of the cancer is considered as the most efficient treatment of a paraneoplastic neurological syndrome (PNS) a second neoplasia was suspected in the patient. By the aid of whole body positron emission tomography with 18-fluorine fluoro-2-deoxy-glucose (FDG-PET) an adenocarcinoma of the cecum could be detected. Two months after surgery anti-Ma antibodies were negative. We conclude that a second neoplasia should be considered, if effective cancer treatment does not lead to improvement or stabilisation of a PNS. Tumor search should be exhaustive and include PET when conventional imaging fails to show a malignancy.

Cytotoxic and anti-colorectal tumor effects of sulfated saponins from sea cucumber Holothuria moebii.

PubMed

Yu, Siran; Ye, Xuewei; Chen, Lu; Xie, Xin; Zhou, Qian; Lian, Xiao-Yuan; Zhang, Zhizhen

2015-11-15

Whether sulfated saponins from Holothuria moebii inhibit the proliferation of colorectal cancer cells and have anti-colorectal tumor effects in animal model has not been investigated. To evaluate the cytotoxic and anti-colorectal tumor effects of sulfated saponins from sea cucumber Holothuria moebii. (1) Column chromatography was used to prepare the total and individual saponins and HPLC was applied to define the components of the total saponins; (2) the activity of the total and individual saponins inhibiting the proliferation of human colorectal cancer cells was determined by SRB assay and the apoptosis induced by the saponins was qualified using cytometric analysis with Annexin V-FITC/PI double staining; and (3) the antitumor effects of the sulfated saponins on colorectal CT-26 tumor-bearing Balb/c mice were tested. The total and individual sulfated saponins significantly inhibited the proliferation of four different human colorectal cancer cells with IC50 values ranging from 1.04 to 4.08 μM (or 1.46 to 3.24 μg/ml for total saponins) and induced late apoptosis at an early treatment time in cancer cells. The total saponins (120 mg/kg) had antitumor activity in colorectal CT-26 tumor-bearing Balb/c mice. The sulfated saponins from H. moebii remarkably inhibited the proliferation of different human colorectal cancer cells and had significant anti-colorectal tumor activity in animal model. Copyright © 2015 Elsevier GmbH. All rights reserved.

NKT Cells as an Ideal Anti-Tumor Immunotherapeutic

PubMed Central

Fujii, Shin-ichiro; Shimizu, Kanako; Okamoto, Yoshitaka; Kunii, Naoki; Nakayama, Toshinori; Motohashi, Shinichiro; Taniguchi, Masaru

2013-01-01

Human natural killer T (NKT) cells are characterized by their expression of an invariant T cell antigen receptor α chain variable region encoded by a Vα24Jα18 rearrangement. These NKT cells recognize α-galactosylceramide (α-GalCer) in conjunction with the MHC class I-like CD1d molecule and bridge the innate and acquired immune systems to mediate efficient and augmented immune responses. A prime example of one such function is adjuvant activity: NKT cells augment anti-tumor responses because they can rapidly produce large amounts of IFN-γ, which acts on NK cells to eliminate MHC negative tumors and also on CD8 cytotoxic T cells to kill MHC positive tumors. Thus, upon administration of α-GalCer-pulsed DCs, both MHC negative and positive tumor cells can be effectively eliminated, resulting in complete tumor eradication without tumor recurrence. Clinical trials have been completed in a cohort of 17 patients with advanced non-small cell lung cancers and 10 cases of head and neck tumors. Sixty percent of advanced lung cancer patients with high IFN-γ production had significantly prolonged median survival times of 29.3 months with only the primary treatment. In the case of head and neck tumors, 10 patients who completed the trial all had stable disease or partial responses 5 weeks after the combination therapy of α-GalCer-DCs and activated NKT cells. We now focus on two potential powerful treatment options for the future. One is to establish artificial adjuvant vector cells containing tumor mRNA and α-GalCer/CD1d. This stimulates host NKT cells followed by DC maturation and NK cell activation but also induces tumor-specific long-term memory CD8 killer T cell responses, suppressing tumor metastasis even 1 year after the initial single injection. The other approach is to establish induced pluripotent stem (iPS) cells that can generate unlimited numbers of NKT cells with adjuvant activity. Such iPS-derived NKT cells produce IFN-γ in vitro and in vivo upon

Tumor surrogate blood vessel subtypes exhibit differential susceptibility to anti-VEGF therapy

PubMed Central

Sitohy, Basel; Nagy, Janice A.; Shih, Shou-Ching; Dvorak, Harold F.

2011-01-01

Anti-vascular therapy directed against VEGF or its receptors has been successful when administered at early stages of tumor vessel growth, but is less effective when administered later. Tumor blood vessels are heterogeneous, so vessel subpopulations may differ in their requirements for tumor cell-secreted VEGF and in their susceptibility to anti-VEGF/VEGFR therapy. Human cancers contain several distinct blood vessel types, including mother vessels (MV), glomeruloid microvascular proliferations (GMP), vascular malformations (VM), feeding arteries (FA) and draining veins (DV), all of which can be generated in mice in the absence of tumor cells using expression vectors for VEGF-A164. In this study, we investigated the sensitivity of each of these vessel types to anti-VEGF therapy with aflibercept ® (VEGF Trap), a potent inhibitor of VEGF-A164. Administering VEGF Trap treatment before or shortly after injection of a recombinant VEGF-A164 expressing adenovirus could prevent or regress tumor-free neovasculature, but it was progressively less effective if initiated at later times. Early-forming MVs and GMPs in which the lining endothelial cells expressed high levels of VEGFR-2 were highly susceptible to blockade by VEGF Trap. In contrast, late-forming VMs, FAs, and DVs that expressed low levels of VEGFR-2 were largely resistant. Together, our findings define the susceptibility of different blood vessel subtypes to anti-VEGF therapy, offering a possible explanation for the limited effectiveness of anti-VEGF-A/VEGFR treatment of human cancers, which are typically present for months to years before discovery and are largely populated by late-forming blood vessels. PMID:21937680

Nordihydroguaiaretic acid ameliorates cisplatin induced nephrotoxicity and potentiates its anti-tumor activity in DMBA induced breast cancer in female Sprague-Dawley rats.

PubMed

Mundhe, Nitin Arunrao; Kumar, Parveen; Ahmed, Sahabuddin; Jamdade, Vinayak; Mundhe, Sanjay; Lahkar, Mangala

2015-09-01

Cisplatin is a widely used antineoplastic drug, but its clinical usefulness is limited due to dose dependent nephrotoxicity. Nordihydroguaiaretic acid (NDGA) is a natural compound with broad pharmacological properties like antioxidant, anti-inflammatory and anticancer activity. The present study was undertaken to evaluate the possible beneficial effects of NDGA on cisplatin induced nephrotoxicity as well as its anticancer activity in rats bearing DMBA induced mammary tumors. The effect of NDGA on cisplatin induced nephrotoxicity was evaluated by checking serum nephrotoxicity markers, antioxidant enzymes and inflammatory markers level and kidney histopathology. NDGA induced amelioration of cisplatin nephrotoxicity was clearly visible from significant reductions in serum blood urea nitrogen (86.51 g/dl) and creatinine (5.30 g/dl) levels and significant improvement in body weight change (-10.34 g) and kidney weight (728 mg/kg). The protective effect of NDGA against cisplatin induced nephrotoxicity in the rats was further confirmed by significant restoration of antioxidant enzymes like SOD (86.28% inhibition), inflammatory markers like TNF-α (34.6 pg/ml) and histopathological examination. Moreover, our results showed that NDGA potentiated anti-breast cancer activity of cisplatin through an increment in the expression of antioxidant enzymes like SOD (85.35% inhibition) in breast cancer tissue. These results indicated that NDGA potentiated the anti-breast cancer activity of cisplatin, which was clearly evident from the tumor volume and % tumor inhibition in breast cancer rats. The current study demonstrated that NDGA may modify the therapeutic effect of cisplatin in DMBA induced breast cancer in female Sprague-Dawley rats. Copyright © 2015 Elsevier B.V. All rights reserved.

Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma.

PubMed

Brown, Christine E; Aguilar, Brenda; Starr, Renate; Yang, Xin; Chang, Wen-Chung; Weng, Lihong; Chang, Brenda; Sarkissian, Aniee; Brito, Alfonso; Sanchez, James F; Ostberg, Julie R; D'Apuzzo, Massimo; Badie, Behnam; Barish, Michael E; Forman, Stephen J

2018-01-03

T cell immunotherapy is emerging as a powerful strategy to treat cancer and may improve outcomes for patients with glioblastoma (GBM). We have developed a chimeric antigen receptor (CAR) T cell immunotherapy targeting IL-13 receptor α2 (IL13Rα2) for the treatment of GBM. Here, we describe the optimization of IL13Rα2-targeted CAR T cells, including the design of a 4-1BB (CD137) co-stimulatory CAR (IL13BBζ) and a manufacturing platform using enriched central memory T cells. Utilizing orthotopic human GBM models with patient-derived tumor sphere lines in NSG mice, we found that IL13BBζ-CAR T cells improved anti-tumor activity and T cell persistence as compared to first-generation IL13ζ-CAR CD8 + T cells that had shown evidence for bioactivity in patients. Investigating the impact of corticosteroids, given their frequent use in the clinical management of GBM, we demonstrate that low-dose dexamethasone does not diminish CAR T cell anti-tumor activity in vivo. Furthermore, we found that local intracranial delivery of CAR T cells elicits superior anti-tumor efficacy as compared to intravenous administration, with intraventricular infusions exhibiting possible benefit over intracranial tumor infusions in a multifocal disease model. Overall, these findings help define parameters for the clinical translation of CAR T cell therapy for the treatment of brain tumors. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

The B-Raf status of tumor cells may be a significant determinant of both antitumor and anti-angiogenic effects of pazopanib in xenograft tumor models.

PubMed

Gril, Brunilde; Palmieri, Diane; Qian, Yong; Anwar, Talha; Ileva, Lilia; Bernardo, Marcelino; Choyke, Peter; Liewehr, David J; Steinberg, Seth M; Steeg, Patricia S

2011-01-01

Pazopanib is an FDA approved Vascular Endothelial Growth Factor Receptor inhibitor. We previously reported that it also inhibits tumor cell B-Raf activity in an experimental brain metastatic setting. Here, we determine the effects of different B-Raf genotypes on pazopanib efficacy, in terms of primary tumor growth and anti-angiogenesis. A panel of seven human breast cancer and melanoma cell lines harboring different mutations in the Ras-Raf pathway was implanted orthotopically in mice, and tumor growth, ERK1/2, MEK1/2 and AKT activation, and blood vessel density and permeability were analyzed. Pazopanib was significantly inhibitory to xenografts expressing either exon 11 mutations of B-Raf, or HER2 activated wild type B-Raf; no significant inhibition of a xenograft expressing the common V600E B-Raf mutation was observed. Decreased pMEK staining in the responsive tumors confirmed that B-Raf was targeted by pazopanib. Interestingly, pazopanib inhibition of tumor cell B-Raf also correlated with its anti-angiogenic activity, as quantified by vessel density and area. In conclusion, using pazopanib, tumor B-Raf status was identified as a significant determinant of both tumor growth and angiogenesis.

The B-Raf Status of Tumor Cells May Be a Significant Determinant of Both Antitumor and Anti-Angiogenic Effects of Pazopanib in Xenograft Tumor Models

PubMed Central

Gril, Brunilde; Palmieri, Diane; Qian, Yong; Anwar, Talha; Ileva, Lilia; Bernardo, Marcelino; Choyke, Peter; Liewehr, David J.; Steinberg, Seth M.; Steeg, Patricia S.

2011-01-01

Pazopanib is an FDA approved Vascular Endothelial Growth Factor Receptor inhibitor. We previously reported that it also inhibits tumor cell B-Raf activity in an experimental brain metastatic setting. Here, we determine the effects of different B-Raf genotypes on pazopanib efficacy, in terms of primary tumor growth and anti-angiogenesis. A panel of seven human breast cancer and melanoma cell lines harboring different mutations in the Ras-Raf pathway was implanted orthotopically in mice, and tumor growth, ERK1/2, MEK1/2 and AKT activation, and blood vessel density and permeability were analyzed. Pazopanib was significantly inhibitory to xenografts expressing either exon 11 mutations of B-Raf, or HER2 activated wild type B-Raf; no significant inhibition of a xenograft expressing the common V600E B-Raf mutation was observed. Decreased pMEK staining in the responsive tumors confirmed that B-Raf was targeted by pazopanib. Interestingly, pazopanib inhibition of tumor cell B-Raf also correlated with its anti-angiogenic activity, as quantified by vessel density and area. In conclusion, using pazopanib, tumor B-Raf status was identified as a significant determinant of both tumor growth and angiogenesis. PMID:21998674

The preparation of three selenium-containing Cordyceps militaris polysaccharides: Characterization and anti-tumor activities.

PubMed

Liu, Fei; Zhu, Zhen-Yuan; Sun, Xiaoli; Gao, Hui; Zhang, Yong-Min

2017-06-01

In the present work, three fractions of selenized Cordyceps militaris polysaccharides (SeCPS) named SeCPS- I, SeCPS- II and SeCPS- III were isolated and purified by ultra-filtration. Their selenium content were measured as 541.3, 863.7 and 623.3μg/g respectively by a graphite furnace atomic absorption spectroscopy. The monosaccharide comformation analysis showed that they were mainly consisted of D-Mannose, D-Glucose, and D-Galactose in mole ratios of 1:7.63:0.83, 1:1.34:0.31 and 1:3.77:0.41 respectively. Their structure characteristics were compared by IFR and NMR spectroscopy. Scanning electron microscopy (SEM) and Congo red (CR) spectrophotometric method were used to investigate their morphological characteristics and conformational transition. SeCPS-II showed the strongest anti-tumor effects judging from the result of in vitro anti-tumor assays against two tumor cell lines (hepatocellular carcinoma HepG-2 cells and lung adenocarcinom A549 cells). Copyright © 2017 Elsevier B.V. All rights reserved.

Anti-tumor activities of luteolin and silibinin in glioblastoma cells: overexpression of miR-7-1-3p augmented luteolin and silibinin to inhibit autophagy and induce apoptosis in glioblastoma in vivo.

PubMed

Chakrabarti, Mrinmay; Ray, Swapan K

2016-03-01

Glioblastoma is the deadliest brain tumor in humans. High systemic toxicity of conventional chemotherapies prompted the search for natural compounds for controlling glioblastoma. The natural flavonoids luteolin (LUT) and silibinin (SIL) have anti-tumor activities. LUT inhibits autophagy, cell proliferation, metastasis, and angiogenesis and induces apoptosis; while SIL activates caspase-8 cascades to induce apoptosis. However, synergistic anti-tumor effects of LUT and SIL in glioblastoma remain unknown. Overexpression of tumor suppressor microRNA (miR) could enhance the anti-tumor effects of LUT and SIL. Here, we showed that 20 µM LUT and 50 µM SIL worked synergistically for inhibiting growth of two different human glioblastoma U87MG (wild-type p53) and T98G (mutant p53) cell lines and natural combination therapy was more effective than conventional chemotherapy (10 µM BCNU or 100 µM TMZ). Combination of LUT and SIL caused inhibition of growth of glioblastoma cells due to induction of significant amounts of apoptosis and complete inhibition of invasion and migration. Further, combination of LUT and SIL inhibited rapamycin (RAPA)-induced autophagy, a survival mechanism, with suppression of PKCα and promotion of apoptosis through down regulation of iNOS and significant increase in expression of the tumor suppressor miR-7-1-3p in glioblastoma cells. Our in vivo studies confirmed that overexpression of miR-7-1-3p augmented anti-tumor activities of LUT and SIL in RAPA pre-treated both U87MG and T98G tumors. In conclusion, our results clearly demonstrated that overexpression of miR-7-1-3p augmented the anti-tumor activities of LUT and SIL to inhibit autophagy and induce apoptosis for controlling growth of different human glioblastomas in vivo.

Endoplasmic reticulum stress regulates tumor growth and anti-tumor immunity: a promising opportunity for cancer immunotherapy.

PubMed

Mohamed, Eslam; Cao, Yu; Rodriguez, Paulo C

2017-08-01

The endoplasmic reticulum (ER) stress is a cellular process that occurs as a consequence of several stress circumstances, such as the accumulation of unfolded proteins in the lumen of the ER or distinct insults that disturb the ER normal function. Different conditions in the tumor microenvironment (TME), including hypoxia, nutrient deprivation, and the elevated production of reactive oxygen and nitrogen species destabilize the loading and dispatching of the newly synthesized proteins, triggering ER stress in cancer cells and tumor-infiltrating leukocytes. In order to cope with TME-induced ER stress, tumor and stromal cells initiate an adaptive response process that aims to resolve ER stress and to restore cellular homeostasis, which is referred as the unfolded protein responses (UPR). Paradoxically, the UPR can also induce cell death under severe and/or permanent ER stress. The UPR is started through three mediators, the activation of the inositol-requiring enzyme-1α, the pancreatic ER kinase-like ER kinase, and the activating transcription factor 6. In this minireview, we will discuss the pro- and anti-tumorigenic role of the UPR in cancer cells. In addition, we will describe the effects of the TME-induced ER stress in the immunosuppressive activity of tumor-infiltrating myeloid cells. Also, we will review the results of emerging therapeutic interventions that target ER stress and the UPR mediators in cancer. We postulate that the inhibition of ER stress or the UPR-related elements could represent a significant approach to increase the efficacy of various forms of cancer immunotherapy.

[The role of regulatory T cells in the modulation of anti-tumor immune response].

PubMed

Radosavljević, Gordana D; Jovanović, Ivan P; Kanjevac, Tatjana V; Arsenijević, Nebojsa N

2013-01-01

Regulatory T cells (Treg) represent a subset of CD4+T cells whose function is to suppress immune responses. Treg lymphocytes can be divided into two subsets: natural nTreg lymphocytes that are developed in the thymus and inducible iTreg lymphocytes, which originate from conventional T lymphocytes on the periphery.The majority of Treg lymphocytes express high levels of interleukin-2 (IL-2) receptor a chain (CD25) and transcription factor FoxP3 (critical for the development and suppressor activity of iTreg lymphocytes). Cancer cells can modulate anti-tumor immune response indirectly, through the activation of Treg lymphocytes. It has been shown that the loss of regulatory function by depletion of tumor-induced Treg lymphocytes may enhance effectors response, resulting in tumor rejection, while the increased number of Treg lymphocytes effectively prevents tumor destruction. nTreg lymphocytes express increasingly CTLA-4 and membrane-bound TGF-beta, which inhibits cytokine production and responses of effectors lymphocytes.iTreg lymphocytes secrete immunosuppressive cytokines such as ILreg-10 and TGF-beta.Treg lymphocytes represent one of important obstruction in anti-tumor immunity.

M-HIFU Inhibits Tumor Growth, Suppresses STAT3 Activity and Enhances Tumor Specific Immunity in a Transplant Tumor Model of Prostate Cancer

PubMed Central

Huang, Xiaoyi; Yuan, Fang; Liang, Meihua; Lo, Hui-Wen; Shinohara, Mari L.; Robertson, Cary; Zhong, Pei

2012-01-01

Objective In this study, we explored the use of mechanical high intensity focused ultrasound (M-HIFU) as a neo-adjuvant therapy prior to surgical resection of the primary tumor. We also investigated the role of signal transducer and activator of transcription 3 (STAT3) in M-HIFU elicited anti-tumor immune response using a transplant tumor model of prostate cancer. Methods RM-9, a mouse prostate cancer cell line with constitutively activated STAT3, was inoculated subcutaneously in C57BL/6J mice. The tumor-bearing mice (with a maximum tumor diameter of 5∼6 mm) were treated by M-HIFU or sham exposure two days before surgical resection of the primary tumor. Following recovery, if no tumor recurrence was observed in 30 days, tumor rechallenge was performed. The growth of the rechallenged tumor, survival rate and anti-tumor immune response of the animal were evaluated. Results No tumor recurrence and distant metastasis were observed in both treatment groups employing M-HIFU + surgery and surgery alone. However, compared to surgery alone, M-HIFU combined with surgery were found to significantly inhibit the growth of rechallenged tumors, down-regulate intra-tumoral STAT3 activities, increase cytotoxic T cells in spleens and tumor draining lymph nodes (TDLNs), and improve the host survival. Furthermore, M-HIFU combined with surgery was found to significantly decrease the level of immunosuppression with concomitantly increased number and activities of dendritic cells, compared to surgery alone. Conclusion Our results demonstrate that M-HIFU can inhibit STAT3 activities, and when combined synergistically with surgery, may provide a novel and promising strategy for the treatment of prostate cancers. PMID:22911830

On dynamic tumor eradication conditions under combined chemical/anti-angiogenic therapies

NASA Astrophysics Data System (ADS)

Starkov, Konstantin E.

2018-02-01

In this paper ultimate dynamics of the five-dimensional cancer tumor growth model at the angiogenesis phase is studied. This model elaborated by Pinho et al. in 2014 describes interactions between normal/cancer/endothelial cells under chemotherapy/anti-angiogenic agents in tumor growth process. The author derives ultimate upper bounds for normal/tumor/endothelial cells concentrations and ultimate upper and lower bounds for chemical/anti-angiogenic concentrations. Global asymptotic tumor clearance conditions are obtained for two versions: the use of only chemotherapy and the combined application of chemotherapy and anti-angiogenic therapy. These conditions are established as the attraction conditions to the maximum invariant set in the tumor free plane, and furthermore, the case is examined when this set consists only of tumor free equilibrium points.

Anti-tumor effect of Coriolus versicolor methanol extract against mouse B16 melanoma cells: in vitro and in vivo study.

PubMed

Harhaji, Lj; Mijatović, S; Maksimović-Ivanić, D; Stojanović, I; Momcilović, M; Maksimović, V; Tufegdzić, S; Marjanović, Z; Mostarica-Stojković, M; Vucinić, Z; Stosić-Grujicić, S

2008-05-01

Numerous studies have shown immunostimulatory and anti-tumor effects of water and standardized aqueous ethanol extracts derived from the medicinal mushroom, Coriolus versicolor, but the biological activity of methanol extracts has not been examined so far. In the present study we investigated the anti-tumor effect of C. versicolor methanol extract (which contains terpenoids and polyphenols) on B16 mouse melanoma cells both in vitro and in vivo. In vitro treatment of the cells with the methanol extract (25-1600 microg/ml) reduced melanoma cell viability in a dose-dependent manner. Furthermore, in the presence of the methanol extract (200 microg/ml, concentration IC(50)) the proliferation of B16 cells was arrested in the G(0)/G(1) phase of the cell cycle, followed by both apoptotic and secondary necrotic cell death. In vivo methanol extract treatment (i.p. 50 mg/kg, for 14 days) inhibited tumor growth in C57BL/6 mice inoculated with syngeneic B16 tumor cells. Moreover, peritoneal macrophages collected 21 days after tumor implantation from methanol extract-treated animals exerted stronger tumoristatic activity ex vivo than macrophages from control melanoma-bearing mice. Taken together, our results demonstrate that C. versicolor methanol extract exerts pronounced anti-melanoma activity, both directly through antiproliferative and cytotoxic effects on tumor cells and indirectly through promotion of macrophage anti-tumor activity.

Alginate hydrogel improves anti-angiogenic bevacizumab activity in cancer therapy.

PubMed

Ferreira, Natália N; M B Ferreira, Leonardo; Miranda-Gonçalves, Vera; Reis, Rui M; Seraphim, Thiago V; Borges, Júlio César; Baltazar, Fátima; Gremião, Maria Palmira D

2017-10-01

Anti-vascular endothelial growth factor (anti-VEGF) therapy applied to solid tumors is a promising strategy, yet, the challenge to deliver these agents at high drug concentrations together with the maintenance of therapeutic doses locally, at the tumor site, minimizes its benefits. To overcome these obstacles, we propose the development of a bevacizumab-loaded alginate hydrogel by electrostatic interactions to design a delivery system for controlled and anti-angiogenic therapy under tumor microenvironmental conditions. The tridimensional hydrogel structure produced provides drug stability and a system able to be introduced as a flowable solution, stablishing a depot after local administration. Biological performance by the chick embryo chorioallantoic membrane (CAM) assay indicated a pH-independent improved anti-angiogenic activity (∼50%) compared to commercial available anti-VEGF drug. Moreover, there was a considerable regression in tumor size when treated with this system. Immunohistochemistry highlighted a reduced number and disorganization of microscopic blood vessels resulting from applied therapy. These results suggest that the developed hydrogel is a promising approach to create an innovative delivery system that offers the possibility to treat different solid tumors by intratumoral administration. Copyright © 2017 Elsevier B.V. All rights reserved.

Fusion Protein Vaccines Targeting Two Tumor Antigens Generate Synergistic Anti-Tumor Effects

PubMed Central

Cheng, Wen-Fang; Chang, Ming-Cheng; Sun, Wei-Zen; Jen, Yu-Wei; Liao, Chao-Wei; Chen, Yun-Yuan; Chen, Chi-An

2013-01-01

Introduction Human papillomavirus (HPV) has been consistently implicated in causing several kinds of malignancies, and two HPV oncogenes, E6 and E7, represent two potential target antigens for cancer vaccines. We developed two fusion protein vaccines, PE(ΔIII)/E6 and PE(ΔIII)/E7 by targeting these two tumor antigens to test whether a combination of two fusion proteins can generate more potent anti-tumor effects than a single fusion protein. Materials and Methods In vivo antitumor effects including preventive, therapeutic, and antibody depletion experiments were performed. In vitro assays including intracellular cytokine staining and ELISA for Ab responses were also performed. Results PE(ΔIII)/E6+PE(ΔIII)/E7 generated both stronger E6 and E7-specific immunity. Only 60% of the tumor protective effect was observed in the PE(ΔIII)/E6 group compared to 100% in the PE(ΔIII)/E7 and PE(ΔIII)/E6+PE(ΔIII)/E7 groups. Mice vaccinated with the PE(ΔIII)/E6+PE(ΔIII)/E7 fusion proteins had a smaller subcutaneous tumor size than those vaccinated with PE(ΔIII)/E6 or PE(ΔIII)/E7 fusion proteins alone. Conclusion Fusion protein vaccines targeting both E6 and E7 tumor antigens generated more potent immunotherapeutic effects than E6 or E7 tumor antigens alone. This novel strategy of targeting two tumor antigens together can promote the development of cancer vaccines and immunotherapy in HPV-related malignancies. PMID:24058440

Pharmacogenomics and the Yin/Yang actions of ginseng: anti-tumor, angiomodulating and steroid-like activities of ginsenosides

PubMed Central

Yue, Patrick Ying Kit; Mak, Nai Ki; Cheng, Yuen Kit; Leung, Kar Wah; Ng, Tzi Bun; Fan, David Tai Ping; Yeung, Hin Wing; Wong, Ricky Ngok Shun

2007-01-01

In Chinese medicine, ginseng (Panax ginseng C.A. Meyer) has long been used as a general tonic or an adaptogen to promote longevity and enhance bodily functions. It has also been claimed to be effective in combating stress, fatigue, oxidants, cancer and diabetes mellitus. Most of the pharmacological actions of ginseng are attributed to one type of its constituents, namely the ginsenosides. In this review, we focus on the recent advances in the study of ginsenosides on angiogenesis which is related to many pathological conditions including tumor progression and cardiovascular dysfunctions. Angiogenesis in the human body is regulated by two sets of counteracting factors, angiogenic stimulators and inhibitors. The 'Yin and Yang' action of ginseng on angiomodulation was paralleled by the experimental data showing angiogenesis was indeed related to the compositional ratio between ginsenosides Rg1 and Rb1. Rg1 was later found to stimulate angiogenesis through augmenting the production of nitric oxide (NO) and vascular endothelial growth factor (VEGF). Mechanistic studies revealed that such responses were mediated through the PI3K→Akt pathway. By means of DNA microarray, a group of genes related to cell adhesion, migration and cytoskeleton were found to be up-regulated in endothelial cells. These gene products may interact in a hierarchical cascade pattern to modulate cell architectural dynamics which is concomitant to the observed phenomena in angiogenesis. By contrast, the anti-tumor and anti-angiogenic effects of ginsenosides (e.g. Rg3 and Rh2) have been demonstrated in various models of tumor and endothelial cells, indicating that ginsenosides with opposing activities are present in ginseng. Ginsenosides and Panax ginseng extracts have been shown to exert protective effects on vascular dysfunctions, such as hypertension, atherosclerotic disorders and ischemic injury. Recent work has demonstrates the target molecules of ginsenosides to be a group of nuclear steroid

Pre-clinical toxicity and immunogenicity evaluation of a MUC1-MBP/BCG anti-tumor vaccine.

PubMed

Hu, Boqi; Wang, Juan; Guo, Yingying; Chen, Tanxiu; Ni, Weihua; Yuan, Hongyan; Zhang, Nannan; Xie, Fei; Tai, Guixiang

2016-04-01

Mucin 1 (MUC1), as an oncogene, plays a key role in the progression and tumorigenesis of many human adenocarcinomas and is an attractive target in tumor immunotherapy. Our previous study showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific Th1-dominant immune response, simulated MUC1-specific cytotoxic T lymphocyte killing activity, and could significantly inhibit MUC1-expression B16 cells' growth in mice. To help move the vaccine into a Phase I clinical trial, in the current study, a pre-clinical toxicity and immunogenicity evaluation of the vaccine was conducted. The evaluation was comprised of a single-dose acute toxicity study in mice, repeat-dose chronic toxicity and immunogenicity studies in rats, and pilot toxicity and immunogenicity studies in cynomolgus monkeys. The results showed that treatment with the MUC1-MBP/BCG anti-tumor vaccine did not cause any organ toxicity, except for arthritis or local nodules induced by BCG in several rats. Furthermore, the vaccine significantly increased the levels of IFN-γ in rats, indicating that Th1 cells were activated. In addition, the results showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific IgG antibody response both in rats and cynomolgus monkeys. Collectively, these data are beneficial to move the MUC1-MBP/BCG anti-tumor vaccine into a Phase I clinical trial. Copyright © 2016 Elsevier B.V. All rights reserved.

COH-203, a novel microtubule inhibitor, exhibits potent anti-tumor activity via p53-dependent senescence in hepatocellular carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qi, Huan; Zuo, Dai-Ying; Bai, Zhao-Shi

Highlights: • COH-203 exhibits anti-hepatoma effects in vitro and in vivo with low toxicity. • COH-203 inhibits tubulin polymerization. • COH-203 induces mitotic arrest followed by mitotic slippage in BEL-7402 cells. • COH-203 induces p53-dependent senescence in BEL-7402 cells. - Abstract: 5-(3-Hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-3H-1, 2-dithiol-3-one (COH-203) is a novel synthesized analogue of combretastatin A-4 that can be classified as a microtubule inhibitor. In this study, we evaluated the anti-hepatoma effect of COH-203 in vitro and in vivo and explored the underlying molecular mechanisms. COH-203 was shown to be more effective in inhibiting the proliferation of liver cancer cells compared with normal livermore » cells. COH-203 also displayed potent anti-tumor activity in a hepatocellular carcinoma xenograft model without significant toxicity. Mechanistic studies demonstrated that treatment with COH-203 induced mitotic arrest by inhibiting tubulin polymerization in BEL-7402 liver cancer cells. Long-term COH-203 treatment in BEL-7402 cells led to mitotic slippage followed by senescence via the p14{sup Arf}–p53–p21 and p16{sup INK4α}–Rb pathways. Furthermore, suppression of p53 via pifithrin-α (p53 inhibitor) and p53-siRNA attenuated COH-203-induced senescence in BEL-7402 cells, suggesting that COH-203 induced senescence p53-dependently. In conclusion, we report for the first time that COH-203, one compound in the combretastatin family, promotes anti-proliferative activity through the induction of p-53 dependent senescence. Our findings will provide a molecular rationale for the development of COH-203 as a promising anti-tumor agent.« less

Water-soluble derivatives of 25-OCH3-PPD and their anti-proliferative activities.

PubMed

Zhou, Wu-Xi; Sun, Yuan-Yuan; Yuan, Wei-Hui; Zhao, Yu-Qing

2017-05-01

(20R)-25-Methoxyl-dammarane-3β,12β,20-triol (25-OCH 3 -PPD, AD-1) is a dammarane-type sapogenin showing anti-tumor potential. In the search for new anti-tumor agents with higher potency than our previously identified compound 25-OCH 3 -PPD, 11 novel sulfamic acid and diacid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 25-OCH 3 -PPD, compounds 1, 4, and 5 exhibited higher cytotoxic activity on almost all cell lines, together with lower toxicity in the normal cell. In particular, compound 1 exhibited the best anti-tumor activity in the in vitro assays. The water solubility of 25-OCH 3 -PPD and its derivatives was tested and the results showed that the solubility of 25-OCH 3 -PPD sulfamic acid and diacid derivatives were better than that of 25-OCH 3 -PPD in water, which may provide valuable data for the research and development of new anti-tumor agents. Copyright © 2017 Elsevier Inc. All rights reserved.

Superior anti-tumor protection and therapeutic efficacy of vaccination with allogeneic and semiallogeneic dendritic cell/tumor cell fusion hybrids for murine colon adenocarcinoma.

PubMed

Yasuda, Takashi; Kamigaki, Takashi; Kawasaki, Kentaro; Nakamura, Tetsu; Yamamoto, Masashi; Kanemitsu, Kiyonori; Takase, Shiro; Kuroda, Daisuke; Kim, Yongsik; Ajiki, Tetsuo; Kuroda, Yoshikazu

2007-07-01

Cancer immunotherapy by dendritic cell (DC)/tumor cell fusion hybrids (DC/TC hybrids) has been shown to elicit potent anti-tumor effects via the induction of immune responses against multiple tumor-associated antigens. In the present study, we compared the anti-tumor effects of vaccinating Balb/c mice (H-2(d)) with CT26CL25 colon carcinoma cells that had been fused with either syngeneic DCs from Balb/c mice, allogeneic DCs from C57BL/6 mice (H-2(b)) or semiallogeneic DCs from B6D2F1 mice (H-2(b/d)). Preimmunization with either semiallogeneic or allogeneic DC/TC hybrids induced complete protection from tumor challenge, whereas mice preimmunized with syngeneic DC/TC hybrids were only partially protected (75% tumor rejection). The average number of pulmonary metastases after intravenous tumor injection decreased significantly following immunization with semiallogeneic or allogeneic DC/TC hybrids (8.3 +/- 7.9 or 16.3 +/- 3.5, mean +/- SD) relative to syngeneic DC/TC hybrids (67.8 +/- 6.3). These data demonstrate that vaccination with semiallogeneic DC/TC hybrids resulted in the greatest anti-tumor efficacy. Anti-tumor effects showed by in vivo studies were virtually accomplished by the frequency of induced CTLs specific to both gp70 and beta-galactosidase assessed by using pentameric assay. Among the fusion vaccines tested, semiallogeneic DC/TC hybrids induced the highest ratio of Th1 cytokine IFN-gamma to Th2 cytokine IL-10. In addition, allogeneic or semiallogeneic DC/TC hybrids elicited a significantly stronger NK activity than syngeneic DC/TC hybrids. These findings suggest that in clinical settings, DCs derived from a healthy donor (which are generally characterized as more semiallogeneic than allogeneic) may be more capable than autologous DCs of inducing promising anti-tumor effects in vaccinations with DC/TC hybrids.

Extracellular vesicles as shuttles of tumor biomarkers and anti-tumor drugs.

PubMed

Zocco, Davide; Ferruzzi, Pietro; Cappello, Francesco; Kuo, Winston Patrick; Fais, Stefano

2014-01-01

Extracellular vesicles (EV) include vesicles released by either normal or tumor cells. EV may exceed the nanometric scale (microvesicles), or to be within the nanoscale, also called exosomes. Thus, it appears that only exosomes and larger vesicles may have the size for potential applications in nanomedicine, in either disease diagnosis or therapy. This is of particular interest for research in cancer, also because the vast majority of existing data on EV are coming from pre-clinical and clinical oncology. We know that the microenvironmental features of cancer may favor cell-to-cell paracrine communication through EV, but EV have been purified, characterized, and quantified from plasma of tumor patients as well, thus suggesting that EV may have a role in promoting and maintaining cancer dissemination and progression. These observations are prompting research efforts to evaluate the use of nanovesicles as tumor biomarkers. Moreover, EVs are emerging as natural delivery systems and in particular, exosomes may represent the ideal natural nanoshuttles for new and old anti-tumor drugs. However, much is yet to be understood about the role of EV in oncology and this article aims to discuss the future of EV in cancer on the basis of current knowledge.

Arctigenin anti-tumor activity in bladder cancer T24 cell line through induction of cell-cycle arrest and apoptosis.

PubMed

Yang, Shucai; Ma, Jing; Xiao, Jianbing; Lv, Xiaohong; Li, Xinlei; Yang, Huike; Liu, Ying; Feng, Sijia; Zhang, Yafang

2012-08-01

Bladder cancer is the most common neoplasm in the urinary system. This study assesses arctigenin anti-tumor activity in human bladder cancer T24 cells in vitro and the underlying molecular events. The flow cytometry analysis was used to detect cell-cycle distribution and apoptosis. Western blotting was used to detect changes in protein expression. The data showed that arctigenin treatment reduced viability of bladder cancer T24 cells in a dose- and time-dependent manner after treatment with arctigenin (10, 20, 40, 80, and 100 μmol/L) for 24 hr and 48 hr. Arctigenin treatment clearly arrested tumor cells in the G1 phase of the cell cycle. Apoptosis was detected by hoechst stain and flow cytometry after Annexin-V-FITC/PI double staining. Early and late apoptotic cells were accounted for 2.32-7.01% and 3.07-7.35%, respectively. At the molecular level, arctigenin treatment decreased cyclin D1 expression, whereas CDK4 and CDK6 expression levels were unaffected. Moreover, arctigenin selectively altered the phosphorylation of members of the MAPK superfamily, decreasing phosphorylation of ERK1/2 and activated phosphorylation of p38 significantly in a dose-dependent manner. These results suggest that arctigenin may inhibit cell viability and induce apoptosis by direct activation of the mitochondrial pathway, and the mitogen-activated protein kinase pathway may play an important role in the anti-tumor effect of arctigenin. The data from the current study demonstrate the usefulness of arctigenin in bladder cancer T24 cells, which should further be evaluated in vivo before translation into clinical trials for the chemoprevention of bladder cancer. Copyright © 2012 Wiley Periodicals, Inc.

Anti-cancer agents counteracting tumor glycolysis

PubMed Central

Granchi, Carlotta

2012-01-01

Can we consider cancer as a “metabolic disease”? Tumors are the result of a metabolic selection, forming tissues composed of heterogeneous cells that generally express an overactive metabolism as a common feature. In fact, cancer cells have to deal with increased needs for both energy and biosynthetic intermediates, in order to support their growth and invasiveness. However, their high proliferation rate often generates regions that are not sufficiently oxygenated. Therefore, their carbohydrate metabolism has to rely mostly on a glycolytic process that is uncoupled from oxidative phosphorylation. This metabolic switch, also known as the “Warburg Effect”, constitutes a fundamental adaptation of the tumor cells to a relatively hostile environment, and supports the evolution of aggressive and metastatic phenotypes. As a result, tumor glycolysis may constitute an attractive target for cancer therapy. This approach has often raised concerns that anti-glycolytic agents may cause serious side effects on normal cells. Actually, the key for a selective action against cancer cells can be found in their hyperbolic addiction to glycolysis, which may be exploited to generate new anti-cancer drugs showing minimal toxicity. In fact, there is growing evidence that supports many glycolytic enzymes and transporters as suitable candidate targets for cancer therapy. Herein we review some of the most relevant anti-glycolytic agents that have been investigated so far for the treatment of cancer. PMID:22684868

Salinomycin possesses anti-tumor activity and inhibits breast cancer stem-like cells via an apoptosis-independent pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

An, Hyunsook; Kim, Ji Young; Lee, Nahyun

Cancer stem cells (CSCs) play important roles in the formation, growth and recurrence of tumors, particularly following therapeutic intervention. Salinomycin has received recent attention for its ability to target breast cancer stem cells (BCSCs), but the mechanisms of action involved are not fully understood. In the present study, we sought to investigate the mechanisms responsible for salinomycin's selective targeting of BCSCs and its anti-tumor activity. Salinomycin suppressed cell viability, concomitant with the downregulation of cyclin D1 and increased p27{sup kip1} nuclear accumulation. Mammosphere formation assays revealed that salinomycin suppresses self-renewal of ALDH1-positive BCSCs and downregulates the transcription factors Nanog, Oct4more » and Sox2. TUNEL analysis of MDA-MB-231-derived xenografts revealed that salinomycin administration elicited a significant reduction in tumor growth with a marked downregulation of ALDH1 and CD44 levels, but seemingly without the induction of apoptosis. Our findings shed further light on the mechanisms responsible for salinomycin's effects on BCSCs. - Highlights: • Salinomycin suppresses mammosphere formation. • Salinomycin reduces ALDH1 activity and downregulates Nanog, Oct4 and Sox2. • Salinomycin targets BCSCs via an apoptosis-independent pathway.« less

α-Tocopherol succinate enhances pterostilbene anti-tumor activity in human breast cancer cells in vivo and in vitro.

PubMed

Tam, Ka-Wai; Ho, Chi-Tang; Tu, Shih-Hsin; Lee, Wen-Jui; Huang, Ching-Shui; Chen, Ching-Shyang; Wu, Chih-Hsiung; Lee, Chia-Hwa; Ho, Yuan-Soon

2018-01-12

Vitamin E (Vit. E) is considered an essential dietary nutrient for humans and animals. An enormous body of evidence indicates the biological and protective effects of Vit. E consumption. Tocopherol-associated protein (TAP) is a major tocopherol-binding protein affecting Vit. E stimulation and downstream signaling transduction. However, how Vit. E utilizes TAP as an anti-cancer mechanism remains unclear. Microarray analysis of signature gene profiles in breast cancer cells treated with α-tocopheryl succinate (α-TOS, a Vit. E isoform) resulted in cell cycle arrest and anti-cancer activity in breast cancer cells. Pterostilbene (PS), a natural dietary antioxidant found in blueberries, in combination with α-TOS synergistically maximized breast cancer cell growth inhibition by disrupting signal transduction, transcription factors and cell cycle proteins. In a xenograft mouse model, PS treatment with Vit. E inhibited breast tumor growth and cell invasion, which were evaluated using our recently developed circulating tumor cell (CTC) detection assay. Because dietary Vit. E and PS supplementation contributed to preventative and therapeutic effects in vitro and in vivo , this combination may benefit breast cancer therapy in the clinic.

In Vitro and In Vivo Anti-tumoral Effects of the Flavonoid Apigenin in Malignant Mesothelioma

PubMed Central

Masuelli, Laura; Benvenuto, Monica; Mattera, Rosanna; Di Stefano, Enrica; Zago, Erika; Taffera, Gloria; Tresoldi, Ilaria; Giganti, Maria Gabriella; Frajese, Giovanni Vanni; Berardi, Ginevra; Modesti, Andrea; Bei, Roberto

2017-01-01

Malignant mesothelioma (MM) is a tumor arising from mesothelium. MM patients’ survival is poor. The polyphenol 4′,5,7,-trihydroxyflavone Apigenin (API) is a “multifunctional drug”. Several studies have demonstrated API anti-tumoral effects. However, little is known on the in vitro and in vivo anti-tumoral effects of API in MM. Thus, we analyzed the in vitro effects of API on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis, and autophagy of human and mouse MM cells. We evaluated the in vivo anti-tumor activities of API in mice transplanted with MM #40a cells forming ascites. API inhibited in vitro MM cells survival, increased reactive oxygen species intracellular production and induced DNA damage. API activated apoptosis but not autophagy. API-induced apoptosis was sustained by the increase of Bax/Bcl-2 ratio, increase of p53 expression, activation of both caspase 9 and caspase 8, cleavage of PARP-1, and increase of the percentage of cells in subG1 phase. API treatment affected the phosphorylation of ERK1/2, JNK and p38 MAPKs in a cell-type specific manner, inhibited AKT phosphorylation, decreased c-Jun expression and phosphorylation, and inhibited NF-κB nuclear translocation. Intraperitoneal administration of API increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of tumor growth. Our findings may have important implications for the design of MM treatment using API. PMID:28674496

Leiodermatolide, a novel marine natural product, has potent cytotoxic and anti-mitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits anti-tumor activity

PubMed Central

Guzmán, Esther A.; Xu, Qunli; Pitts, Tara P.; Mitsuhashi, Kaoru Ogawa; Baker, Cheryl; Linley, Patricia A.; Oestreicher, Judy; Tendyke, Karen; Winder, Priscilla L.; Suh, Edward M.; Wright, Amy E.

2016-01-01

Pancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasis occurs before symptoms manifest. Leiodermatolide, a polyketide macrolide with antimitotic activity isolated from a deep water sponge of the genus Leiodermatium, exhibits potent and selective cytotoxicity towards the pancreatic cancer cell lines AsPC-1, PANC-1, BxPC-3, and MIA PaCa-2, and potent cytotoxicity against skin, breast and colon cancer cell lines. Induction of apoptosis by leiodermatolide was confirmed in the AsPC-1, BxPC-3 and MIA PaCa-2 cells. Leiodermatolide induces cell cycle arrest but has no effects on in vitro polymerization or depolymerization of tubulin alone, while it enhances polymerization of tubulin containing microtubule associated proteins (MAPs). Observations through confocal microscopy show that leiodermatolide, at low concentrations, causes minimal effects on polymerization or depolymerization of the microtubule network in interphase cells, but disruption of spindle formation in mitotic cells. At higher concentrations, depolymerization of the microtubule network is observed. Visualization of the growing microtubule in HeLa cells expressing GFP-tagged plus end binding protein EB-1 showed that leiodermatolide stopped the polymerization of tubulin. These results suggest that leiodermatolide may affect tubulin dynamics without directly interacting with tubulin and hint at a unique mechanism of action. In a mouse model of metastatic pancreatic cancer, leiodermatolide exhibited significant tumor reduction when compared to gemcitabine and controls. The anti-tumor activities of leiodermatolide, as well as the proven utility of anti-mitotic compounds against cancer, make leiodermatolide an interesting compound with potential chemotherapeutic effects that may merit further research. PMID:27376928

The anti-tumor effect of bee honey in Ehrlich ascite tumor model of mice is coincided with stimulation of the immune cells.

PubMed

Attia, W Y; Gabry, M S; El-Shaikh, K A; Othman, G A

2008-01-01

Honey is thought to exhibit a broad spectrum of therapeutic properties including antibacterial, antifungal, cytostatic and anti-inflammatory activity and has been used for the treatment of gastric ulcers, burns, and for storage of skin grafts. The present study investigated the antitumor effect of bee honey against Ehrlich ascites tumor in mice and the possible mode of antitumor action. Peroral administration of mice with honey (10, 100 or 1000 mg/ 100 g BW) every other day for 4 weeks before intraperitoneal inoculation with Ehrlich ascites tumor (EAT, 1 x 10(6) cells) increased the number bone marrow cells as well as peritoneal macrophages, but not peripheral blood leukocytes nor splenocytes. The phagocytic function of macrophages as well as the T- and B-cell functions were also increased. Honey pre-treatment also recovered the total lipids, total proteins, as well as liver and kidney enzyme activities in EAT-bearing mice. In vitro studies on EAT cells demonstrated inhibitory effect of honey on tumor cell proliferation, viability % of tumor cells as well as the size of solid tumor. The present results indicate that the preventive treatment with honey is considerably effective against EAT in mice both in vivo and in vitro. The antitumor activity of honey may occur through the activation of macrophages, T-cells and B-cells.

Development of a Fully Human Anti-PDGFRβ Antibody That Suppresses Growth of Human Tumor Xenografts and Enhances Antitumor Activity of an Anti-VEGFR2 Antibody

PubMed Central

Shen, Juqun; Vil, Marie Danielle; Prewett, Marie; Damoci, Chris; Zhang, Haifan; Li, Huiling; Jimenez, Xenia; Deevi, Dhanvanthri S; Iacolina, Michelle; Kayas, Anthony; Bassi, Rajiv; Persaud, Kris; Rohoza-Asandi, Anna; Balderes, Paul; Loizos, Nick; Ludwig, Dale L; Tonra, James; Witte, Larry; Zhu, Zhenping

2009-01-01

Platelet-derived growth factor receptor β (PDGFRβ) is upregulated in most of solid tumors. It is expressed by pericytes/smooth muscle cells, fibroblast, macrophage, and certain tumor cells. Several PDGF receptor-related antagonists are being developed as potential antitumor agents and have demonstrated promising antitumor activity in both preclinical and clinical settings. Here, we produced a fully human neutralizing antibody, IMC-2C5, directed against PDGFRβ from an antibody phage display library. IMC-2C5 binds to both human and mouse PDGFRβ and blocks PDGF-B from binding to the receptor. IMC-2C5 also blocks ligand-stimulated activation of PDGFRβ and downstream signaling molecules in tumor cells. In animal studies, IMC-2C5 significantly delayed the growth of OVCAR-8 and NCI-H460 human tumor xenografts in nude mice but failed to show antitumor activities in OVCAR-5 and Caki-1 xenografts. Our results indicate that the antitumor efficacy of IMC-2C5 is primarily due to its effects on tumor stroma, rather than on tumor cells directly. Combination of IMC-2C5 and DC101, an anti-mouse vascular endothelial growth factor receptor 2 antibody, resulted in significantly enhanced antitumor activity in BxPC-3, NCI-H460, and HCT-116 xenografts, compared with DC101 alone, and the trend of additive effects to DC101 treatment in several other tumor models. ELISA analysis of NCI-H460 tumor homogenates showed that IMC-2C5 attenuated protein level of vascular endothelial growth factor and basic fibroblast growth factor elevated by DC101 treatment. Finally, IMC-2C5 showed a trend of additive effects when combined with DC101/chemotherapy in MIA-PaCa-2 and NCI-H460 models. Taken together, these results lend great support to the use of PDGFRβ antagonists in combination with other antiangiogenic agents in the treatment of a broad range of human cancers. PMID:19484148

A major component of vitamin E, α-tocopherol inhibits the anti-tumor activity of crizotinib against cells transformed by EML4-ALK.

PubMed

Uchihara, Yuki; Kidokoro, Takayuki; Tago, Kenji; Mashino, Tadahiko; Tamura, Hiroomi; Funakoshi-Tago, Megumi

2018-04-15

Crizotinib is an inhibitor of anaplastic lymphoma kinase (ALK) and is of significant therapeutic benefit to patients with non-small cell lung cancer (NSCLC) harboring the EML4-ALK fusion gene. In the present study, we demonstrated that α-tocopherol, a major component of vitamin E, attenuated the effects of crizotinib independently of its anti-oxidant properties. α-Tocopherol significantly inhibited crizotinib-induced apoptosis in cells transformed by EML4-ALK. It also effectively attenuated the crizotinib-induced inhibition of EML4-ALK and its downstream molecules, STAT3 and ERK, and suppressed the inhibitory effects of crizotinib on EML4-ALK-mediated transformation in the focus formation assay. On the other hand, other members of the vitamin E family, namely, β-tocopherol, γ-tocopherol, δ-tocopherol, and α-tocotrienol, and a water-soluble analog of vitamin E, Trolox had no effects on the anti-tumor activity of crizotinib in cells transformed by EML4-ALK. Collectively, these results revealed the risk of the anti-tumor activity of crizotinib being attenuated when it is administrated in combination with vitamin E supplements containing α-tocopherol as a major component. Copyright © 2018 Elsevier B.V. All rights reserved.

Anti-tumor effects of nitrosylcobalamin against spontaneous tumors in dogs.

PubMed

Bauer, Joseph A; Frye, Gerald; Bahr, Anne; Gieg, Jennifer; Brofman, Peter

2010-10-01

Given the limited options available to treat canine cancers, the use of companion animals for evaluating new drugs may identify better therapies for veterinary and human oncology. The anti-tumor effects of nitrosylcobalamin (NO-Cbl), an apoptosis-inducing, vitamin B12-based carrier of nitric oxide (NO), was evaluated in four dogs with spontaneous cancer. (1) A 13 year-old female spayed Giant Schnauzer with inoperable thyroid carcinoma and hypercalcemia. (2) A 6 year-old male neutered Golden Retriever with a malignant peripheral nerve sheath tumor (MPNST). (3) A ten yr-old neutered male Bichon Frise with apocrine gland anal sac adenocarcinoma (AGACA). (4) A 7 year-old female spayed Labrador mix with spinal meningioma following partial surgical resection. Tumor regression was measured by physical exam and verified using ultrasound (case 1) and MRI (case 2-4). Serum chemistries and hematologic parameters were monitored throughout the studies. (1) The Giant Schnauzer demonstrated a 77% reduction in tumor volume after ten weeks of daily NO-Cbl treatment. (2) The Golden Retriever demonstrated a 53% reduction in tumor volume after 15 months of daily NO-Cbl therapy. (3) The Bichon Frise demonstrated a 43% regression of the primary tumor and a 90% regression of an iliac lymph node measured by MRI after 15 months of treatment. After 61 months, the dog currently has stable disease, normal liver enzymes, CBC analysis, and no evidence of toxicity. (4) The Labrador demonstrated complete regression of the residual tumor after 6 months of treatment. We have shown previously that NO-Cbl is endocytosed by malignant cells, resulting in intra-tumoral NO release. In this study, we have shown that daily long-term use of NO-Cbl induced responses in all dogs without any signs of toxicity. The use of NO-Cbl capitalizes on the tumor-specific properties of the vitamin B12 receptor and represents a promising anti-cancer therapy.

Interleukin-6 Induced "Acute" Phenotypic Microenvironment Promotes Th1 Anti-Tumor Immunity in Cryo-Thermal Therapy Revealed By Shotgun and Parallel Reaction Monitoring Proteomics.

PubMed

Xue, Ting; Liu, Ping; Zhou, Yong; Liu, Kun; Yang, Li; Moritz, Robert L; Yan, Wei; Xu, Lisa X

2016-01-01

Cryo-thermal therapy has been emerged as a promising novel therapeutic strategy for advanced breast cancer, triggering higher incidence of tumor regression and enhanced remission of metastasis than routine treatments. To better understand its anti-tumor mechanism, we utilized a spontaneous metastatic mouse model and quantitative proteomics to compare N-glycoproteome changes in 94 serum samples with and without treatment. We quantified 231 highly confident N-glycosylated proteins using iTRAQ shotgun proteomics. Among them, 53 showed significantly discriminated regulatory patterns over the time course, in which the acute phase response emerged as the most enhanced pathway. The anti-tumor feature of the acute response was further investigated using parallel reaction monitoring target proteomics and flow cytometry on 23 of the 53 significant proteins. We found that cryo-thermal therapy reset the tumor chronic inflammation to an "acute" phenotype, with up-regulation of acute phase proteins including IL-6 as a key regulator. The IL-6 mediated "acute" phenotype transformed IL-4 and Treg-promoting ICOSL expression to Th1-promoting IFN-γ and IL-12 production, augmented complement system activation and CD86(+)MHCII(+) dendritic cells maturation and enhanced the proliferation of Th1 memory cells. In addition, we found an increased production of tumor progression and metastatic inhibitory proteins under such "acute" environment, favoring the anti-metastatic effect. Moreover, cryo-thermal on tumors induced the strongest "acute" response compared to cryo/hyperthermia alone or cryo-thermal on healthy tissues, accompanying by the most pronounced anti-tumor immunological effect. In summary, we demonstrated that cryo-thermal therapy induced, IL-6 mediated "acute" microenvironment shifted the tumor chronic microenvironment from Th2 immunosuppressive and pro-tumorigenic to Th1 immunostimulatory and tumoricidal state. Moreover, the magnitude of "acute" and "danger" signals play a key

Fusion with human lung cancer cells elongates the life span of human umbilical endothelial cells and enhances the anti-tumor immunity.

PubMed

Mu, Xiyan; Fang, Chunju; Zhou, Jing; Xi, Yufeng; Zhang, Li; Wei, Yuquan; Yi, Tao; Wu, Yang; Zhao, Xia

2016-01-01

Human umbilical endothelial cells (HUVECs) have been proved as an effective whole-cell vaccine inhibiting tumor angiogenesis. However, HUVECs divide a very limited number of passages before entering replicative senescence, which limits its application for clinical situation. Here, we fused HUVECs with human pulmonary adenocarcinoma cell line A549s and investigated the anti-tumor immunity of the hybrids against mice Lewis lung cancer. HUVECs were fused with A549s using polyethylene glycol and were sorted by flow cytometry. The fusion cells (HUVEC-A549s) were confirmed by testing the expression of telomerase and VE-cadherin, the senescence-associated β-galactosidase activity, and tube formation ability. HUVEC-A549s were then irradiated and injected into the C57BL/6 mice of protective, therapeutic, and metastatic models. The mechanism of the anti-tumor immunity was explored by analyzing mice sera, spleen T lymphocytes, tumor microenvironment, and histological changes. HUVEC-A549s coexpressed tumor and endothelial markers and maintained the vascular function of tube forming at passage 30 without showing signs of senescence. HUVEC-A549s could induce protective and therapeutic anti-tumor activity for LL(2) model and presented stronger activity against metastasis than HUVECs. Both humoral and cellular immunity were participated in the anti-angiogenic activity, as HUVECs-neutralizing IgG and HUVECs-toxic lymphocytes were increased. Angiogenic mediators (VEGF and TGF-β) and tumor microenvironment cells MDSCs and Tregs were also diminished. Our findings might provide a novel strategy for HUVECs-related immunotherapy, and this vaccine requires lower culture condition than primary HUVECs while enhancing the anti-tumor immunity.

Depletion of regulatory T cells by anti-ICOS antibody enhances anti-tumor immunity of tumor cell vaccine in prostate cancer.

PubMed

Mo, Lijun; Chen, Qianmei; Zhang, Xinji; Shi, Xiaojun; Wei, Lili; Zheng, Dianpeng; Li, Hongwei; Gao, Jimin; Li, Jinlong; Hu, Zhiming

2017-10-13

ICOS + Treg cells exert important immunosuppressive effects in tumor immunity. We adopt a combination approach of ICOS + Treg cells depletion with tumor cell vaccine to evaluate anti-tumor immunity in mouse prostate cancer model. Streptavidin (SA)-mGM-CSF surface-modified RM-1 cells were prepared as the vaccine and the mouse subcutaneous prostate tumor model was used to evaluate the immunity. Tumor growth, flow cytometry, immunohistochemistry, immunofluorescence and enzyme linked immunosorbent assay (ELISA) were performed to evaluate the therapeutic effects. Our results demonstrated that SA-mGM-CSF vaccine was prepared successfully and tumor growth was inhibited. The tumor size in the combination group was much smaller than that in the vaccine with IgG mAb group. The portions of dendritic cells, CD8 + and CD4 + T cells in the mice blood and tumor tissues were increased after treatment with vaccine. There were more immune-suppressing Tregs infiltrated into tumor after treatment with tumor cell vaccine, and ICOS blocking could deplete the infiltrated Tregs, and T lymphocytes increased more dramatically in the combination therapy group. The concentrations of interferon-γ were increased in all vaccine group, the concentrations of Interleukin-10 and Interleukin-4 were much lower in the combination group. Our study demonstrated that ICOS blocking could deplete the tumor-infiltrated ICOS + Treg cells. Combining GM-CSF surface-modified RM-1 cell vaccine with Anti-ICOS antibody could induce better antitumor immunity than a vaccine alone. Copyright © 2017 Elsevier Ltd. All rights reserved.

Influence of Anti-Mouse Interferon Serum on the Growth and Metastasis of Tumor Cells Persistently Infected with Virus and of Human Prostatic Tumors in Athymic Nude Mice

NASA Astrophysics Data System (ADS)

Reid, Lola M.; Minato, Nagahiro; Gresser, Ion; Holland, John; Kadish, Anna; Bloom, Barry R.

1981-02-01

Baby hamster kidney or HeLa cells form tumors in 100% of athymic nude mice. When such cells are persistently infected (PI) with RNA viruses, such as mumps or measles virus, the tumor cells either fail to grow or form circumscribed benign nodules. Neither the parental nor the virus PI tumor cells form invasive or metastatic lesions in nude mice. Previous studies have indicated a correlation between the susceptibility of virus-PI tumor cells in vitro and the cytolytic activity of natural killer (NK) cells and their failure to grow in vivo. Because interferon (IF) is the principal regulatory molecule governing the differentiation of NK cells, it was possible to test the relevance of the IF--NK cell system in vivo to restriction of tumor growth by treatment of nude mice with anti-IF globulin. This treatment was shown to reduce both IF production and NK activity in spleen cells. Both parental and virus-PI tumor cells grew and formed larger tumors in nude mice treated with anti-IF globulin than in control nude mice. The viral-PI tumor cells and the uninfected parental cells formed tumors in treated mice that were highly invasive and often metastatic. Some human tumor types have been notoriously difficult to establish as tumor lines in nude mice (e.g., primary human prostatic carcinomas). When transplanted into nude mice treated either with anti-IF globulin or anti-lymphocyte serum, two prostatic carcinomas grew and produced neoplasms with local invasiveness and some metastases. The results are consistent with the view that interferon may be important in restricting the growth, invasiveness, and metastases of tumor cells by acting indirectly through components of the immune system, such as NK cells.

F14512, a polyamine-vectorized inhibitor of topoisomerase II, exhibits a marked anti-tumor activity in ovarian cancer.

PubMed

Thibault, Benoît; Clement, Emily; Zorza, Grégoire; Meignan, Samuel; Delord, Jean-Pierre; Couderc, Bettina; Bailly, Christian; Narducci, Fabrice; Vandenberghe, Isabelle; Kruczynski, Anna; Guilbaud, Nicolas; Ferré, Pierre; Annereau, Jean-Philippe

2016-01-01

Epithelial ovarian cancer is the fourth cause of death among cancer-bearing women and frequently associated with carboplatin resistance, underlining the need for more efficient and targeted therapies. F14512 is an epipodophylotoxin-core linked to a spermine chain which enters cells via the polyamine transport system (PTS). Here, we investigate this novel concept of vectorization in ovarian cancer. We compared the effects of etoposide and F14512 on a panel of five carboplatin-sensitive or resistant ovarian cancer models. We assessed the incorporation of F17073, a spermine-linked fluorescent probe, in these cells and in 18 clinical samples. We then showed that F14512 exhibits a high anti-proliferative and pro-apoptotic activity, particularly in cells with high levels of F17073 incorporation. Consistently, F14512 significantly inhibited tumor growth compared to etoposide, in a cisplatin-resistant A2780R subcutaneous model, at a dose of 1.25 mg/kg. In addition, ex vivo analysis indicated that 15 out of 18 patients presented a higher F17073 incorporation into tumor cells compared to normal cells. Overall, our data suggest that F14512, a targeted drug with a potent anti-tumor efficacy, constitutes a potential new therapy for highly PTS-positive and platinum-resistant ovarian cancer-bearing patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

YSL-12, a novel microtubule-destabilizing agent, exerts potent anti-tumor activity against colon cancer in vitro and in vivo.

PubMed

Cai, De; Qiu, Zhiqing; Yao, Weimin; Liu, Yuyu; Huang, Haixiang; Liao, Sihai; Luo, Qun; Xie, Liming; Lin, Zhixiu

2016-06-01

Microtubules play a central role in various fundamental cell functions and thus become an attractive target for cancer therapy. A novel compound YSL-12 is a combretastatin A-4 (CA-4) analogue with more stability. We investigated its anti-tumor activity and mechanisms in vitro and in vivo for the first time. Cytotoxicity was evaluated by MTT method. In vitro microtubule polymerization assay was performed using a fluorescence-based method by multifunction fluorescence microplate reader. Intracellular microtubule network was detected by immunofluorescence method. Cell cycle analysis and apoptosis were measured by flow cytometry. Metabolic stability was recorded by liquid chromatography-ultraviolet detection and liquid chromatography-mass spectrometry. In vivo anti-tumor activity was assessed using HT-29 colon carcinoma xenografts established in BALB/c nude mice. YSL-12 displayed nanomolar-level cytotoxicity against various human cancer cell lines. A high selectivity toward normal cells and potent activity toward drug-resistant cells were also observed. YSL-12 was identified as tubulin polymerization inhibitor evidenced by effectively inhibits tubulin polymerization and heavily disrupted microtubule networks in living HT-29 cells. YSL-12 displayed potent disruption effect of pre-established tumor vasculature in vitro. In addition, YSL-12 treatment also caused cell cycle arrest in the G2/M phase and induced cell apoptosis in a dose-dependent manner. In vitro metabolic stability study revealed YSL-12 displayed considerable better stability than CA-4 in liver microsomes. In vivo, YSL-12 delayed tumor growth with 69.4 % growth inhibition. YSL-12 is a promising microtubule inhibitor that has great potential for the treatment of colon carcinoma in vitro and in vivo and worth being a candidate for further development of cancer therapy.

Extracellular Vesicles as Shuttles of Tumor Biomarkers and Anti-Tumor Drugs

PubMed Central

Zocco, Davide; Ferruzzi, Pietro; Cappello, Francesco; Kuo, Winston Patrick; Fais, Stefano

2014-01-01

Extracellular vesicles (EV) include vesicles released by either normal or tumor cells. EV may exceed the nanometric scale (microvesicles), or to be within the nanoscale, also called exosomes. Thus, it appears that only exosomes and larger vesicles may have the size for potential applications in nanomedicine, in either disease diagnosis or therapy. This is of particular interest for research in cancer, also because the vast majority of existing data on EV are coming from pre-clinical and clinical oncology. We know that the microenvironmental features of cancer may favor cell-to-cell paracrine communication through EV, but EV have been purified, characterized, and quantified from plasma of tumor patients as well, thus suggesting that EV may have a role in promoting and maintaining cancer dissemination and progression. These observations are prompting research efforts to evaluate the use of nanovesicles as tumor biomarkers. Moreover, EVs are emerging as natural delivery systems and in particular, exosomes may represent the ideal natural nanoshuttles for new and old anti-tumor drugs. However, much is yet to be understood about the role of EV in oncology and this article aims to discuss the future of EV in cancer on the basis of current knowledge. PMID:25340037

Effects of extraction methods on the yield, chemical structure and anti-tumor activity of polysaccharides from Cordyceps gunnii mycelia.

PubMed

Zhu, Zhen-Yuan; Dong, Fengying; Liu, Xiaocui; Lv, Qian; YingYang; Liu, Fei; Chen, Ling; Wang, Tiantian; Wang, Zheng; Zhang, Yongmin

2016-04-20

This study was to investigate the effects of different extraction methods on the yield, chemical structure and antitumor activity of polysaccharides from Cordyceps gunnii (C. gunnii) mycelia. Five extraction methods were used to extract crude polysaccharides (CPS), which include room-temperature water extraction (RWE), hot-water extraction (HWE), microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE) and cellulase-assisted extraction (CAE). Then Sephadex G-100 was used for purification of CPS. As a result, the antitumor activities of CPS and PPS on S180 cells were evaluated. Five CPS and purified polysaccharides (PPS) were obtained. The yield of CPS by microwave-assisted extraction (CPSMAE) was the highest and its anti-tumor activity was the best and its macromolecular polysaccharide (3000-1000kDa) ratio was the largest. The PPS had the same monosaccharide composition, but their obvious difference was in the antitumor activity and the physicochemical characteristics, such as intrinsic viscosity, specific rotation, scanning electron microscopy and circular dichroism spectra. Copyright © 2015 Elsevier Ltd. All rights reserved.

Safety and activity of PD-1 blockade-activated DC-CIK cells in patients with advanced solid tumors.

PubMed

Chen, Chang-Long; Pan, Qiu-Zhong; Weng, De-Sheng; Xie, Chuan-Miao; Zhao, Jing-Jing; Chen, Min-Shan; Peng, Rui-Qing; Li, Dan-Dan; Wang, Ying; Tang, Yan; Wang, Qi-Jing; Zhang, Zhi-Ling; Zhang, Xiao-Fei; Jiang, Li-Juan; Zhou, Zi-Qi; Zhu, Qian; He, Jia; Liu, Yuan; Zhou, Fang-Jian; Xia, Jian-Chuan

2018-01-01

Cytokine-induced killer (CIK) cells that are stimulated using mature dendritic cells (DCs), referred to as (DC-CIK cells) exhibit superior anti-tumor potency. Anti-programmed death-1 (PD-1) antibodies reinvigorate T cell-mediated antitumor immunity. This phase I study aimed to assess the safety and clinical activity of immunotherapy with PD-1 blockade (pembrolizumab)-activated autologous DC-CIK cells in patients with advanced solid tumors. Patients with selected types of advanced solid tumors received a single intravenous infusion of activated autologous DC-CIK cells weekly for the first month and every 2 weeks thereafter. The primary end points were safety and adverse event (AE) profiles. Antitumor responses, overall survival (OS), progression-free survival (PFS) and cytolytic activity were secondary end points. Treatment-related AEs occurred in 20/31 patients. Grade 3 or 4 toxicities, including fever and chills, were observed in two patients. All treatment-related AEs were reversible or controllable. The cytotoxicity of DC-CIK cells induced up-regulation of PD-L1 expression on autologous tumor cells. When activated using pembrolizumab ex vivo , DC-CIK cells exerted superior antitumor properties and elevated IFN-γ secretion. Objective responses (complete or partial responses) were observed in 7 of the 31patients.These responses were durable, with 6 of 7 responses lasting more than 5 months. The overall disease control rate in the patients was 64.5%. At the time of this report, the median OS and PFS were 270 and 162 days, respectively. In conclusions, treatment with pembrolizumab-activated autologous DC-CIK cells was safe and exerted encouraging antitumor activity in advanced solid tumors. A larger phase II trial is warranted.

Dihydroartemisinin Exerts Anti-Tumor Activity by Inducing Mitochondrion and Endoplasmic Reticulum Apoptosis and Autophagic Cell Death in Human Glioblastoma Cells

PubMed Central

Qu, Chengbin; Ma, Jun; Liu, Xiaobai; Xue, Yixue; Zheng, Jian; Liu, Libo; Liu, Jing; Li, Zhen; Zhang, Lei; Liu, Yunhui

2017-01-01

Glioblastoma (GBM) is the most advanced and aggressive form of gliomas. Dihydroartemisinin (DHA) has been shown to exhibit anti-tumor activity in various cancer cells. However, the effect and molecular mechanisms underlying its anti-tumor activity in human GBM cells remain to be elucidated. Our results proved that DHA treatment significantly reduced cell viability in a dose- and time-dependent manner by CCK-8 assay. Further investigation identified that the cell viability was rescued by pretreatment either with Z-VAD-FMK, 3-methyladenine (3-MA) or in combination. Moreover, DHA induced apoptosis of GBM cells through mitochondrial membrane depolarization, release of cytochrome c and activation of caspases-9. Enhanced expression of GRP78, CHOP and eIF2α and activation of caspase 12 were additionally confirmed that endoplasmic reticulum (ER) stress pathway of apoptosis was involved in the cytotoxicity of DHA. DHA-treated GBM cells exhibited the morphological and biochemical changes typical of autophagy. Co-treatment with chloroquine (CQ) significantly induced the above effects. Furthermore, ER stress and mitochondrial dysfunction were involved in the DHA-induced autophagy. Further study revealed that accumulation of reactive oxygen species (ROS) was attributed to the DHA induction of apoptosis and autophagy. The illustration of these molecular mechanisms will present a novel insight for the treatment of human GBM. PMID:29033794

Anti-inflammatory and antiproliferative activities of trifolirhizin, a flavonoid from Sophora flavescens roots

PubMed Central

Zhou, Huiping; Lutterodt, Herman; Cheng, Zhihong; Yu, Liangli (Lucy)

2009-01-01

Trifolirhizin, a pterocarpan flavonoid, was isolated from the roots of Sophora flavescens, and its chemical structure was confirmed by1H and 13C NMR and MS spectra. Its anti-inflammatory activity was examined in lipopolysaccharide (LPS)-stimulated mouse J774A.1 macrophages. Trifolirhizin not only dose-dependently inhibited LPS-induced expression of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), but also inhibited lipopolysaccharide (LPS)-induced expression of cyclooxygenase-2 (COX-2). In addition, trifolirhizin showed in vitro inhibitory effects on the growth of human A2780 ovarian and H23 lung cancer cells. These results suggest that trifolirhizin possesses potential anti-inflammatory and anti-cancer activities. PMID:19402641

Tannic acid ameliorates doxorubicin-induced cardiotoxicity and potentiates its anti-cancer activity: Potential role of tannins in cancer chemotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tikoo, Kulbhushan, E-mail: tikoo.k@gmail.com; Sane, Mukta Subhash; Gupta, Chanchal

2011-03-15

Doxorubicin, an anthracycline antibiotic, is widely used in the treatment of various solid tumors including breast cancer. However, its use is limited due to a variety of toxicities including cardiotoxicity. The present study aimed to evaluate the effect of tannic acid, a PARG/PARP inhibitor and an antioxidant, on doxorubicin-induced cardiotoxicity in H9c2 embryonic rat heart myoblasts and its anti-cancer activity in MDA-MB-231 human breast cancer cells as well as in DMBA-induced mammary tumor animals. Doxorubicin-induced cardiotoxicity was assessed by measurement of heart weight, plasma LDH level and histopathology. Bcl-2, Bax, PARP-1 and p53 expression were examined by western blotting. Ourmore » results show that tannic acid prevents activation of PARP-1, reduces Bax and increases Bcl-2 expression in H9c2 cells, thus, preventing doxorubicin-induced cell death. Further, it reduces the cell viability of MDA-MB-231 breast cancer cells, increases p53 expression in mammary tumors and shows maximum tumor volume reduction, suggesting that tannic acid potentiates the anti-cancer activity of doxorubicin. To the best of our knowledge, this is the first report which shows that tannic acid ameliorates doxorubicin-induced cardiotoxicity and potentiates its anti-cancer activity both in vitro (H9c2 and MDA-MB-231 cells) as well as in in vivo model of DMBA-induced mammary tumor animals.« less

Ancient Chinese Formula Qiong-Yu-Gao Protects Against Cisplatin-Induced Nephrotoxicity Without Reducing Anti-tumor Activity

PubMed Central

Teng, Zhi-Ying; Cheng, Xiao-Lan; Cai, Xue-Ting; Yang, Yang; Sun, Xiao-Yan; Xu, Jin-Di; Lu, Wu-Guang; Chen, Jiao; Hu, Chun-Ping; Zhou, Qian; Wang, Xiao-Ning; Li, Song-Lin; Cao, Peng

2015-01-01

Cisplatin is a highly effective anti-cancer chemotherapeutic agent; however, its clinical use is severely limited by serious side effects, of which nephrotoxicity is the most important. In this study, we investigated whether Qiong-Yu-Gao (QYG), a popular traditional Chinese medicinal formula described 840 years ago, exhibits protective effects against cisplatin-induced renal toxicity. Using a mouse model of cisplatin-induced renal dysfunction, we observed that pretreatment with QYG attenuated cisplatin-induced elevations in blood urea nitrogen and creatinine levels, ameliorated renal tubular lesions, reduced apoptosis, and accelerated tubular cell regeneration. Cisplatin-mediated elevations in tumor necrosis factor alpha (TNF-α) mRNA, interleukin-1 beta (IL-1β) mRNA, and cyclooxygenase-2 (COX-2) protein in the kidney were also significantly suppressed by QYG treatment. Furthermore, QYG reduced platinum accumulation in the kidney by decreasing the expression of copper transporter 1 and organic cation transporter 2. An in vivo study using implanted Lewis lung cancer cells revealed that concurrent administration of QYG and cisplatin did not alter the anti-tumor activity of cisplatin. Our findings suggest that the traditional Chinese medicinal formula QYG inhibits cisplatin toxicity by several mechanisms that act simultaneously, without compromising its therapeutic efficacy. Therefore, QYG may be useful in the clinic as a protective agent to prevent cisplatin-induced nephrotoxicity. PMID:26510880

Novel anti-angiogenic effects of formononetin in human colon cancer cells and tumor xenograft.

PubMed

Auyeung, Kathy Ka-Wai; Law, Pui-Ching; Ko, Joshua Ka-Shun

2012-12-01

Formononetin is a novel herbal isoflavonoid isolated from Astragalus membranaceus, a medicinal plant that possesses antitumorigenic properties. Our previous findings demonstrated that formononetin initiates growth-inhibitory and pro-apoptotic activities in human colon cancer cells. In the present study, we aimed to further examine the potential of formononetin in controlling angiogenesis and tumor cell invasiveness in human colon cancer cells and tumor xenografts. The results showed that formononetin downregulated the expression of the key pro-angiogenic factors, including vascular endothelial growth factor (VEGF) and matrix metalloproteinases. We also discovered that the invasiveness of metastatic colon cancer cells was alleviated following drug treatment. The potential anti-angiogenic effect of formononetin was examined in nude mouse xenografts. The tumor size and the number of proliferating cells were reduced in the tumor tissues obtained from the formononetin-treated group. The serum VEGF level was also reduced in the drug-treated animals when compared to the controls. These findings suggest that formononetin inhibits angiogenesis and tumor cell invasion, and thus support its use in the treatment of advanced and metastatic colon cancers.

Anti-inflammatory, Anti-estrogenic, and Anti-implantation Activity of Bergia suffruticosa (Delile) Fenzl

PubMed Central

Bind, Sandeep Kumar; Jivrajani, Mehul; Anandjiwala, Sheetal; Nivsarkar, Manish

2015-01-01

�-sitosteroln-Hexane extract showed in vivo anti-inflammatory activity in both acute and chronic model of inflammation in ratsn-Hexane extract possess significant anti-estrogenic activityn-Hexane extract altered the levels superoxide anion radical and superoxide dismutase enzyme activity during the blastocyst implantationAnti-implantation activity of n-hexane extract is attributed to its anti-inflammatory and anti-estrogenic potential. Abbreviations used: TLC: Thin layer chromatography; LPO: Lipid peroxidation; SOD: Superoxide dismutase; B. suffruticosa: Bergia suffruticosa; TNF-α: Tumor necrosis factor-α; NO: Nitric oxide; IL-1: Interleukin-1; LIF: Leukemia inhibitory factor; CSF-1: Colony-stimulating factor; COX: Cyclooxygenase; SDS: Sodium dodecyl sulfate; IAEC: Animal House Ethics Committee; CPCSEA: Committee for the Purpose of Control and Supervision of Experiments on Animals; HBSS: Hank's balanced salt solution; MDA: Malonaldehyde; and TBA: Thiobarbituric acid. PMID:26929574

α-Tocopherol succinate enhances pterostilbene anti-tumor activity in human breast cancer cells in vivo and in vitro

PubMed Central

Tam, Ka-Wai; Ho, Chi-Tang; Tu, Shih-Hsin; Lee, Wen-Jui; Huang, Ching-Shui; Chen, Ching-Shyang; Wu, Chih-Hsiung

2018-01-01

Vitamin E (Vit. E) is considered an essential dietary nutrient for humans and animals. An enormous body of evidence indicates the biological and protective effects of Vit. E consumption. Tocopherol-associated protein (TAP) is a major tocopherol-binding protein affecting Vit. E stimulation and downstream signaling transduction. However, how Vit. E utilizes TAP as an anti-cancer mechanism remains unclear. Microarray analysis of signature gene profiles in breast cancer cells treated with α-tocopheryl succinate (α-TOS, a Vit. E isoform) resulted in cell cycle arrest and anti-cancer activity in breast cancer cells. Pterostilbene (PS), a natural dietary antioxidant found in blueberries, in combination with α-TOS synergistically maximized breast cancer cell growth inhibition by disrupting signal transduction, transcription factors and cell cycle proteins. In a xenograft mouse model, PS treatment with Vit. E inhibited breast tumor growth and cell invasion, which were evaluated using our recently developed circulating tumor cell (CTC) detection assay. Because dietary Vit. E and PS supplementation contributed to preventative and therapeutic effects in vitro and in vivo, this combination may benefit breast cancer therapy in the clinic. PMID:29435127

Anemone rivularis inhibits pyruvate dehydrogenase kinase activity and tumor growth.

PubMed

Chung, Tae-Wook; Lee, Jung Hee; Choi, Hee-Jung; Park, Mi-Ju; Kim, Eun-Yeong; Han, Jung Ho; Jang, Se Bok; Lee, Syng-Ook; Lee, Sang Woo; Hang, Jin; Yi, Li Wan; Ha, Ki-Tae

2017-05-05

Anemone rivularis Buch.-Ham. ex DC. (Ranunculaceae) have been used as a traditional remedy for treatment of inflammation and cancer. However, there is no report demonstrating experimental evidence on anti-tumor action of A. rivularis. The Warburg's effect, preference of aerobic glycolysis rather than oxidative phosphorylation (OXPHOS) even in oxygen rich condition, is focused as one of major characteristics of malignant tumor. Thus, we investigated the effect of A. rivularis on the Pyruvate dehydrogenase (PDH) kinases (PDHKs), a major molecular targets for reducing aerobic glycolysis. The ethanol extract of whole plant of A. rivularis (ARE), fingerprinted by high performance liquid chromatography (HPLC), was applied to in vitro and cell-based PDHK activity assays. The effect of ARE on cell viabilities of several tumor cells was estimated by MTT assay. The expression of phosphor-PDH, PDH and PDHK1 were measured by Western blot analysis. The production of reactive oxygen species (ROS) and apoptosis was measured by fluorescence-activated cell sorting analysis, using 5-(and-6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate (carboxy-H2DCFDA) and Annexin V/propidium iodide (PI) staining, respectively. Mitochondrial membrane potential was examined by tetramethylrhodamine methyl ester (TMRM) staining. In vivo anti-tumor efficacy of ARE was estimated by means of tumor volume and weight using allograft injection of murine Lewis lung carcinoma (LLC) cells to dorsa of C57BL/6 mice. ARE inhibited the viabilities of several cancer cells, including MDA-MB321, K562, HT29, Hep3B, DLD-1, and LLC. ARE suppressed PDHK activity in in vitro kinase assay, and also inhibited aerobic glycolysis by reducing phosphorylation of PDHA in human DLD-1 colon cancer and murine LLC cells. The expression of PDHK1, a major isoform of PDHKs in cancer, was not affected by ARE treatment. Moreover, ARE increased the both ROS production and mitochondrial damage. In addition, ARE suppressed the in vitro

Synergistic anti-tumor therapy by a comb-like multifunctional antibody nanoarray with exceptionally potent activity

NASA Astrophysics Data System (ADS)

Li, Huafei; Sun, Yun; Chen, Di; Zhao, He; Zhao, Mengxin; Zhu, Xiandi; Ke, Changhong; Zhang, Ge; Jiang, Cheng; Zhang, Li; Zhang, Fulei; Wei, Huafeng; Li, Wei

2015-10-01

Simultaneously blocking multiple mediators offers new hope for the treatment of complex diseases. However, the curative potential of current combination therapy by chronological administration of separate monoclonal antibodies (mAbs) or multi-specific mAbs is still moderate due to inconvenient manipulation, low cooperative effectors, poor pharmacokinetics and insufficient tumor accumulation. Here, we describe a facile strategy that arms distinct mAbs with cooperative effectors onto a long chain to form a multicomponent comb-like nano mAb. Unlike dissociative parental mAbs, the multifunctional mAb nanoarray (PL-RB) constructed from type I/II anti-CD20 mAbs shows good pharmacokinetics. This PL-RB simultaneously targets distinct epitopes on a single antigen (Ag) and neighboring Ags on different lymphocytes. This unique intra- and intercellular Ag cross-linking endows the multifunctional mAb nanoarray with potent apoptosis activity. The exceptional apoptosis, complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) that are synchronously evoked by the nano PL-RB are further synergistically promoted via enhanced permeability and retention (EPR), which resulted in high intratumor accumulation and excellent anti-lymphoma efficiency.

Synergistic anti-tumor therapy by a comb-like multifunctional antibody nanoarray with exceptionally potent activity.

PubMed

Li, Huafei; Sun, Yun; Chen, Di; Zhao, He; Zhao, Mengxin; Zhu, Xiandi; Ke, Changhong; Zhang, Ge; Jiang, Cheng; Zhang, Li; Zhang, Fulei; Wei, Huafeng; Li, Wei

2015-10-28

Simultaneously blocking multiple mediators offers new hope for the treatment of complex diseases. However, the curative potential of current combination therapy by chronological administration of separate monoclonal antibodies (mAbs) or multi-specific mAbs is still moderate due to inconvenient manipulation, low cooperative effectors, poor pharmacokinetics and insufficient tumor accumulation. Here, we describe a facile strategy that arms distinct mAbs with cooperative effectors onto a long chain to form a multicomponent comb-like nano mAb. Unlike dissociative parental mAbs, the multifunctional mAb nanoarray (PL-RB) constructed from type I/II anti-CD20 mAbs shows good pharmacokinetics. This PL-RB simultaneously targets distinct epitopes on a single antigen (Ag) and neighboring Ags on different lymphocytes. This unique intra- and intercellular Ag cross-linking endows the multifunctional mAb nanoarray with potent apoptosis activity. The exceptional apoptosis, complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) that are synchronously evoked by the nano PL-RB are further synergistically promoted via enhanced permeability and retention (EPR), which resulted in high intratumor accumulation and excellent anti-lymphoma efficiency.

Anti-tumor effect of evodiamine by inducing Akt-mediated apoptosis in hepatocellular carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Fan; Shi, Le; Liang, Tao

Background: Evodiamine is an alkaloid extracted from Euodia rutaecarpa (Juss.) Benth. There is little information about the mechanisms of evodiamine on the apoptosis of hepatocellular carcinoma (HCC). Materials and methods: A xenograft model and CCK8 assay were used to investigate the anti-HCC effect of evodiamine. The effect of evodiamine on apoptosis was evaluated by DAPI staining and flow cytometry. Western blot analyses and immunohistochemistry were processed to assess the protein expressions of Akt and apoptotic proteins. Results: Evodiamine suppressed tumor growth, improved the expression of cleaved-caspase3 and decreased tumor specific growth factor (TSGF) and alpha fetoprotein (AFP) activities. Furthermore, evodiaminemore » inhibited cell viability and induced cell cycle arrest. DAPI staining revealed nuclear condensation in evodiamine-treated groups. Meanwhile, evodiamine increased the number of apoptotic cells. Furthermore, evodiamine suppressed Akt and regulated apoptotic proteins in HepG2 cells. Evodiamine decreased p-Akt levels activated by SC79, which led to the increase of bax/bcl-2 and cleaved-caspase3. Conclusions: Our findings suggested that evodiamine could exert anti-HCC effect through inducing Akt-mediated apoptosis. Evodiamine has the potential to be a therapeutic medicine for HCCs. - Highlights: • Anti-tumor effect of evodiamine in hepatocellular carcinoma. • Evodiamine induces apoptosis in hepatocellular carcinoma. • The correlation between induction of apoptosis and Akt expression.« less

Combination of lentivector immunization and low-dose chemotherapy or PD-1/PD-L1 blocking primes self-reactive T cells and induces anti-tumor immunity.

PubMed

Sierro, Sophie R; Donda, Alena; Perret, Rachel; Guillaume, Philippe; Yagita, Hideo; Levy, Frédéric; Romero, Pedro

2011-08-01

In the last two decades, anti-cancer vaccines have yielded disappointing clinical results despite the fact that high numbers of self/tumor-specific T cells can be elicited in immunized patients. Understanding the reasons behind this lack of efficacy is critical in order to design better treatment regimes. Recombinant lentivectors (rLVs) have been successfully used to induce antigen-specific T cells to foreign or mutated tumor antigens. Here, we show that rLV expressing a murine nonmutated self/tumor antigen efficiently primes large numbers of self/tumor-specific CD8(+) T cells. In spite of the large number of tumor-specific T cells, however, no anti-tumor activity could be measured in a therapeutic setting, in mice vaccinated with rLV. Accumulating evidence shows that, in the presence of malignancies, inhibition of T-cell activity may predominate overstimulation. Analysis of tumor-infiltrating lymphocytes revealed that specific anti-tumor CD8(+) T cells fail to produce cytokines and express high levels of inhibitory receptors such as programmed death (PD)-1. Association of active immunization with chemotherapy or antibodies that block inhibitory pathways often leads to better anti-tumor effects. We show here that combining rLV vaccination with either cyclophosphamide or PD-1 and PD-L1 blocking antibodies enhances rLV vaccination efficacy and improves anti-tumor immunity. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biodegradable polymeric micelle-encapsulated doxorubicin suppresses tumor metastasis by killing circulating tumor cells

NASA Astrophysics Data System (ADS)

Deng, Senyi; Wu, Qinjie; Zhao, Yuwei; Zheng, Xin; Wu, Ni; Pang, Jing; Li, Xuejing; Bi, Cheng; Liu, Xinyu; Yang, Li; Liu, Lei; Su, Weijun; Wei, Yuquan; Gong, Changyang

2015-03-01

Circulating tumor cells (CTCs) play a crucial role in tumor metastasis, but it is rare for any chemotherapy regimen to focus on killing CTCs. Herein, we describe doxorubicin (Dox) micelles that showed anti-metastatic activity by killing CTCs. Dox micelles with a small particle size and high encapsulation efficiency were obtained using a pH-induced self-assembly method. Compared with free Dox, Dox micelles exhibited improved cytotoxicity, apoptosis induction, and cellular uptake. In addition, Dox micelles showed a sustained release behavior in vitro, and in a transgenic zebrafish model, Dox micelles exhibited a longer circulation time and lower extravasation from blood vessels into surrounding tissues. Anti-tumor and anti-metastatic activities of Dox micelles were investigated in transgenic zebrafish and mouse models. In transgenic zebrafish, Dox micelles inhibited tumor growth and prolonged the survival of tumor-bearing zebrafish. Furthermore, Dox micelles suppressed tumor metastasis by killing CTCs. In addition, improved anti-tumor and anti-metastatic activities were also confirmed in mouse tumor models, where immunofluorescent staining of tumors indicated that Dox micelles induced more apoptosis and showed fewer proliferation-positive cells. There were decreased side effects in transgenic zebrafish and mice after administration of Dox micelles. In conclusion, Dox micelles showed stronger anti-tumor and anti-metastatic activities and decreased side effects both in vitro and in vivo, which may have potential applications in cancer therapy.

Evaluating Dual Activity LPA Receptor Pan-Antagonist/Autotaxin Inhibitors as Anti-Cancer Agents in vivo using Engineered Human Tumors

PubMed Central

Xu, Xiaoyu; Yang, Guanghui; Zhang, Honglu; Prestwich, Glenn D.

2009-01-01

Using an in situ crosslinkable hydrogel that mimics the extracellular matrix (ECM), cancer cells were encapsulated and injected in vivo following a “tumor engineering” strategy for orthotopic xenografts. Specifically, we created several three-dimensional (3-D) human tumor xenografts and evaluated the tumor response to BrP-LPA, a novel dual function LPA antagonist/ATX inhibitor (LPAa/ATXi). First, we describe the model system and the optimization of semi-synthetic ECM (sECM) compositions and injection parameters for engineered xenografts. Second, we summarize a study to compare angiogenesis inhibition in vivo, comparing BrP-LPA to the kinase inhibitor sunitinib maleate (Sutent). Third, we compare treatment of engineered breast tumors with LPAa/ATXi alone with treatment with Taxol. Fourth, using a re-optimized sECM for non-small cell lung cancer cells, we created reproducibly sized subcutaneous lung tumors and evaluated their response to treatment with LPAa/ATXi. Fifth, we summarize the data on the use of LPAa/ATXi to treat a model for colon cancer metastasis to the liver. Taken together, these improved, more realistic xenografts show considerable utility for evaluating the potential of novel anti-metastatic, anti-proliferative, and anti-angiogenic compounds that modify signal transduction through the LPA signaling pathway. PMID:19682598

Differential anti-tumor activity of coriolus versicolor (Yunzhi) extract through p53- and/or Bcl-2-dependent apoptotic pathway in human breast cancer cells.

PubMed

Ho, Cheong-Yip; Kim, Chi-Fai; Leung, Kwok-Nam; Fung, Kwok-Pui; Tse, Tak-Fu; Chan, Helen; Lau, Clara Bik-San

2005-06-01

Coriolus versicolor (CV), also called Yunzhi, has been demonstrated to exert anti-tumor effects on various types of cancer cells, but the underlying mechanism has not been fully elucidated. The present study aimed to evaluate the in vitro anti-tumor activity of a standardized aqueous ethanol extract prepared from CV on four breast cancer cell lines using MTT assay, and test whether the mechanism involves apoptosis induction and modulation of p53 and Bcl-2 protein expressions using cell death detection ELISA, p53 and Bcl-2 ELISAs respectively. Our results demonstrated that the CV extract dose-dependently suppressed the proliferation of three breast tumor cell lines, with ascending order of IC50 values: T-47D, MCF-7, MDA-MB-231, while BT-20 cells were not significantly affected. Tumoricidal activity of the CV extract was found to be comparable to a chemotherapeutic anti-cancer drug, mitomycin C. Nucleosome productions in apoptotic MDA-MB-231, MCF-7 and T-47D cells were significantly augmented in a time-dependent manner and paralleled the anti-proliferative activity of CV extract. Expression of p53 protein was significantly upregulated only in T-47D cells treated with the CV extract in a dose- and time-dependent fashion, but not in MCF-7 (except at 400 mug/ml after 16 h) and MDA-MB-231 cells. The CV extract significantly induced a dose-dependent downregulation of Bcl-2 protein expression in MCF-7 and T-47D cells, but not in MDA-MB-231 cells. These results suggested that apoptosis induction, differentially dependent of p53 and Bcl-2 expressions, might be the possible mechanism of CV extract-mediated cytotoxicity in human breast cancer cells in vitro.

Anti-Tumor Immunity in Head and Neck Cancer: Understanding the Evidence, How Tumors Escape and Immunotherapeutic Approaches

PubMed Central

Allen, Clint T.; Clavijo, Paul E.; Van Waes, Carter; Chen, Zhong

2015-01-01

Many carcinogen- and human papilloma virus (HPV)-associated head and neck cancers (HNSCC) display a hematopoietic cell infiltrate indicative of a T-cell inflamed phenotype and an underlying anti-tumor immune response. However, by definition, these tumors have escaped immune elimination and formed a clinically significant malignancy. A number of both genetic and environmental mechanisms may allow such immune escape, including selection of poorly antigenic cancer cell subsets, tumor produced proinflammatory and immunosuppressive cytokines, recruitment of immunosuppressive immune cell subsets into the tumor and expression of checkpoint pathway components that limit T-cell responses. Here, we explore concepts of antigenicity and immunogenicity in solid tumors, summarize the scientific and clinical data that supports the use of immunotherapeutic approaches in patients with head and neck cancer, and discuss immune-based treatment approaches currently in clinical trials. PMID:26690220

Armed oncolytic adenovirus expressing PD-L1 mini-body enhances anti-tumor effects of chimeric antigen receptor T-cells in solid tumors

PubMed Central

Tanoue, Kiyonori; Shaw, Amanda Rosewell; Watanabe, Norihiro; Porter, Caroline; Rana, Bhakti; Gottschalk, Stephen; Brenner, Malcolm; Suzuki, Masataka

2017-01-01

Chimeric antigen receptor-modified T cells (CAR T-cells) produce pro-inflammatory cytokines that increase expression of T cell checkpoint signals such as PD-L1, which may inhibit their functionality against solid tumors. In this study, we evaluated in human tumor xenograft models the pro-inflammatory properties of an oncolytic adenovirus (Onc.Ad) with a helper-dependent Ad (HDAd) that expresses a PD-L1 blocking mini-antibody (mini-body) (HDPDL1), as a strategy to enhance CAR T-cell killing. Co-administration of these agents (CAd-VECPDL1) exhibited oncolytic effects with production of PD-L1 mini-body locally at the tumor site. On their own, HDPDL1 exhibited no anti-tumor effect and CAd-VECPDL1 alone reduced tumors only to volumes comparable to Onc.Ad treatment. However, combining CAd-VECPDL1 with HER2.CAR T-cells enhanced anti-tumor activity compared to treatment with either HER2.CAR T-cells alone, or HER2.CAR T-cells plus Onc.Ad. The benefits of locally produced PD-L1 mini-body by CAd-VECPDL1 could not be replicated by infusion of anti-PD-L1 IgG plus HER2.CAR T-cells and co-administration of Onc.Ad in a HER2+ prostate cancer xenograft model. Overall, our data document the superiority of local production of PD-L1 mini-body by CAd-VECPDL1 combined with administration of tumor-directed CAR T-cells to control the growth of solid tumors. PMID:28235763

A novel anti-EGFR monoclonal antibody inhibiting tumor cell growth by recognizing different epitopes from cetuximab.

PubMed

Hong, Kwang-Won; Kim, Chang-Goo; Lee, Seung-Hyun; Chang, Ki-Hwan; Shin, Yong Won; Ryoo, Kyung-Hwan; Kim, Se-Ho; Kim, Yong-Sung

2010-01-01

The epidermal growth factor receptor (EGFR) overexpressed in many epithelial tumors is an attractive target for tumor therapy since numerous blocking agents of EGFR signaling have proven their anti-tumor activity. Here we report a novel monoclonal antibody (mAb), A13, which was generated from mice immunized with human cervical carcinoma A431 cells. In addition to binding to soluble EGFR with affinity of K(D) approximately 5.8nM, mAb A13 specifically bound to a variety of tumor cells and human placenta tissues expressing EGFR. A13 efficiently inhibited both EGF-dependant EGFR tyrosine phosphorylation in cervical and breast tumor cells and also in vitro colony formation of EGFR-overexpressing lung tumors. Competition and sandwich ELISAs, competitive surface plasmon resonance, and domain-level epitope mapping analyses demonstrated that mAb A13 competitively bound to the domain III (amino acids 302-503) of EGFR with EGF, but recognized distinct epitopes from those of cetuximab (Erbitux). Our results demonstrated that anti-EGFR mAb A13 interfered with EGFR proliferation signaling by blocking EGF binding to EGFR with different epitopes from those of cetuximab, suggesting that combination therapies of mAb A13 with cetuximab may prove beneficial for anti-tumor therapy.

Enhanced anti-tumor activity and cytotoxic effect on cancer stem cell population of metformin-butyrate compared with metformin HCl in breast cancer.

PubMed

Lee, Kyung-Min; Lee, Minju; Lee, Jiwoo; Kim, Sung Wuk; Moon, Hyeong-Gon; Noh, Dong-Young; Han, Wonshik

2016-06-21

Metformin, which is a drug commonly used to treat type 2 diabetes, has shown anti-tumor effects in numerous experimental, epidemiologic, observational, and clinical studies. Here, we report a new metformin derivative, metformin-butyrate (MFB). Compared to metformin-HCl, it more potently activates AMPK, inhibits mTOR, and impairs cell cycle progression at S and G2/M phases. Moreover, MFB inhibits the mammosphere formation of breast cancer cells and shows cytotoxic effects against CD44+CD24-/low populations in vitro and in vivo, indicating that it might have preferential effects on the cancer stem cell population. MFB showed synergistic cytotoxicity with docetaxel and cisplatin, and MFB pretreatment of breast cancer cells prior to their injection into the mammary fat pads of mice significantly decreased the obtained xenograft tumor volumes, compared with untreated or metformin-pretreated cells. Overall, MFB showed greater anti-neoplastic activity and greater efficacies in targeting the G2/M phase and breast cancer stem cell population, compared to metformin-HCl. This suggests that MFB may be a promising therapeutic agent against aggressive and resistant breast cancers.

Bovine lactoferrin binds oleic acid to form an anti-tumor complex similar to HAMLET.

PubMed

Fang, Bing; Zhang, Ming; Tian, Mai; Jiang, Lu; Guo, Hui Yuan; Ren, Fa Zheng

2014-04-04

α-Lactalbumin (α-LA) can bind oleic acid (OA) to form HAMLET-like complexes, which exhibited highly selective anti-tumor activity in vitro and in vivo. Considering the structural similarity to α-LA, we conjectured that lactoferrin (LF) could also bind OA to obtain a complex with anti-tumor activity. In this study, LF-OA was prepared and its activity and structural changes were compared with α-LA-OA. The anti-tumor activity was evaluated by methylene blue assay, while the apoptosis mechanism was analyzed using flow cytometry and Western blot. Structural changes of LF-OA were measured by fluorescence spectroscopy and circular dichroism. The interactions of OA with LF and α-LA were evaluated by isothermal titration calorimetry (ITC). LF-OA was obtained by heat-treatment at pH8.0 with LD50 of 4.88, 4.95 and 4.62μM for HepG2, HT29, and MCF-7 cells, respectively, all of which were 10 times higher than those of α-LA-OA. Similar to HAMLET, LF-OA induced apoptosis in tumor cells through both death receptor- and mitochondrial-mediated pathways. Exposure of tryptophan residues and the hydrophobic regions as well as the loss of tertiary structure were observed in LF-OA. Besides these similarities, LF showed different secondary structure changes when compared with α-LA, with a decrease of α-helix and β-turn and an increase of β-sheet and random coil. ITC results showed that there was a higher binding number of OA to LF than to α-LA, while both of the proteins interacted with OA through van der Waals forces and hydrogen bonds. This study provides a theoretical basis for further exploration of protein-OA complexes. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

The anti-tumor effect and mechanisms of action of penta-acetyl geniposide.

PubMed

Peng, C H; Huang, C N; Wang, C J

2005-06-01

Gardenia, the fruit of Gardenia jasminoides Ellis, has been widely used to treat liver and gall bladder disorders in Chinese medicine. It has been shown recently that geniposide, the main ingredient of Gardenia Fructus, exhibits the anti-tumor effect. In this review, we discuss the anti-tumor effect and possible mechanisms of a derivative from Gardenia Fructus, penta-acetyl geniposide ((Ac)5GP). It has been demonstrated that (Ac)5GP plays more potent roles than geniposide in chemoprevention. (Ac)5GP decreased DNA damage and hepatocarcinogenesis induced by aflatoxin B1 (AFB1) by activating the phase II enzymes glutathione S-transferase (GST) and GSH peroxidase (GSH-Px). It reduced the growth and development of inoculated C6 glioma cells especially in pre-treated rats. In addition to the preventive effect, (Ac)5GP exerts its actions on apoptosis and growth arrest. Treatment of (Ac)5GP caused DNA fragmentation of glioma cells. (Ac)5GP induced sub- G1 peak through the activation of apoptotic cascades PKCdelta/JNK/Fas/caspase8 and caspase 3. Besides, p53/Bax signaling was suggested to be involved in (Ac)5GP-induced apoptosis, though its downstream cascades needs further clarified. (Ac)5GP has also been shown to inhibit DNA synthesis of tumor cells. It arrested cell cycle at G0/ G1 by inducing the expression of p21, thus suppressing the cyclin D1/cdk4 complex formation and the phosphorylation of E2F. The phosphorylation status of p53 on serine 392 correlated with the process of growth arrest. Evidences from the in vivo experiments showed that (Ac)5GP is not harmful to liver, heart and kidney. In conclusion, (Ac)5GP is highly suggested to be an anti-tumor agent for development in the future.

The humanized anti-human AMHRII mAb 3C23K exerts an anti-tumor activity against human ovarian cancer through tumor-associated macrophages.

PubMed

Bougherara, Houcine; Némati, Fariba; Nicolas, André; Massonnet, Gérald; Pugnière, Martine; Ngô, Charlotte; Le Frère-Belda, Marie-Aude; Leary, Alexandra; Alexandre, Jérôme; Meseure, Didier; Barret, Jean-Marc; Navarro-Teulon, Isabelle; Pèlegrin, André; Roman-Roman, Sergio; Prost, Jean-François; Donnadieu, Emmanuel; Decaudin, Didier

2017-11-21

Müllerian inhibiting substance, also called anti-Müllerian hormone (AMH), inhibits proliferation and induces apoptosis of AMH type II receptor-positive tumor cells, such as human ovarian cancers (OCs). On this basis, a humanized glyco-engineered monoclonal antibody (3C23K) has been developed. The aim of this study was therefore to experimentally confirm the therapeutic potential of 3C23K in human OCs. We first determined by immunofluorescence, immunohistochemistry and cytofluorometry analyses the expression of AMHRII in patient's tumors and found that a majority (60 to 80% depending on the detection technique) of OCs were positive for this marker. We then provided evidence that the tumor stroma of OC is enriched in tumor-associated macrophages and that these cells are responsible for 3C23K-induced killing of tumor cells through ADCP and ADCC mechanisms. In addition, we showed that 3C23K reduced macrophages induced-T cells immunosuppression. Finally, we evaluated the therapeutic efficacy of 3C23K alone and in combination with a carboplatin-paclitaxel chemotherapy in a panel of OC Patient-Derived Xenografts. In those experiments, we showed that 3C23K significantly increased the proportion and the quality of chemotherapy-based in vivo responses. Altogether, our data support the potential interest of AMHRII targeting in human ovarian cancers and the evaluation of 3C23K in further clinical trials.

The humanized anti-human AMHRII mAb 3C23K exerts an anti-tumor activity against human ovarian cancer through tumor-associated macrophages

PubMed Central

Bougherara, Houcine; Némati, Fariba; Nicolas, André; Massonnet, Gérald; Pugnière, Martine; Ngô, Charlotte; Le Frère-Belda, Marie-Aude; Leary, Alexandra; Alexandre, Jérôme; Meseure, Didier; Barret, Jean-Marc; Navarro-Teulon, Isabelle; Pèlegrin, André; Roman-Roman, Sergio; Prost, Jean-François; Donnadieu, Emmanuel; Decaudin, Didier

2017-01-01

Müllerian inhibiting substance, also called anti-Müllerian hormone (AMH), inhibits proliferation and induces apoptosis of AMH type II receptor-positive tumor cells, such as human ovarian cancers (OCs). On this basis, a humanized glyco-engineered monoclonal antibody (3C23K) has been developed. The aim of this study was therefore to experimentally confirm the therapeutic potential of 3C23K in human OCs. We first determined by immunofluorescence, immunohistochemistry and cytofluorometry analyses the expression of AMHRII in patient’s tumors and found that a majority (60 to 80% depending on the detection technique) of OCs were positive for this marker. We then provided evidence that the tumor stroma of OC is enriched in tumor-associated macrophages and that these cells are responsible for 3C23K-induced killing of tumor cells through ADCP and ADCC mechanisms. In addition, we showed that 3C23K reduced macrophages induced-T cells immunosuppression. Finally, we evaluated the therapeutic efficacy of 3C23K alone and in combination with a carboplatin-paclitaxel chemotherapy in a panel of OC Patient-Derived Xenografts. In those experiments, we showed that 3C23K significantly increased the proportion and the quality of chemotherapy-based in vivo responses. Altogether, our data support the potential interest of AMHRII targeting in human ovarian cancers and the evaluation of 3C23K in further clinical trials. PMID:29245952

Anti-m antibody in solid tumors-two case reports.

PubMed

Soni, Shiv Kumar; Goyal, Hari; Sood, S K; Setia, Rasika

2014-09-01

Anti-M antibodies are usually of IgM, appear as cold agglutinins and are clinically insignificant. We are reporting two cases of anti-M in cases of solid tumors where the anti-M caused discrepancy in blood grouping, reacted in coombs phase of crossmatching. Anti-M in first case showed dosage effect. These antibodies can be clinical significant when detected in coombs phase, making M antigen negative coombs compatible unit transfusion imperative.

Advances in the study of berberine and its derivatives: a focus on anti-inflammatory and anti-tumor effects in the digestive system.

PubMed

Zou, Kun; Li, Zhao; Zhang, Yong; Zhang, Hao-Yue; Li, Bo; Zhu, Wei-Liang; Shi, Ji-Ye; Jia, Qi; Li, Yi-Ming

2017-02-01

It has been widely recognized that inflammation, particularly chronic inflammation, can increase the risk of cancer and that the simultaneous treatment of inflammation and cancer may produce excellent therapeutic effects. Berberine, an alkaloid isolated from Rhizoma coptidis, has broad applications, particularly as an antibacterial agent in the clinic with a long history. Over the past decade, many reports have demonstrated that this natural product and its derivatives have high activity against both cancer and inflammation. In this review, we summarize the advances in studing berberine and its derivatives as anti-inflammatory and anti-tumor agents in the digestive system; we also discuss their structure-activity relationship. These data should be useful for the development of this natural product as novel anticancer drugs with anti-inflammation activity.

2-methoxyestradiol-mediated anti-tumor effect increases osteoprotegerin expression in osteosarcoma cells.

PubMed

Benedikt, Michaela B; Mahlum, Eric W; Shogren, Kristen L; Subramaniam, Malayannan; Spelsberg, Thomas C; Yaszemski, Michael J; Maran, Avudaiappan

2010-04-01

Osteosarcoma is a bone tumor that frequently develops during adolescence. 2-Methoxyestradiol (2-ME), a naturally occurring metabolite of 17beta-estradiol, induces cell cycle arrest and cell death in human osteosarcoma cells. To investigate whether the osteoprotegrin (OPG) protein plays a role in 2-ME actions, we studied the effect of 2-ME treatment on OPG gene expression in human osteosarcoma cells. 2-ME treatment induced OPG gene promoter activity and mRNA levels. Also, Western blot analysis showed that 2-ME treatment increased OPG protein levels in MG63, KHOS, 143B and LM7 osteosarcoma cells by 3-, 1.9-, 2.8-, and 2.5-fold, respectively, but did not affect OPG expression in normal bone cells. In addition, increases in OPG protein levels were observed in osteosarcoma cell culture media after 3 days of 2-ME treatment. The effect of 2-ME on osteosarcoma cells was ligand-specific as parent estrogen, 17beta-estradiol and a tumorigenic estrogen metabolite, 16alpha-hydroxyestradiol, which do not affect osteosarcoma cell cycle and cell death, had no effect on OPG protein expression. Furthermore, co-treating osteosarcoma cells with OPG protein did not further enhance 2-ME-mediated anti-tumor effects. OPG-released in 2-ME-treated cultures led to an increase in osteoblastic activity and a decrease in osteoclast number, respectively. These findings suggest that OPG is not directly involved in 2-ME-mediated anti-proliferative effects in osteosarcoma cells, but rather participates in anti-resorptive functions of 2-ME in bone tumor environment. Copyright 2010 Wiley-Liss, Inc.

Discovery of NKT cells and development of NKT cell-targeted anti-tumor immunotherapy

PubMed Central

TANIGUCHI, Masaru; HARADA, Michishige; DASHTSOODOL, Nyambayar; KOJO, Satoshi

2015-01-01

Natural Killer T (NKT) cells are unique lymphocytes characterized by their expression of a single invariant antigen receptor encoded by Vα14Jα18 in mice and Vα24Jα18 in humans, which recognizes glycolipid antigens in association with the monomorphic CD1d molecule. NKT cells mediate adjuvant activity to activate both CD8T cells to kill MHC-positive tumor cells and NK cells to eliminate MHC-negative tumor at the same time in patients, resulting in the complete eradication of tumors without relapse. Therefore, the NKT cell-targeted therapy can be applied to any type of tumor and also to anyone individual, regardless of HLA type. Phase IIa clinical trials on advanced lung cancers and head and neck tumors have been completed and showed significantly prolonged median survival times with only the primary treatment. Another potential treatment option for the future is to use induced pluripotent stem cell (iPS)-derived NKT cells, which induced adjuvant effects on anti-tumor responses, inhibiting in vivo tumor growth in a mouse model. PMID:26194854

Anti-tumor-promoting activity of a polyphenolic fraction isolated from grape seeds in the mouse skin two-stage initiation-promotion protocol and identification of procyanidin B5-3'-gallate as the most effective antioxidant constituent.

PubMed

Zhao, J; Wang, J; Chen, Y; Agarwal, R

1999-09-01

Procyanidins present in grape seeds are known to exert anti-inflammatory, anti-arthritic and anti-allergic activities, prevent skin aging, scavenge oxygen free radicals and inhibit UV radiation-induced peroxidation activity. Since most of these events are associated with the tumor promotion stage of carcinogenesis, these studies suggest that grape seed polyphenols and the procyanidins present therein could be anticarcinogenic and/or anti-tumor-promoting agents. Therefore, we assessed the anti-tumor-promoting effect of a polyphenolic fraction isolated from grape seeds (GSP) employing the 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol 13-acetate (TPA)-promoted SENCAR mouse skin two-stage carcinogenesis protocol as a model system. Following tumor initiation with DMBA, topical application of GSP at doses of 0.5 and 1.5 mg/mouse/application to the dorsal initiated mouse skin resulted in a highly significant inhibition of TPA tumor promotion. The observed anti-tumor-promoting effects of GSP were dose dependent and were evident in terms of a reduction in tumor incidence (35 and 60% inhibition), tumor multiplicity (61 and 83% inhibition) and tumor volume (67 and 87% inhibition) at both 0.5 and 1.5 mg GSP, respectively. Based on these results, we directed our efforts to separate and identify the individual polyphenols present in GSP and assess their antioxidant activity in terms of inhibition of epidermal lipid peroxidation. Employing HPLC followed by comparison with authentic standards for retention times in HPLC profiles, physiochemical properties and spectral analysis, nine individual polyphenols were identified as catechin, epicatechin, procyanidins B1-B5 and C1 and procyanidin B5-3'-gallate. Five of these individual polyphenols with evident structural differences, namely catechin, procyanidin B2, procyanidin B5, procyanidin C1 and procyanidin B5-3'-gallate, were assessed for antioxidant activity. All of them significantly inhibited

Synergistic anti-tumor effect of glycosylphosphatidylinositol-anchored IL-2 and IL-12.

PubMed

Ji, Jianfei; Li, Jinhua; Holmes, Lillia M; Burgin, Kelly E; Yu, Xianzhong; Wagner, Thomas E; Wei, Yanzhang

2004-07-01

Preclinical and clinical studies have demonstrated that interleukin 2 (IL-2), interleukin 12 (IL-12), and some other cytokines, play important roles in activating host immune responses against tumor growth. However, severe side effects caused by systemic high-dose administration of these cytokines limit their clinical application. In our previous study, local high doses of IL-2 were achieved by a GPI-anchoring technology; therefore, it will be interesting to know if this technology works for other cytokines. A fusion gene containing murine IL-12 and the glycosylphosphatidylinositol (GPI) anchor signal sequence was generated and transfected into the murine melanoma tumor cell line B16F0 either alone or together with a vector encoding GPI-anchored IL-2. The GPI-anchored cytokine expression of the selected stable clones was assayed in vitro by ELISA and their anti-tumor effects were analyzed in vivo by tumor lymphocyte infiltration and tumor growth studies. GPI-anchored IL-12 was successfully expressed on the cell surface as indicated by FACS analysis and IL-12 ELISA assay. The GPI-anchored IL-12 enhanced lymphocyte infiltration and significantly inhibited tumor growth. More importantly, when GPI-anchored IL-12 and GPI-anchored IL-2 were co-delivered, a synergistic anti-tumor effect was observed in both subcutaneous and intravenous tumor models. GPI anchorage of cytokines represents a new approach to locally deliver high doses of cytokines without the severe adverse effects normally accompanied with systematic high-dose administration of these cytokines. Copyright 2004 John Wiley & Sons, Ltd.

Concurrent, but not sequential, PD-1 blockade with a DNA vaccine elicits anti-tumor responses in patients with metastatic, castration-resistant prostate cancer.

PubMed

McNeel, Douglas G; Eickhoff, Jens C; Wargowski, Ellen; Zahm, Christopher; Staab, Mary Jane; Straus, Jane; Liu, Glenn

2018-05-22

T-cell checkpoint inhibitors have demonstrated dramatic clinical activity against multiple cancer types, however little activity in patients with prostate cancer. Conversely, an anti-tumor vaccine was approved for the treatment of prostate cancer, having demonstrated an improvement in overall survival, despite few objective disease responses. In murine studies, we found that PD-1 expression on CD8+ T cells increased following anti-tumor vaccination, and that PD-1/PD-L1 blockade at the time of immunization elicited greater anti-tumor responses. Based on these data we initiated a pilot trial evaluating the immunological and clinical efficacy of a DNA encoding prostatic acid phosphatase (PAP) when delivered in combination with pembrolizumab. 26 patients were treated for 12 weeks with vaccine and received pembrolizumab either during this time or during the subsequent 12 weeks. Adverse events included grade 2 and 3 fatigue, diarrhea, thyroid dysfunction, and hepatitis. Median time to radiographic progression was not different between study arms. 8/13 (62%) of patients treated concurrently, and 1/12 (8%, p=0.01) of patients treated sequentially, experienced PSA declines from baseline. Of these, two were over 50% and one was a complete PSA response. No confirmed CR or PR were observed, however 4/5 patients treated concurrently had measurable decreases in tumor volume at 12 weeks. PSA declines were associated with the development of PAP-specific Th1-biased T cell immunity and CD8+ T cell infiltration in metastatic tumor biopsy specimens. These data are the first report of a clinical trial demonstrating that the efficacy of an anti-tumor vaccine can be augmented by concurrent PD-1 blockade.

Eriocalyxin B, a novel autophagy inducer, exerts anti-tumor activity through the suppression of Akt/mTOR/p70S6K signaling pathway in breast cancer.

PubMed

Zhou, Xunian; Yue, Grace Gar-Lee; Chan, Andrew Man-Lok; Tsui, Stephen Kwok-Wing; Fung, Kwok-Pui; Sun, Handong; Pu, Jianxin; Lau, Clara Bik-San

2017-10-15

Eriocalyxin B (EriB), a natural ent-kaurane diterpenoid presented in the plant Isodon eriocalyx var. laxiflora, has been reported to diminish angiogenesis-dependent breast tumor growth. In the present study, the effects of EriB on human breast cancer and its underlying mechanisms were further investigated. The in vitro anti-breast cancer activity of EriB was determined using MCF-7 and MDA-MB-231 cell lines. MDA-MB-231 xenograft model of human breast cancer was also established to explore the anti-tumor effect in vivo. We found that EriB was able to induce apoptosis accompanied by the activation of autophagy, which was evidenced by the increased accumulation of autophagosomes, acidic vesicular organelles formation, the microtubule-associated protein 1A/1B-light chain 3B-II (LC3B-II) conversion from LC3B-I and p62 degradation. Meanwhile, EriB treatment time-dependently decreased the phosphorylation of Akt, mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (p70S6K), leading to the inhibition of Akt/mTOR/p70S6K signaling pathway. Moreover, the blockage of autophagy obviously sensitized EriB-induced cell death, which suggested the cytoprotective function of autophagy in both MCF-7 and MDA-MB-231 cells. Interestingly, the autophagic features and apoptosis induction were prevented by reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine, indicating that ROS played an essential role in the mediation of EriB-induced cell death. Furthermore, in MDA-MB-231 xenograft model, EriB displayed a significant anti-tumor effect via the activation of autophagy and apoptosis in breast tumor cells. Taken together, our findings firstly demonstrated that EriB suppressed breast cancer cells growth both in vitro and in vivo, and thus could be developed as a promising anti-breast tumor agent. Copyright © 2017 Elsevier Inc. All rights reserved.

Suppression of NF-κB Survival Signaling by Nitrosylcobalamin Sensitizes Neoplasms to the Anti-tumor Effects of Apo2L/TRAIL*

PubMed Central

Chawla-Sarkar, Mamta; Bauer, Joseph A.; Lupica, Joseph A.; Morrison, Bei H.; Tang, Zhuo; Oates, Rhonda K.; Almasan, Alex; DiDonato, Joseph A.; Borden, Ernest C.; Lindner, Daniel J.

2007-01-01

We have previously demonstrated the anti-tumor activity of nitrosylcobalamin (NO-Cbl), an analog of vitamin B12 that delivers nitric oxide (NO) and increases the expression of tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) and its receptors in human tumors. The specific aim of this study was to examine whether NO-Cbl could sensitize drug-resistant melanomas to Apo2L/TRAIL. Antiproliferative effects of NO-Cbl and Apo2L/TRAIL were assessed in malignant melanomas and non-tumorigenic melanocyte and fibro-blast cell lines. Athymic nude mice bearing human melanoma A375 xenografts were treated with NO-Cbl and Apo2L/TRAIL. Apoptosis was measured by TUNEL and confirmed by examining levels and activity of key mediators of apoptosis. The activation status of NF-κB was established by assaying DNA binding, luciferase reporter activity, the phosphorylation status of IκBα, and in vitro IKK activity. NO-Cbl sensitized Apo2L/TRAIL-resistant melanoma cell lines to growth inhibition by Apo2L/TRAIL but had minimal effect on normal cell lines. NO-Cbl and Apo2L/TRAIL exerted synergistic anti-tumor activity against A375 xenografts. Treatment with NO-Cbl followed by Apo2L/TRAIL induced apoptosis in Apo2L/TRAIL-resistant tumor cells, characterized by cleavage of caspase-3, caspase-8, and PARP. NO-Cbl inhibited IKK activation, characterized by decreased phosphorylation of IκBα and inhibition of NF-κB DNA binding activity. NO-Cbl suppressed Apo2L/TRAIL- and TNF-α-mediated activation of a transfected NF-κB-driven luciferase reporter. XIAP, an inhibitor of apoptosis, was inactivated by NO-Cbl. NO-Cbl treatment rendered Apo2L/TRAIL-resistant malignancies sensitive to the anti-tumor effects of Apo2L/TRAIL in vitro and in vivo. The use of NO-Cbl and Apo2L/TRAIL capitalizes on the tumor-specific properties of both agents and represents a promising anti-cancer combination. PMID:12881518

Tumor-derived vaccines containing CD200 inhibit immune activation: implications for immunotherapy.

PubMed

Xiong, Zhengming; Ampudia-Mesias, Elisabet; Shaver, Rob; Horbinski, Craig M; Moertel, Christopher L; Olin, Michael R

2016-09-01

There are over 400 ongoing clinical trials using tumor-derived vaccines. This approach is especially attractive for many types of brain tumors, including glioblastoma, yet so far the clinical response is highly variable. One contributor to poor response is CD200, which acts as a checkpoint blockade, inducing immune tolerance. We demonstrate that, in response to vaccination, glioma-derived CD200 suppresses the anti-tumor immune response. In contrast, a CD200 peptide inhibitor that activates antigen-presenting cells overcomes immune tolerance. The addition of the CD200 inhibitor significantly increased leukocyte infiltration into the vaccine site, cytokine and chemokine production, and cytolytic activity. Our data therefore suggest that CD200 suppresses the immune system's response to vaccines, and that blocking CD200 could improve the efficacy of cancer immunotherapy.

The anti-tumor effect of aspirin: What we know and what we expect.

PubMed

Ma, Ji; Cai, Zhonglin; Wei, Hongliang; Liu, Xinlan; Zhao, Qingli; Zhang, Tao

2017-11-01

Aspirin has been widely used as an antipyretic analgesic drug. More and more evidences have shown that aspirin may be play some role on anti-tumor. In this article, we reviewed the research history of aspirin in the treatment and prevention of cancer. Many epidemiological and clinical studies have shown that aspirin can reduce the risk of a variety of malignant tumors and reduce cancer mortality. In addition, we discuss the specific mechanisms of aspirin in the anti-tumor effects. It has been found that aspirin mainly depends on the COX pathway and non-COX pathway to inhibit tumor cell growth and to curb tumor development. In this article, clinical studies and anti-tumor mechanism studies published in recent years are reviewed. Copyright © 2017. Published by Elsevier Masson SAS.

In vivo and in vitro anti-tumor and anti-metastasis effects of Coriolus versicolor aqueous extract on mouse mammary 4T1 carcinoma.

PubMed

Luo, Ke-Wang; Yue, Grace Gar-Lee; Ko, Chun-Hay; Lee, Julia Kin-Ming; Gao, Si; Li, Long-Fei; Li, Gang; Fung, Kwok-Pui; Leung, Ping-Chung; Lau, Clara Bik-San

2014-01-01

Coriolus versicolor (CV), a medicinal mushroom widely consumed in Asian countries, has been demonstrated to be effective in stimulation of immune system and inhibition of tumor growth. The present study aimed to investigate the anti-tumor and anti-metastasis effects of CV aqueous extract in mouse mammary carcinoma 4T1 cells and in 4T1-tumor bearing mouse model. Our results showed that CV aqueous extract (0.125-2 mg/ml) did not inhibit 4T1 cell proliferation while the non-cytotoxic dose of CV extract (1-2 mg/ml) significantly inhibited cell migration and invasion (p<0.05). Besides, the enzyme activities and protein levels of MMP-9 were suppressed by CV extract significantly. Animal studies showed that CV aqueous extract (1 g/kg, orally-fed daily for 4 weeks) was effective in decreasing the tumor weight by 36%, and decreased the lung metastasis by 70.8% against untreated control. Besides, micro-CT analysis of the tumor-bearing mice tibias indicated that CV extract was effective in bone protection against breast cancer-induced bone destruction as the bone volume was significantly increased. On the other hand, CV aqueous extract treatments resulted in remarkable immunomodulatory effects, which was reflected by the augmentation of IL-2, 6, 12, TNF-α and IFN-γ productions from the spleen lymphocytes of CV-treated tumor-bearing mice. In conclusion, our results demonstrated for the first time that the CV aqueous extract exhibited anti-tumor, anti-metastasis and immunomodulation effects in metastatic breast cancer mouse model, and could protect the bone from breast cancer-induced bone destruction. These findings provided scientific evidences for the clinical application of CV aqueous extract in breast cancer patients. Copyright © 2014 Elsevier GmbH. All rights reserved.

Exploring the anti-cancer activity of novel thiosemicarbazones generated through the combination of retro-fragments: dissection of critical structure-activity relationships.

PubMed

Serda, Maciej; Kalinowski, Danuta S; Rasko, Nathalie; Potůčková, Eliška; Mrozek-Wilczkiewicz, Anna; Musiol, Robert; Małecki, Jan G; Sajewicz, Mieczysław; Ratuszna, Alicja; Muchowicz, Angelika; Gołąb, Jakub; Simůnek, Tomáš; Richardson, Des R; Polanski, Jaroslaw

2014-01-01

Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized "soft" donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination.

ErbB activation signatures as potential biomarkers for anti-ErbB3 treatment in HNSCC.

PubMed

Alvarado, Diego; Ligon, Gwenda F; Lillquist, Jay S; Seibel, Scott B; Wallweber, Gerald; Neumeister, Veronique M; Rimm, David L; McMahon, Gerald; LaVallee, Theresa M

2017-01-01

Head and neck squamous cell carcinoma (HNSCC) accounts for 3-5% of all tumor types and remains an unmet medical need with only two targeted therapies approved to date. ErbB3 (HER3), the kinase-impaired member of the EGFR/ErbB family, has been implicated as a disease driver in a number of solid tumors, including a subset of HNSCC. Here we show that the molecular components required for ErbB3 activation, including its ligand neuregulin-1 (NRG1), are highly prevalent in HNSCC and that HER2, but not EGFR, is the major activating ErbB3 kinase partner. We demonstrate that cetuximab treatment primarily inhibits the ERK signaling pathway and KTN3379, an anti-ErbB3 monoclonal antibody, inhibits the AKT signaling pathway, and that dual ErbB receptor inhibition results in enhanced anti-tumor activity in HNSCC models. Surprisingly, we found that while NRG1 is required for ErbB3 activation, it was not sufficient to fully predict for KTN3379 activity. An evaluation of HNSCC patient samples demonstrated that NRG1 expression was significantly associated with expression of the EGFR ligands amphiregulin (AREG) and transforming growth factor α (TGFα). Furthermore, NRG1-positive HNSCC cell lines that secreted high levels of AREG and TGFα or contained high levels of EGFR homodimers (H11D) demonstrated a better response to KTN3379. Although ErbB3 and EGFR activation are uncoupled at the receptor level, their respective signaling pathways are linked through co-expression of their respective ligands. We propose that NRG1 expression and EGFR activation signatures may enrich for improved efficacy of anti-ErbB3 therapeutic mAb approaches when combined with EGFR-targeting therapies in HNSCC.

The anti-tumor effect of the quinoline-3-carboxamide tasquinimod: blockade of recruitment of CD11b(+) Ly6C(hi) cells to tumor tissue reduces tumor growth.

PubMed

Deronic, Adnan; Tahvili, Sahar; Leanderson, Tomas; Ivars, Fredrik

2016-07-11

Previous work has demonstrated immunomodulatory, anti-tumor, anti-metastatic and anti-angiogenic effects of the small molecule quinoline-3-carboxamide tasquinimod in pre-clinical cancer models. To better understand the anti-tumor effects of tasquinimod in transplantable tumor models, we have evaluated the impact of the compound both on recruitment of myeloid cells to tumor tissue and on tumor-induced myeloid cell expansion as these cells are known to promote tumor development. Mice bearing subcutaneous 4 T1 mammary carcinoma tumors were treated with tasquinimod in the drinking water. A BrdU-based flow cytometry assay was utilized to assess the impact of short-term tasquinimod treatment on myeloid cell recruitment to tumors. Additionally, long-term treatment was performed to study the anti-tumor effect of tasquinimod as well as its effects on splenic myeloid cells and their progenitors. Myeloid cell populations were also immune-depleted by in vivo antibody treatment. Short-term tasquinimod treatment did not influence the proliferation of splenic Ly6C(hi) and Ly6G(hi) cells, but instead reduced the influx of Ly6C(hi) cells to the tumor. Treatment with tasquinimod for various periods of time after tumor inoculation revealed that the anti-tumor effect of this compound mainly operated during the first few days of tumor growth. Similar to tasquinimod treatment, antibody-mediated depletion of Ly6C(hi) cells within that same time frame, caused reduced tumor growth, thereby confirming a significant role for these cells in tumor development. Additionally, long-term tasquinimod treatment reduced the splenomegaly and expansion of splenic myeloid cells during a later phase of tumor development. In this phase, tasquinimod normalized the tumor-induced alterations in myeloerythroid progenitor cells in the spleen but had only limited impact on the same populations in the bone marrow. Our results indicate that tasquinimod treatment reduces tumor growth by operating early after

Location of Primary Tumor and Benefit From Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies in Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer.

PubMed

Moretto, Roberto; Cremolini, Chiara; Rossini, Daniele; Pietrantonio, Filippo; Battaglin, Francesca; Mennitto, Alessia; Bergamo, Francesca; Loupakis, Fotios; Marmorino, Federica; Berenato, Rosa; Marsico, Valentina Angela; Caporale, Marta; Antoniotti, Carlotta; Masi, Gianluca; Salvatore, Lisa; Borelli, Beatrice; Fontanini, Gabriella; Lonardi, Sara; De Braud, Filippo; Falcone, Alfredo

2016-08-01

Right- and left-sided colorectal cancers (CRCs) differ in clinical and molecular characteristics. Some retrospective analyses suggested that patients with right-sided tumors derive less benefit from anti-epidermal growth factor receptor (EGFR) antibodies; however, molecular selection in those studies was not extensive. Patients with RAS and BRAF wild-type metastatic CRC (mCRC) who were treated with single-agent anti-EGFRs or with cetuximab-irinotecan (if refractory to previous irinotecan) were included in the study. Differences in outcome between patients with right- and left-sided tumors were investigated. Of 75 patients, 14 and 61 had right- and left-sided tumors, respectively. None of the right-sided tumors responded according to RECIST, compared with 24 left-sided tumors (overall response rate: 0% vs. 41%; p = .0032), and only 2 patients with right-sided tumors (15%) versus 47 patients with left-sided tumors (80%) achieved disease control (p < .0001). The median duration of progression-free survival was 2.3 and 6.6 months in patients with right-sided and left-sided tumors, respectively (hazard ratio: 3.97; 95% confidence interval: 2.09-7.53; p < .0001). Patients with right-sided RAS and BRAF wild-type mCRC seemed to derive no benefit from single-agent anti-EGFRs. Right- and left-sided colorectal tumors have peculiar epidemiological and clinicopathological characteristics, distinct gene expression profiles and genetic alterations, and different prognoses. This study assessed the potential predictive impact of primary tumor site with regard to anti-epidermal growth factor receptor (EGFR) monoclonal antibody treatment in patients with RAS and BRAF wild-type metastatic colorectal cancer. The results demonstrated the lack of activity of anti-EGFRs in RAS and BRAF wild-type, right-sided tumors, thus suggesting a potential role for primary tumor location in driving treatment choices. ©AlphaMed Press.

Advances in the study of berberine and its derivatives: a focus on anti-inflammatory and anti-tumor effects in the digestive system

PubMed Central

Zou, Kun; Li, Zhao; Zhang, Yong; Zhang, Hao-yue; Li, Bo; Zhu, Wei-liang; Shi, Ji-ye; Jia, Qi; Li, Yi-ming

2017-01-01

It has been widely recognized that inflammation, particularly chronic inflammation, can increase the risk of cancer and that the simultaneous treatment of inflammation and cancer may produce excellent therapeutic effects. Berberine, an alkaloid isolated from Rhizoma coptidis, has broad applications, particularly as an antibacterial agent in the clinic with a long history. Over the past decade, many reports have demonstrated that this natural product and its derivatives have high activity against both cancer and inflammation. In this review, we summarize the advances in studing berberine and its derivatives as anti-inflammatory and anti-tumor agents in the digestive system; we also discuss their structure-activity relationship. These data should be useful for the development of this natural product as novel anticancer drugs with anti-inflammation activity. PMID:27917872

Potentiation of Tumor Necrosis Factor-α-induced Tumor Cell Apoptosis by a Small Molecule Inhibitor for Anti-apoptotic Protein hPEBP4

PubMed Central

Qiu, Jianming; Xiao, Jianfeng; Han, Chaofeng; Li, Nan; Shen, Xu; Jiang, Hualiang; Cao, Xuetao

2010-01-01

hPEBP4 (human phosphatidylethanolamine-binding protein 4) has been identified to be able to potentiate the resistance of breast, prostate, and ovarian cancers, with the preferential expression of hPEBP4, to tumor necrosis factor-α (TNF-α) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, suggesting that inhibitors targeting the anti-apoptotic protein hPEBP4 may be useful to increase the sensitivity of hPEBP4-expressing cancer cells to TNF-α or TRAIL-induced apoptosis. By structure-based virtual screening and following surface plasmon resonance-based binding assay, seven small compounds were found to potently bind with hPEBP4. The hit compounds were further functionally screened for their ability to inhibit cancer cell growth, and one small compound, IOI-42, was identified to be able to promote TNF-α-mediated growth inhibition of MCF-7 breast cancer cells. IOI-42 could potentiate TNF-α-induced apoptosis of MCF-7 cells by inhibiting hPEBP4 and could suppress anchorage-independent cell growth of MCF-7 cells. We further demonstrated that IOI-42 could reduce the endogenous association of hPEBP4 with Raf-1/MEK1 and enhance the activation of ERK1/2 and JNK while inhibiting Akt activation. Furthermore, IOI-42 also promoted TRAIL-induced cell apoptosis of prostate cancer cells. Taken together, our data suggest that IOI-42, as the first chemical inhibitor of anti-apoptotic protein hPEBP4, may serve as a potential anti-tumor drug by sensitizing tumor cells to apoptotic inducers. PMID:20177075

Combination of PDT and a DNA demethylating agent produces anti-tumor immune response in a mouse tumor model

NASA Astrophysics Data System (ADS)

Mroz, Pawel; Hamblin, Michael R.

2009-06-01

Epigenetic mechanisms, which involve DNA methylation and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. However, these changes must be actively maintained after each cell division rendering them a promising target for pharmacologic inhibition. DNA methyltransferase inhibitors like 5-aza-deoxycytidine (5-aza-dC) induce and/or up-regulate the expression of MAGE-type antigens in human and mice cancer cells. Photodynamic therapy (PDT) has been shown to be an effective locally ablative anti-cancer treatment that has the additional advantage of stimulating tumor-directed immune response. We studied the effects of a new therapy that combined the demethylating agent 5-aza-dC with PDT in the breast cancer model 4T1 syngenic to immunocompetent BALB/c mice. PDT was used as a locally ablating tumor treatment that is capable of eliciting strong and tumor directed immune response while 5-aza-dC pretreatment was used promote de novo induction of the expression of P1A.protein. This is the mouse homolog of human MAGE family antigens and is reported to function as a tumor rejection antigen in certain mouse tumors. This strategy led to an increase in PDT-mediated immune response and better treatment outcome. These results strongly suggest that the MAGE family antigens are important target for PDT mediated immune response but that their expression can be silenced by epigenetic mechanisms. Therefore the possibility that PDT can be combined with epigenetic strategies to elicit anti-tumor immunity in MAGE-positive tumor models is highly clinically significant and should be studied in detail.

[Anti-FGF23 antibody therapy for patients with tumor-induced osteomalacia].

PubMed

Kinoshita, Yuka; Fukumoto, Seiji

2014-08-01

Tumor-induced osteomalacia (TIO) is a disease caused by fibroblast growth factor 23 (FGF23) secreted from the causative tumor. This disease is cured by complete surgical removal of the tumor. However, there are several difficult cases in which the responsible tumors cannot be found, are incompletely removed, or relapse after the surgery. Anti-FGF23 antibody is being studied as a novel therapy for FGF23-related hypophosphatemic diseases. The efficacy of anti-FGF23 antibodies were confirmed using a murine model of X-linked hypophosphatemic rickets (XLHR) , which is the most common heritable form of FGF23-related hypophosphatemic disease. In addition, results of phase I study of single injection of humanized anti-FGF23 antibody for adult patients with XLHR were recently published and the safety and effectiveness of this antibody was shown. This antibody therapy may be useful for patients with TIO with similar pathogenesis to that of XLHR.

Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma.

PubMed

Keunen, Olivier; Johansson, Mikael; Oudin, Anaïs; Sanzey, Morgane; Rahim, Siti A Abdul; Fack, Fred; Thorsen, Frits; Taxt, Torfinn; Bartos, Michal; Jirik, Radovan; Miletic, Hrvoje; Wang, Jian; Stieber, Daniel; Stuhr, Linda; Moen, Ingrid; Rygh, Cecilie Brekke; Bjerkvig, Rolf; Niclou, Simone P

2011-03-01

Bevacizumab, an antibody against vascular endothelial growth factor (VEGF), is a promising, yet controversial, drug in human glioblastoma treatment (GBM). Its effects on tumor burden, recurrence, and vascular physiology are unclear. We therefore determined the tumor response to bevacizumab at the phenotypic, physiological, and molecular level in a clinically relevant intracranial GBM xenograft model derived from patient tumor spheroids. Using anatomical and physiological magnetic resonance imaging (MRI), we show that bevacizumab causes a strong decrease in contrast enhancement while having only a marginal effect on tumor growth. Interestingly, dynamic contrast-enhanced MRI revealed a significant reduction of the vascular supply, as evidenced by a decrease in intratumoral blood flow and volume and, at the morphological level, by a strong reduction of large- and medium-sized blood vessels. Electron microscopy revealed fewer mitochondria in the treated tumor cells. Importantly, this was accompanied by a 68% increase in infiltrating tumor cells in the brain parenchyma. At the molecular level we observed an increase in lactate and alanine metabolites, together with an induction of hypoxia-inducible factor 1α and an activation of the phosphatidyl-inositol-3-kinase pathway. These data strongly suggest that vascular remodeling induced by anti-VEGF treatment leads to a more hypoxic tumor microenvironment. This favors a metabolic change in the tumor cells toward glycolysis, which leads to enhanced tumor cell invasion into the normal brain. The present work underlines the need to combine anti-angiogenic treatment in GBMs with drugs targeting specific signaling or metabolic pathways linked to the glycolytic phenotype.

Intratumoral CpG-B promotes anti-tumoral neutrophil, cDC, and T cell cooperation without reprograming tolerogenic pDC.

PubMed

Humbert, Marion; Guery, Leslie; Brighouse, Dale; Lemeille, Sylvain; Hugues, Stephanie

2018-03-27

Cancer immunotherapies utilize distinct mechanisms to harness the power of the immune system to eradicate cancer cells. Therapeutic vaccines, aimed at inducing active immune responses against an existing cancer, are highly dependent on the immunological microenvironment, where many immune cell types display high levels of plasticity and, depending on the context, promote very different immunological outcomes. Among them, plasmacytoid dendritic cells (pDC), known to be highly immunogenic upon inflammation, are maintained in a tolerogenic state by the tumor microenvironment. Here we report that intratumoral (i.t.) injection of established solid tumors with CpG oligonucleotides-B (CpG-B) inhibits tumor growth. Interestingly, control of tumor growth was independent of tumor-associated (TA) pDC, which remained refractory to CpG-B stimulation and whose depletion did not alter the efficacy of the treatment. Instead, tumor growth inhibition subsequent to i.t. CpG-B injection depended on the recruitment of neutrophils into the milieu, resulting in the activation of conventional dendritic cells (cDC), subsequent increased anti-tumor T cell priming in draining lymph nodes, and enhanced effector T cell infiltration in the tumor microenvironment. These results reinforce the concept that intratumoral delivery of TLR9 agonists alters the tumor microenvironment by improving the anti-tumor activity of both innate and adaptive immune cells. Copyright ©2018, American Association for Cancer Research.

Enhanced anti-tumor activity by the combination of a conditionally replicating adenovirus mediated interleukin-24 and dacarbazine against melanoma cells via induction of apoptosis.

PubMed

Jiang, Guan; Liu, Yan-Qun; Wei, Zhi-Ping; Pei, Dong-Sheng; Mao, Li-Jun; Zheng, Jun-Nian

2010-08-28

Malignant melanoma is one of the most lethal and aggressive human malignancies. It is notoriously resistant to all of the current therapeutic modalities, including chemotherapy. Suppressed apoptosis and extraordinary invasiveness are the distinctive features that contribute to the malignancy of melanoma. Dacarbazine (DTIC) has been considered as the gold standard for melanoma treatment with a response rate of 15-20%. Unfortunately, the resistance to this chemotherapeutic agent occurs frequently. ZD55-IL-24 is a selective conditionally replicating adenovirus that can mediate the expression of interleukin-24 (IL-24) gene, which has a strong anti-tumor effect. In this study, we hypothesized that a combination of ZD55-IL-24-mediated gene virotherapy and chemotherapy using DTIC would produce an increased cytotoxicity against human melanoma cells in comparison with these agents alone. Our results showed that the combination of ZD55-IL-24 and DTIC significantly enhanced the anti-tumor activity by more effectively inducing apoptosis in melanoma cells than either agent used alone without any overlapping toxicity against normal cells. This additive or synergistic effect of ZD55-IL-24 in combination with DTIC in killing human malignant melanoma cells implies a promising novel approach for melanoma therapy. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Epigenetic regulation of cancer biology and anti-tumor immunity by EZH2.

PubMed

Christofides, Anthos; Karantanos, Theodoros; Bardhan, Kankana; Boussiotis, Vassiliki A

2016-12-20

Polycomb group proteins regulate chromatin structure and have an important regulatory role on gene expression in various cell types. Two polycomb group complexes (Polycomb repressive complex 1 (PRC1) and 2 (PRC2)) have been identified in mammalian cells. Both PRC1 and PRC2 compact chromatin, and also catalyze histone modifications. PRC1 mediates monoubiquitination of histone H2A, whereas PRC2 catalyzes methylation of histone H3 on lysine 27. These alterations of histones can lead to altered gene expression patterns by regulating chromatin structure. Numerous studies have highlighted the role of the PRC2 catalytic component enhancer of zeste homolog 2 (EZH2) in neoplastic development and progression, and EZH2 mutations have been identified in various malignancies. Through modulating the expression of critical genes, EZH2 is actively involved in fundamental cellular processes such as cell cycle progression, cell proliferation, differentiation and apoptosis. In addition to cancer cells, EZH2 also has a decisive role in the differentiation and function of T effector and T regulatory cells. In this review we summarize the recent progress regarding the role of EZH2 in human malignancies, highlight the molecular mechanisms by which EZH2 aberrations promote the pathogenesis of cancer, and discuss the anti-tumor effects of EZH2 targeting via activating direct anti-cancer mechanisms and anti-tumor immunity.

Epigenetic regulation of cancer biology and anti-tumor immunity by EZH2

PubMed Central

Bardhan, Kankana; Boussiotis, Vassiliki A.

2016-01-01

Polycomb group proteins regulate chromatin structure and have an important regulatory role on gene expression in various cell types. Two polycomb group complexes (Polycomb repressive complex 1 (PRC1) and 2 (PRC2)) have been identified in mammalian cells. Both PRC1 and PRC2 compact chromatin, and also catalyze histone modifications. PRC1 mediates monoubiquitination of histone H2A, whereas PRC2 catalyzes methylation of histone H3 on lysine 27. These alterations of histones can lead to altered gene expression patterns by regulating chromatin structure. Numerous studies have highlighted the role of the PRC2 catalytic component enhancer of zeste homolog 2 (EZH2) in neoplastic development and progression, and EZH2 mutations have been identified in various malignancies. Through modulating the expression of critical genes, EZH2 is actively involved in fundamental cellular processes such as cell cycle progression, cell proliferation, differentiation and apoptosis. In addition to cancer cells, EZH2 also has a decisive role in the differentiation and function of T effector and T regulatory cells. In this review we summarize the recent progress regarding the role of EZH2 in human malignancies, highlight the molecular mechanisms by which EZH2 aberrations promote the pathogenesis of cancer, and discuss the anti-tumor effects of EZH2 targeting via activating direct anti-cancer mechanisms and anti-tumor immunity. PMID:27793053

Improved anti-tumor efficacy via combination of oxaliplatin and fibrin glue in colorectal cancer

PubMed Central

Hu, Yuzhu; Yu, Ting; Liu, Xiaoxiao; He, Yihong; Deng, Lihong; Guo, Jiajuan; Hua, Yuanqi; Luo, Ting; Gao, Xiang

2018-01-01

Colorectal cancer is very common worldwide and advanced colorectal cancer exhibited very poor clinical outcome. Oxaliplatin (OXP) is one of the principal chemotherapeutic agents in colorectal cancer treatment presenting impressive anti-tumor ability, limited by adverse effect in clinical practice. Fibrin glue (FG) is a biocompatible formulation made of fibrinogen and thrombin, extensively used in surgery for hemostasis, tissue adhesion and sealing. In this study, FG was innovatively applied as OXP delivery system and results showed enhanced anti-tumor performance in subcutaneous model and abdominal metastasis model of murine colorectal cancer compared with that of OXP used alone. It is revealed that combination of OXP and FG could increase activated CD8+ T cells, reduce regulatory T (Treg) cells and increase interferon-γ (IFN-γ). Furthermore, results showed promoted tumor apoptosis, decreased proliferation and inhibited tumor angiogenesis by OXP and FG combination. No obvious systemic toxicity was observed in this study. Finally, our findings provided basis for promising application of OXP and FG combination in colorectal cancer treatment. PMID:29416788

[Research advances of anti-tumor immune response induced by pulse electric field ablation].

PubMed

Cui, Guang-ying; Diao, Hong-yan

2015-11-01

As a novel tumor therapy, pulse electric field has shown a clinical perspective. This paper reviews the characteristics of tumor ablation by microsecond pulse and nanosecond pulse electric field, and the research advances of anti-tumor immune response induced by pulse electric field ablation. Recent researches indicate that the pulse electric field not only leads to a complete ablation of local tumor, but also stimulates a protective immune response, thereby inhibiting tumor recurrence and metastasis. These unique advantages will show an extensive clinical application in the future. However, the mechanism of anti-tumor immune response and the development of related tumor vaccine need further studies.

Interferon-γ Drives Treg Fragility to Promote Anti-tumor Immunity.

PubMed

Overacre-Delgoffe, Abigail E; Chikina, Maria; Dadey, Rebekah E; Yano, Hiroshi; Brunazzi, Erin A; Shayan, Gulidanna; Horne, William; Moskovitz, Jessica M; Kolls, Jay K; Sander, Cindy; Shuai, Yongli; Normolle, Daniel P; Kirkwood, John M; Ferris, Robert L; Delgoffe, Greg M; Bruno, Tullia C; Workman, Creg J; Vignali, Dario A A

2017-06-01

Regulatory T cells (T regs ) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral T reg stability and function but is dispensable for peripheral immune tolerance. T reg -restricted Nrp1 deletion results in profound tumor resistance due to T reg functional fragility. Thus, identifying the basis for Nrp1 dependency and the key drivers of T reg fragility could help to improve immunotherapy for human cancer. We show that a high percentage of intratumoral NRP1 + T regs correlates with poor prognosis in melanoma and head and neck squamous cell carcinoma. Using a mouse model of melanoma where Nrp1-deficient (Nrp1 -/- ) and wild-type (Nrp1 +/+ ) T regs can be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1 -/- T regs produce interferon-γ (IFNγ), which drives the fragility of surrounding wild-type T regs , boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFNγ-induced T reg fragility is required for response to anti-PD1, suggesting that cancer therapies promoting T reg fragility may be efficacious. Copyright © 2017 Elsevier Inc. All rights reserved.

Discovery of LY2457546: a multi-targeted anti-angiogenic kinase inhibitor with a novel spectrum of activity and exquisite potency in the acute myelogenous leukemia-Flt-3-internal tandem duplication mutant human tumor xenograft model.

PubMed

Burkholder, Timothy P; Clayton, Joshua R; Rempala, Mark E; Henry, James R; Knobeloch, John M; Mendel, David; McLean, Johnathan A; Hao, Yan; Barda, David A; Considine, Eileen L; Uhlik, Mark T; Chen, Yuefeng; Ma, Liandong; Bloem, Laura J; Akunda, Jacqueline K; McCann, Denis J; Sanchez-Felix, Manuel; Clawson, David K; Lahn, Michael M; Starling, James J

2012-06-01

LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. In biochemical and cellular assays, LY2457546 demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRβ, FLT-3, Tie-2 and members of the Eph family of receptors. With activities against both Tie2 and Eph receptors, LY2457546 possesses an activity profile that distinguishes it from multikinase inhibitors. When compared head to head with sunitinib, LY2457546 was more potent for inhibition of endothelial tube formation in an in vitro angiogenesis co-culture model with an intermittent treatment design. In vivo, LY2457546 inhibited VEGF-driven autophosphorylation of lung KDR in the mouse and rat in a dose and concentration dependent manner. LY2457546 was well tolerated and exhibited efficacy in a 13762 syngeneic rat mammary tumor model in both once and twice daily continuous dosing schedules and in mouse human tumor xenograft models of lung, colon, and prostate origin. Additionally, LY2457546 caused complete regression of well-established tumors in an acute myelogenous leukemia (AML) FLT3-ITD mutant xenograft tumor model. The observed efficacy that was displayed by LY2457546 in the AML FLT3-ITD mutant tumor model was superior to sunitinib when both were evaluated using equivalent doses normalized to in vivo inhibition of pKDR in mouse lung. LY2457546 was well tolerated in non-clinical toxicology studies conducted in rats and dogs. The majority of the toxicities observed were similar to those observed with other multi-targeted anti-angiogenic kinase inhibitors (MAKs) and included bone marrow hypocellularity, hair and skin depigmentation, cartilage dysplasia and lymphoid organ degeneration and necrosis. Thus, the unique spectrum of target activity, potent in vivo anti-tumor efficacy in a variety of rodent and human solid tumor models, exquisite potency against a clinically relevant model of AML, and non

Evidence of the anti-Helicobacter pylori, gastroprotective and anti-inflammatory activities of Cuphea aequipetala infusion.

PubMed

Palacios-Espinosa, Juan Francisco; Arroyo-García, Oscar; García-Valencia, Guillermo; Linares, Edelmira; Bye, Robert; Romero, Irma

2014-02-03

Cuphea aequipetala (Lythraceae) is a medicinal plant highly appreciated in Mexico to treat stomach ailments such as pain and burning sensation, stomach infections, ulcers, diarrhea, dysentery, and different types of tumors and bruises. In this work, the infusion of aerial parts of this plant (CAI) was investigated for its polypharmacological potential. In vitro anti-Helicobacter pylori activity was assessed by broth dilution method. Pharmacological studies included acute toxicity in mice using Lorke´s model, anti-inflammatory activity by xylene and TPA induced ear edema assay, as well as gastroprotection with ethanol-induced gastric ulcer model. DPPH and ABTS assays were used to determine antioxidant capacity. Polyphenols and flavonoid contents were determined by Folin-Ciocalteu method and AlCl3 reaction, respectively. CAI showed good anti-Helicobacter pylori activity with a MIC of 125μg/mL. The infusion was not toxic according to Lorke's model with a LD50 greater than 5g/kg. CAI exhibited low anti-edematogenic action in the models assayed. Oral administration of 300mg/kg CAI significantly reduced gastric lesions by 87.9%. The effect was reversed only by indomethacin and N-ethylmaleimide demonstrating the role of endogenous prostaglandins and sulfhydryl compounds in gastroprotection. Total phenolic and flavonoid contents of CAI were 109.9mg GAE/g DW and 28.1mg QE/g DW, respectively, and the infusion exhibited a good antioxidant activity that is thought to play a role in its biological activity. The analysis of a preliminary fractionation of the infusion indicates that the complete extract conserves all its pharmacological activities in contrast to fractionated extracts. Cuphea aequipetala is a promising native herb in an integral therapy for the treatment of bacterial or non-bacterial gastric ulcer because it possesses some anti-inflammatory properties, as well as exhibits good gastroprotective and antibacterial effects. It represents an important source for the

Atypical responses in patients with advanced melanoma, lung cancer, renal-cell carcinoma and other solid tumors treated with anti-PD-1 drugs: A systematic review.

PubMed

Queirolo, Paola; Spagnolo, Francesco

2017-09-01

Anti-programmed death receptor 1 (PD-1) drugs nivolumab and pembrolizumab were recently approved for the treatment of advanced melanoma and other solid tumors. Atypical patterns of response (i.e. tumor shrinkage or stabilization after initial progression) were observed in about 10% of metastatic melanoma patients treated with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) drug ipilimumab and were associated with improved survival; however, the rate of atypical response patterns to anti-PD-1 therapy is not clear. An electronic search was performed to identify clinical trials evaluating response to anti-PD-1 therapy with nivolumab and pembrolizumab in patients with advanced solid tumors. Thirty-eight studies were included in our analysis for a total of 7069 patients with advanced cancer treated with anti-PD-1 therapy. Responses were evaluated by unconventional response criteria in 19 trials and were observed for all cancer types but tumors with mismatch-repair deficiency and head and neck squamous cell carcinoma. Overall, 151 atypical responses were observed in 2400 patients (6%) evaluated by unconventional response criteria. The results of our systematic review highlight the clinical relevance of unconventional responses to anti-PD-1 therapy and support further investigation into the development of tools that may assist evaluation of the antitumor activity of immunotherapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Hydroquinone Exhibits In Vitro and In Vivo Anti-Cancer Activity in Cancer Cells and Mice.

PubMed

Byeon, Se Eun; Yi, Young-Su; Lee, Jongsung; Yang, Woo Seok; Kim, Ji Hye; Kim, Jooyoung; Hong, Suntaek; Kim, Jong-Hoon; Cho, Jae Youl

2018-03-19

Hydroquinone (HQ, 1,4-benzenediol) is a hydroxylated benzene metabolite with various biological activities, including anti-oxidative, neuroprotective, immunomodulatory, and anti-inflammatory functions. However, the anti-cancer activity of HQ is not well understood. In this study, the in vitro and in vivo anti-cancer activity of HQ was investigated in various cancer cells and tumor-bearing mouse models. HQ significantly induced the death of A431, SYF, B16F10, and MDA-MB-231 cells and also showed a synergistic effect on A431 cell death with other anti-cancer agents, such as adenosine-2',3'-dialdehyde and buthionine sulfoximine. In addition, HQ suppressed angiogenesis in fertilized chicken embryos. Moreover, HQ prevented lung metastasis of melanoma cells in mice in a dose-dependent manner without toxicity and adverse effects. HQ (10 mg/kg) also suppressed the generation of colon and reduced the thickness of colon tissues in azoxymethane/dextran sodium sulfate-injected mice. This study strongly suggests that HQ possesses in vitro and in vivo anti-cancer activity and provides evidence that HQ could be developed as an effective and safe anti-cancer drug.

Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer

PubMed Central

Shu, Guangwen; Wan, Dingrong; He, Feng; Loaec, Morgann; Ding, Yali; Li, Jun; Dovat, Sinisa; Yang, Gaungzhong; Song, Chunhua

2016-01-01

Chemotherapy is the main treatment for patients with breast cancer metastases, but natural alternatives have been receiving attention for their potential as novel anti-tumor reagents. Amplexicaule A (APA) is a flavonoid glucoside isolated from rhizomes of Polygonum amplexicaule D. Don var. sinense Forb (PADF). We found that APA has anti-tumor effects in a breast cancer xenograft mouse model and induces apoptosis in breast cancer cell lines. APA increased levels of cleaved caspase-3,-8,-9 and PARP, which resulted from suppression of MCL-1 and BCL-2 expression in the cells. APA also inactivated the Akt/mTOR pathway in breast cancer cells. Thus, APA exerts a strong anti-tumor effect on breast cancer cells, most likely through induction of apoptosis. Our study is the first to identify this novel anti-tumor compound and provides a new strategy for isolation and separation of single compounds from herbs. PMID:26943775

The influence of physical activity in the anti-tumor immune response in experimental breast tumor.

PubMed

Bianco, Thiago M; Abdalla, Douglas R; Desidério, Chamberttan S; Thys, Sofie; Simoens, Cindy; Bogers, John-Paul; Murta, Eddie F C; Michelin, Márcia A

2017-10-01

This study aimed to investigate the influence of physical activity in innate immunity to conduce to an effective antitumoral immune response analyzing the phenotype and activation status of infiltrating cells. We analysed the intracellular cytokines and the transcription factors of tumor infiltrating lymphocytes (TILS) and spleen leukocytes. The Nos2 gene expression was evaluated in spleen cells and futhermore the ROS production was measured and spleen cells; another cell evaluated was dendritic cells (TIDCs), their cytokines expression and membrane molecules; finally to understood the results obtained, we analysed the dendritic cells obtained from bone marrow. Were used female Balb/c mice divided into 4 groups: two controls without tumor, sedentary (GI) and trained (GII) and two groups with tumor, sedentary (GIII) or trained (GIV). The physical activity (PA) was realized acoording swimming protocol. Tumor was induced by injection of 4T1 cells. All experiments were performed in biological triplicate. After the experimental period, the tumor was removed and the cells were identified by flow cytometry with labeling to CD4, CD8, CD11c, CD11b, CD80, CD86 and Ia, and intracelular staining IL-10, IL-12, TNF-α, IFN-γ, IL-17, Tbet, GATA3, RORγt and FoxP3. The bone marrow of the animals was obtained to analyse the derivated DCs by flow cytometry and culture cells to obtain the supernatant to measure the cytokines. Our results demonstrated that the PA inhibit the tumoral growth although not to change the number of TILS, but reduced expression of GATA-3, ROR-γT, related with poor prognosis, and TNF-α intracellular; however occur one significantly reduction in TIDCS, but these cells expressed more co-stimulatory and presentation molecules. Furthermore, we observed that the induced PA stimulated the gene expression of Tbet and the production of inflammatory cytokines suggesting an increase of Th1 systemic response. The results evaluating the systemic influence in DCs

The anti-tumor effect and biological activities of the extract JMM6 from the stem-barks of the Chinese Juglans mandshurica Maxim on human hepatoma cell line BEL-7402.

PubMed

Zhang, Yongli; Cui, Yuqiang; Zhu, Jiayong; Li, Hongzhi; Mao, Jianwen; Jin, Xiaobao; Wang, Xiangsheng; Du, Yifan; Lu, Jiazheng

2013-01-01

Juglans mandshurica Maxim is a traditional herbal medicines in China, and its anti-tumor bioactivities are of research interest. Bioassay-guided fractionation method was employed to isolate anti-tumor compounds from the stem barks of the Juglans mandshurica Maxim. The anti-tumor effect and biological activities of the extracted compound JMM6 were studied in BEL-7402 cells by MTT, Cell cycle analysis, Hoechst 33342 staining, Annexin V-FITC/PI assay and Detection of mitochondrial membrane potential (ΔΨm). After treatment with the JMM6, the growth of BEL-7402 cells was inhibited and cells displayed typical morphological apoptotic characteristics. Further investigations revealed that treatment with JMM6 mainly caused G2/M cell cycle arrest and induced apoptosis in BEL-7402 cells. To evaluate the alteration of mitochondria in JMM6 induced apoptosis. The data showed that JMM6 decreased significantly the ΔΨm, causing the depolarization of the mitochondrial membrane. Our results show that the JMM6 will have a potential advantage of anti-tumor, less harmful to normal cells. This paper not only summarized the JMM6 pick-up technology from Juglans mandshurica Maxim and biological characteristic, but also may provide further evidence to exploit the potential medicine compounds from the stem-barks of the Chinese Juglans mandshurica Maxim.

In vitro anti-proliferative and anti-angiogenic activities of thalidomide dithiocarbamate analogs.

PubMed

El-Aarag, Bishoy Y A; Kasai, Tomonari; Zahran, Magdy A H; Zakhary, Nadia I; Shigehiro, Tsukasa; Sekhar, Sreeja C; Agwa, Hussein S; Mizutani, Akifumi; Murakami, Hiroshi; Kakuta, Hiroki; Seno, Masaharu

2014-08-01

Inhibition of angiogenesis is currently perceived as a promising strategy in the treatment of cancer. The anti-angiogenicity of thalidomide has inspired a second wave of research on this teratogenic drug. The present study aimed to investigate the anti-proliferative and anti-angiogenic activities of two thalidomide dithiocarbamate analogs by studying their anti-proliferative effects on human umbilical vein endothelial cells (HUVECs) and MDA-MB-231 human breast cancer cell lines. Their action on the expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 was also assessed. Furthermore, their effect on angiogenesis was evaluated through wound healing, migration, tube formation, and nitric oxide (NO) assays. Results illustrated that the proliferation of HUVECs and MDA-MB-231 cells was not significantly affected by thalidomide at 6.25-100μM. Thalidomide failed to block angiogenesis at similar concentrations. By contrast, thalidomide dithiocarbamate analogs exhibited significant anti-proliferative action on HUVECs and MDA-MB-231 cells without causing cytotoxicity and also showed powerful anti-angiogenicity in wound healing, migration, tube formation, and NO assays. Thalidomide analogs 1 and 2 demonstrated more potent activity to suppress expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 than thalidomide. Analog 1 consistently, showed the highest potency and efficacy in all the assays. Taken together, our results support further development and evaluation of novel thalidomide analogs as anti-tumor and anti-angiogenic agents. Copyright © 2014. Published by Elsevier B.V.

Anti-inflammatory, anti-tumor-promoting, and cytotoxic activities of constituents of marigold (Calendula officinalis) flowers.

PubMed

Ukiya, Motohiko; Akihisa, Toshihiro; Yasukawa, Ken; Tokuda, Harukuni; Suzuki, Takashi; Kimura, Yumiko

2006-12-01

Ten oleanane-type triterpene glycosides, 1-10, including four new compounds, calendulaglycoside A 6'-O-methyl ester (2), calendulaglycoside A 6'-O-n-butyl ester (3), calendulaglycoside B 6'-O-n-butyl ester (5), and calendulaglycoside C 6'-O-n-butyl ester (8), along with five known flavonol glycosides, 11-15, were isolated from the flowers of marigold (Calendula officinalis). Upon evaluation of compounds 1-9 for inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation (1 microg/ear) in mice, all of the compounds, except for 1, exhibited marked anti-inflammatory activity, with ID50 values of 0.05-0.20 mg per ear. In addition, when 1-15 were evaluated against the Epstein-Barr virus early antigen (EBV-EA) activation induced by TPA, compounds 1-10 exhibited moderate inhibitory effects (IC50 values of 471-487 mol ratio/32 pmol TPA). Furthermore, upon evaluation of the cytotoxic activity against human cancer cell lines in vitro in the NCI Developmental Therapeutics Program, two triterpene glycosides, 9 and 10, exhibited their most potent cytotoxic effects against colon cancer, leukemia, and melanoma cells.

Activation of Stat3 in renal tumors.

PubMed

Guo, Charles; Yang, Guanyu; Khun, Kyle; Kong, Xiantian; Levy, David; Lee, Peng; Melamed, Jonathan

2009-02-28

Signal transducer and activator of transcription 3 (Stat3) plays a vital role in signal transduction pathways that mediate transformation and inhibit apoptosis. Oncogenic Stat3 is persistently activated in several human cancers and transformed cell lines. Previous studies indicate activation of Stat3 in renal cell carcinoma (RCC). However, the detailed characterization of the Stat3 expression pattern in different histologic types of RCC is lacking. We have analyzed the immunoprofile of activated or phosphorylated Stat3 (pStat3) in a tissue microarray of renal tumors of different histologic types, including 42 cases of conventional clear cell type, 24 chromophobe, and 7 papillary, 15 oncocytoma, 7 urothelial carcinoma and 21 normal kidney tissues using an anti-pStat3 antibody (recognizes only activated STAT3). pStat3 nuclear staining was observed in 25 of 42 conventional clear cell RCC (59.5 %), 8 of 24 chromophobe RCC (33.3%), 4 of 7 papillary RCC (57.1%). In the other tumor groups, 4 of 15 oncocytomas (26.7%) and 6 of 7 urothelial carcinomas (85.7%) showed positive nuclear staining. Weak nuclear immunoreactivity for pStat3 was seen in 4 of 21 cases of non-neoplastic kidney tissue (19.0%). The extent of Stat3 activation as determined by nuclear expression of its phosphorylated form is increased in histologic types of renal tumors with greater malignant potential, specifically conventional clear cell RCC, papillary RCC and urothelial carcinoma, only slightly increased in chromophobe RCC, and not increased in oncocytoma. These results suggest a role of Stat3 activation in different types of renal neoplasia, possibly serving as a prognostic marker or therapeutic target.

Activation of Stat3 in renal tumors

PubMed Central

Guo, Charles; Yang, Guanyu; Khun, Kyle; Kong, Xiantian; Levy, David; Lee, Peng; Melamed, Jonathan

2009-01-01

Signal transducer and activator of transcription 3 (Stat3) plays a vital role in signal transduction pathways that mediate transformation and inhibit apoptosis. Oncogenic Stat3 is persistently activated in several human cancers and transformed cell lines. Previous studies indicate activation of Stat3 in renal cell carcinoma (RCC). However, the detailed characterization of the Stat3 expression pattern in different histologic types of RCC is lacking. We have analyzed the immunoprofile of activated or phosphorylated Stat3 (pStat3) in a tissue microarray of renal tumors of different histologic types, including 42 cases of conventional clear cell type, 24 chromophobe, and 7 papillary, 15 oncocytoma, 7 urothelial carcinoma and 21 normal kidney tissues using an anti-pStat3 antibody (recognizes only activated STAT3). pStat3 nuclear staining was observed in 25 of 42 conventional clear cell RCC (59.5 %), 8 of 24 chromophobe RCC (33.3%), 4 of 7 papillary RCC (57.1%). In the other tumor groups, 4 of 15 oncocytomas (26.7%) and 6 of 7 urothelial carcinomas (85.7%) showed positive nuclear staining. Weak nuclear immunoreactivity for pStat3 was seen in 4 of 21 cases of non-neoplastic kidney tissue (19.0%). The extent of Stat3 activation as determined by nuclear expression of its phosphorylated form is increased in histologic types of renal tumors with greater malignant potential, specifically conventional clear cell RCC, papillary RCC and urothelial carcinoma, only slightly increased in chromophobe RCC, and not increased in oncocytoma. These results suggest a role of Stat3 activation in different types of renal neoplasia, possibly serving as a prognostic marker or therapeutic target. PMID:19956438

Angiostatic, tumor inflammatory and anti-tumor effects of CXCL4(47-70) and CXCL4L1(47-70) in an EGF-dependent breast cancer model.

PubMed

Van Raemdonck, Katrien; Berghmans, Nele; Vanheule, Vincent; Bugatti, Antonella; Proost, Paul; Opdenakker, Ghislain; Presta, Marco; Van Damme, Jo; Struyf, Sofie

2014-11-15

CXCL4 and CXCL4L1, platelet-derived CXC chemokines, and their carboxy-terminal peptides CXCL4(47-70) and CXCL4L1(47-70) previously displayed angiostatic and anti-tumoral activity in a melanoma model. Here, we found CXCL4(47-70) and CXCL4L1(47-70) to inhibit lymphatic endothelial cell proliferation in vitro. Furthermore, the angiostatic potential of CXCL4(47-70) and CXCL4L1(47-70) was tested against different angiogenic stimuli (FGF1, FGF2, FGF8, EGF and VEGF). Besides reducing FGF2-induced vascular endothelial cell growth, CXCL4(47-70) and CXCL4L1(47-70) efficiently counteracted EGF. Consequently, we considered their anti-tumoral potential in EGF-dependent MDA-MB-231 breast tumors. In tumor-bearing mice, CXCL4(47-70) reduced tumor growth better than CXCL4L1(47-70). In CXCL4(47-70)-treated tumors significantly more intratumoral monocytes/macrophages and dendritic cells were present and higher expression levels of CCL5 and IFN- γ were detected by qPCR on tumor lysates. Because neither peptide was able to specifically bind CXCR3A or CXCR3B, differential glycosaminoglycan binding and direct interaction with cytokines (EGF and CCL5) might explain any differences in anti-tumoral effects. Notably, CCL5-induced monocyte chemotaxis in vitro was increased by addition of CXCL4(47-70) or CXCL4L1(47-70). Finally, CXCL4(47-70) and CXCL4L1(47-70) inhibited proliferation of MDA-MB-231 cells. Our results suggest a tumor type-dependent responsiveness to either CXCL4(47-70) or CXCL4L1(47-70) treatment, defined by anti-proliferative, angiostatic and inflammatory actions, and substantiate their therapeutic potential.

Angiostatic, tumor inflammatory and anti-tumor effects of CXCL447–70 and CXCL4L147–70 in an EGF-dependent breast cancer model

PubMed Central

Van Raemdonck, Katrien; Berghmans, Nele; Vanheule, Vincent; Bugatti, Antonella; Proost, Paul; Opdenakker, Ghislain; Presta, Marco; Van Damme, Jo; Struyf, Sofie

2014-01-01

CXCL4 and CXCL4L1, platelet-derived CXC chemokines, and their carboxy-terminal peptides CXCL447–70 and CXCL4L147–70 previously displayed angiostatic and anti-tumoral activity in a melanoma model. Here, we found CXCL447–70 and CXCL4L147–70 to inhibit lymphatic endothelial cell proliferation in vitro. Furthermore, the angiostatic potential of CXCL447–70 and CXCL4L147–70 was tested against different angiogenic stimuli (FGF1, FGF2, FGF8, EGF and VEGF). Besides reducing FGF2-induced vascular endothelial cell growth, CXCL447–70 and CXCL4L147–70 efficiently counteracted EGF. Consequently, we considered their anti-tumoral potential in EGF-dependent MDA-MB-231 breast tumors. In tumor-bearing mice, CXCL447–70 reduced tumor growth better than CXCL4L147–70. In CXCL447–70-treated tumors significantly more intratumoral monocytes/macrophages and dendritic cells were present and higher expression levels of CCL5 and IFN-γ were detected by qPCR on tumor lysates. Because neither peptide was able to specifically bind CXCR3A or CXCR3B, differential glycosaminoglycan binding and direct interaction with cytokines (EGF and CCL5) might explain any differences in anti-tumoral effects. Notably, CCL5-induced monocyte chemotaxis in vitro was increased by addition of CXCL447–70 or CXCL4L147–70. Finally, CXCL447–70 and CXCL4L147–70 inhibited proliferation of MDA-MB-231 cells. Our results suggest a tumor type-dependent responsiveness to either CXCL447–70 or CXCL4L147–70 treatment, defined by anti-proliferative, angiostatic and inflammatory actions, and substantiate their therapeutic potential. PMID:25373734

Anti-tumor immunotherapy by blockade of the PD-1/PD-L1 pathway with recombinant human PD-1-IgV.

PubMed

Zhang, C; Wu, S; Xue, X; Li, M; Qin, X; Li, W; Han, W; Zhang, Y

2008-01-01

Blockade of the programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway can delay tumor growth and prolong the survival of tumor-bearing mice. The extracellular immunoglobulin (Ig) V domain of PD-1 is important for the interaction between PD-1 and PD-L1, suggesting that PD-1-IgV may be a potential target for anti-tumor immunotherapy. The extracellular sequence of human PD-1-IgV (hPD-1-IgV) was expressed in Escherichia coli and purified. The anti-tumor effect of hPD-1-IgV on tumor-bearing mice was tested. hPD-1-IgV recombinant protein could bind PD-L1 at molecular and cellular levels and enhance Cytotoxic T Lymphocyte (CTL) activity and anti-tumor effect on tumor-bearing mice in vivo. The percentage of CD4(+)CD25(+) T cells in tumor-bearing mice was decreased compared with control mice after administration of the recombinant protein. Our results suggest that inhibition of the interaction between PD-1 and PD-L1 by hPD-1-IgV may be a promising strategy for specific tumor immunotherapy.

Curcumin-docetaxel co-loaded nanosuspension for enhanced anti-breast cancer activity.

PubMed

Sahu, Bhanu P; Hazarika, Hemanga; Bharadwaj, Rituraj; Loying, Pojul; Baishya, Rinku; Dash, Suvakanta; Das, Malay K

2016-08-01

A curcumin-docetaxel co-loaded nanosuspension with increased anti-breast cancer activity was developed. Curcumin is a potential anticancer agent with p-glycoprotein (p-gp) inhibiting activity may be co-administered with docetaxel as a nanosuspension to enhance its anticancer effect by increasing the oral bioavailability and decreasing drug efflux. Nanosuspensions of curcumin and docetaxel were prepared by precipitation-homozenisation technique and evaluated for particle size, polydispersity, zeta potential and drug release. The in vitro MTT assay was conducted using MCF-7 for anti-breast cancer activity. The in vivo biodistribution by radiolabeling and tumor inhibition study was conducted in mice. Homogenous nanosuspensions of 80 ± 20 nm were obtained with increased solubility. The drugs as nanosuspensions showed higher cytotoxicity on MCF-7 cell line compared to their suspensions due to the increased in vitro cellular uptake. Due to this increased solubility, sensitization of tumor cells and inhibition of p-gp the in-vivo results showed greater tumor inhibition rate of up to 70% in MCF-7 treated mice. Histopathological results showed higher apoptotic activity and reduced level of angiogenesis. The in vitro and in vivo study of the nanosuspensions has shown that Co-administration of Curcumin as a p-gp inhibitor with docetaxel may have the potential to increase the anti-breast cancer efficacy of both drugs.

Evaluation of dimethoxydop-NU as a novel anti-tumor agent.

PubMed

Mukherjee, A; Dutta, S; Sanyal, U

2007-12-01

Dimethoxydop-NU, 1-[2-{3-(2-Chloroethyl)-3-nitrosoureido}ethyl]-3,4-dimethoxy-benzene (Compound 1), was synthesized from 3,4-dimethoxy-phenethylamine as a novel anti-tumor agent based on the structures of the clinical drug CCNU and dopamine, an important endogenous biological amine having anti-angiogenesis property. In vitro screening in two human tumor cell lines, namely promyelocytic leukemia HL-60 and histiocytic lymphoma U-937, revealed its cytotoxicity greater than that of hydroxyurea and comparable to BCNU used as standards. Its in vivo anti-tumoral potency was assessed in the murine ascites tumors Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times of drug treated (T) over untreated control (C) mice. Results revealed significant tumor regression effects in these tumors. The survival time of treated mice was markedly increased by combination of the compound 1 with dopamine hydrochloride. Its toxicity was assessed in vivo in normal and EAC bearing mice by measuring drug-induced changes in hematological parameters, femoral bone marrow and splenic cellularities as well as biochemical parameters sequentially on days 9, 14 and 19 following drug treatment at the optimum dose of 30 mg/kg from day 1 to 7. Results indicated that initial suppression in the femoral bone marrow cellularity seen on day 9 reached normalcy by day 19. Other parameters were within normal limit. Histopathological studies of liver revealed mild hepatotoxicity on day 9 in treated groups that substantially recovered on day 19. Similar studies with heart and kidney revealed no cardio toxicity or nephrotoxicity. Compound 1 comparable to standards inhibited the synthesis of DNA and RNA in S-180 tumor cells.

Systemic treatment with n-6 polyunsaturated fatty acids attenuates EL4 thymoma growth and metastasis through enhancing specific and non-specific anti-tumor cytolytic activities and production of TH1 cytokines.

PubMed

Salem, Mohamed Labib

2005-06-01

Recently, there has been a great interest in the effects of different types of n-6 polyunsaturated acids (n-6 PUFAs) upon the immune system and cancer development. However, the effects of n-6 PUFAs are still controversial and as yet undefined. The present study aimed to investigate the anti-tumor effects of n-6 PUFAs against EL4 thymoma and the associated immune mechanisms. To this, sesame oil, a vegetable oil enriched with n-6 PUFAs, or free linoleic acid (LA) were administered intraperitoneally into C57BL/6 mice before and after challenge with EL4 lymphoma cells. Treatment with either sesame oil or LA attenuated the growth and metastasis of EL4 lymphoma. The anti-tumor effect of LA was superior to that of sesame oil, and associated with an increase in the survival rate of the tumor-bearing mice. In addition, both sesame oil and LA showed dose-dependent anti-lymphoma growth in vitro. Treatment with LA generated significant increases in the anti-lymphoma cytolytic and cytostatic activities of T cells and macrophages, respectively, and enhanced production of IL-2 and IFN-gamma while decreased production of IL-4, IL-6 and IL-10. In summation, the results suggest that n-6 PUFAs, represented by LA, can attenuate EL4 lymphoma growth and metastasis through enhancing the specific and non-specific anti-tumor cytolytic activities and production of TH1 cytokines. These findings might be of great importance for a proper design of systemic nourishment with PUFAs emulsions for cancer patients.

ME-10TUMOR MICROENVIRONMENT INFILTRATING MYELOID DERIVED SUPPRESSOR CELLS INHIBIT ANTI-TUMOR T CELL RESPONSES

PubMed Central

Kamran, Neha; Ayala, Mariela; Li, Youping; Assi, Hikmat; Candolfi, Marianela; Dzaman, Marta; Lowenstein, Pedro; Castro, Maria

2014-01-01

MDSCs represent a population of immature myeloid cells at various stages of differentiation that inhibit anti-tumor T cell-mediated responses. We demonstrate the accumulation of MDSCs in GL26 induced glioma and B16 melanoma bearing mice. Absolute numbers of Ly-6G+ (Gr-1high) MDSCs showed a 200 fold increase within the tumor microenvironment (TME) 28 days post-tumor implantation. The numbers of Ly-6C+ (Gr-1low) MDSCs also showed a similar trend within the TME. While this massive influx of MDSCs was noted within intracranial tumors, MDSC levels did not increase in the dLNs, spleen or bone marrow (BM) of intracranial tumor bearing mice. MDSCs numbers were significantly elevated in the blood of GL26 intracranial tumor bearing mice at 28 days. Mice bearing B16 tumors in the flank showed a ∼5 fold increased influx of Ly-6G+ MDSCs while the Ly6C+ MDSCs increased marginally by 1.1 fold within the tumor mass. Levels of circulating MDSCs also increased by ∼10 fold, while the levels of splenic MDSCs did not change. While both Ly-6G+ and Ly6C+ MDSCs isolated from the brain TME of GL26 intracranial tumor bearing mice inhibited antigen-specific T cell proliferation, Ly6C+ MDSC were found to be more efficient. Ly6G+ or Ly6C+ MDSCs from the bone marrow of intracranial tumor bearing mice failed to suppress antigen-specific T cell proliferation. Splenic and bone marrow MDSCs from naïve mice also did not inhibit antigen-specific T cell proliferation suggesting that TME derived factors may activate MDSCs to exert their immune-suppressive properties. Microarray analysis of glioma cell lines showed elevated levels of CXCL1 mRNA and splenic MDSCs from GL26 tumor mice showed upregulation of the CXCR2 mRNA. Preliminary experiments indicate that CXCR2 signaling mediates MDSC chemotaxis. Overall, our data suggests that strategies that inhibit MDSC recruitment to the TME and/or block their activity could enhance the T cell mediated tumor clearance.

Phosphorylation of interleukin (IL)-24 is required for mediating its anti-cancer activity.

PubMed

Panneerselvam, Janani; Shanker, Manish; Jin, Jiankang; Branch, Cynthia D; Muralidharan, Ranganayaki; Zhao, Yan D; Chada, Sunil; Munshi, Anupama; Ramesh, Rajagopal

2015-06-30

Interleukin (IL)-24 is a tumor suppressor/cytokine gene that undergoes post-translational modifications (PTMs). Glycosylation and ubiquitination are important for IL-24 protein stabilization and degradation respectively. Little is known about IL-24 protein phosphorylation and its role in IL-24-mediated anti-tumor activities. In this study we conducted molecular studies to determine whether IL-24 phosphorylation is important for IL-24-mediated anti-cancer activity.Human H1299 lung tumor cell line that was stably transfected with a doxycycline (DOX)-inducible (Tet-on) plasmid vector carrying the cDNA of IL-24-wild-type (IL-24wt) or IL-24 with all five phosphorylation sites replaced (IL-24mt) was used in the present study. Inhibition of tumor cell proliferation, cell migration and invasion, and induction of G2/M cell cycle arrest was observed in DOX-induced IL-24wt-expressing cells but not in IL-24mt-expressing cells. Secretion of IL-24mt protein was greatly reduced compared to IL-24wt protein. Further, IL-24wt and IL-24mt proteins markedly differed in their subcellular organelle localization. IL-24wt but not IL-24mt inhibited the AKT/mTOR signaling pathway. SiRNA-mediated AKT knockdown and overexpression of myristolyated AKT protein confirmed that IL-24wt but not IL-24mt mediated its anti-cancer activity by inhibiting the AKT signaling pathway.Our results demonstrate that IL-24 phosphorylation is required for inhibiting the AKT/mTOR signaling pathway and exerting its anti-cancer activities.

Anti-Tumor Activity of Cytotoxic T Lymphocytes Elicited with Recombinant and Synthetic Forms of a Model Tumor-Associated Antigen

PubMed Central

Wang, Michael; Chen, Pauline W.; Bronte, Vincenzo; Rosenberg, Steven A.; Restifo, Nicholas P.

2008-01-01

Summary The recent cloning of tumor-associated antigens (TAAs) recognized by CD8 + T lymphocytes (TCD8−) has made it possible to use recombinant and synthetic forms of TAAs to generate TCD8− with anti-tumor activity. To explore new therapeutic strategies in a mouse model, we retrovirally transduced the experimental murine tumor CT26 (H-2d), with the lacZ gene encoding our model TAA, (β-galactosidase (β-gal). The transduced cell line, CT26.CL25, grew as rapidly and as lethally as the parental cell line in normal, immuno-competent animals. In an attempt to elicit TCD8+ directed against our model TAA by using purely recombinant and synthetic forms of our model TAA, we synthesized a nine-amino-acid long immunodominant peptide of (β-gal (TPH-PARIGL), corresponding to amino acid residues 876–884, which was known to be presented by the Ld major histocompatibility complex (MHC) class I molecule, and a recombinant vaccinia virus encoding the full-length β-gal protein (VJS6). Splenocytes obtained from naïve mice and co-cultured with (β-gal peptide could not be expanded in primary ex vivo cultures. However, mice immunized with VJS6, but not with a control recombinant vaccinia virus, yielded splenocytes that were capable of specifically lysing CT26.CL25 in vitro after co-culture with (β-gal peptide. Most significantly, adoptive transfer of these cells could effectively treat mice bearing 3-day-old established pulmonary metastases. These observations show that therapeutic TCD8+ directed against a model TAA could be generated by using purely recombinant and synthetic forms of this antigen. These findings point the way to a potentially useful immunotherapeutic strategy, which has been made possible by the recent cloning of immunogenic TAAs that are expressed by human malignancies. PMID:8770769

Anti-tumor immunity induced by an anti-idiotype antibody mimicking human Her-2/neu.

PubMed

Mohanty, Kartik; Saha, Asim; Pal, Smarajit; Mallick, Palash; Chatterjee, Sunil K; Foon, Kenneth A; Bhattacharya-Chatterjee, Malaya

2007-07-01

Our goal is to apply an anti-idiotype (Id) antibody based vaccine approach for the treatment of Her-2/neu-positive human cancer. Amplification and/or over-expression of Her-2/neu occur in multiple human malignancies and are associated with poor prognosis. Her-2/neu proto-oncogene is a suitable target for cancer immunotherapy. We have developed and characterized a murine monoclonal anti-Id antibody, 6D12 that mimics a specific epitope of Her-2/neu and can be used as a surrogate antigen for Her-2/neu. In this study, the efficacy of 6D12 as a tumor vaccine was evaluated in a murine tumor model. Immunization of immunocompetent C57BL/6 mice with 6D12 conjugated to keyhole limpet hemocyanin and mixed with Freund's adjuvant or 6D12 combined with the adjuvant QS21 induced anti-6D12 as well as anti-Her-2/neu immunity. Her-2/neu-positive human breast carcinoma cells, SK-BR-3 reacted with immunized mice sera as determined by ELISA and flow cytometry. Flow cytometry analysis also demonstrated strong reactivity of immunized mice sera with human Her-2/neu transfected EL4 cells (EL4-Her-2), but no reactivity with nontransfected parental EL4 cells. Antibody dependent cellular cytotoxicity against EL4-Her-2 cells was also observed in presence of immune sera. Mice immunized with 6D12 were protected against a challenge with lethal doses of EL4-Her-2 cells, whereas no protection was observed against parental EL4 cells or when mice were immunized with an unrelated anti-Id antibody and challenged with EL4-Her-2 cells. These data suggest that anti-Id 6D12 vaccine can induce protective Her-2/neu specific antitumor immunity and may serve as a potential network antigen for the treatment of patients with Her-2/neu-positive tumors.

In vitro and in vivo anti-plasmodial activity of essential oils, including hinokitiol.

PubMed

Fujisaki, Ryuichi; Kamei, Kiyoko; Yamamura, Mariko; Nishiya, Hajime; Inouye, Shigeharu; Takahashi, Miki; Abe, Shigeru

2012-03-01

Abstract. The anti-plasmodial activity of 47 essential oils and 10 of their constituents were screened for in vitro activity against Plasmodium falciparum. Five of these essential oils (sandalwood, caraway, monarda, nutmeg, and Thujopsis dolabrata var. hondai) and 2 constituents (thymoquinone and hinokitiol) were found to be active against P. falciparum in vitro, with 50% inhibitory concentration (IC50) values equal to or less than 1.0 microg/ml. Furthermore, in vivo analysis using a rodent model confirmed the anti-plasmodial potential of subcutaneously administered sandalwood oil, and percutaneously administered hinokitiol and caraway oil against rodent P. berghei. Notably, these oils showed no efficacy when administered orally, intraperitoneally or intravenously. Caraway oil and hinokitiol dissolved in carrier oil, applied to the skin of hairless mice caused high levels in the blood, with concentrations exceeding their IC50 values.

Anti-tumor immune response after photodynamic therapy

NASA Astrophysics Data System (ADS)

Mroz, Pawel; Castano, Ana P.; Wu, Mei X.; Kung, Andrew L.; Hamblin, Michael R.

2009-06-01

Anti-tumor immunity is stimulated after PDT due a number of factors including: the acute inflammatory response caused by PDT, release of antigens from PDT-damaged tumor cells, priming of the adaptive immune system to recognize tumor-associated antigens (TAA), and induction of heat-shock proteins. The induction of specific CD8+ T-lymphocyte cells that recognize major histocompatibility complex class I (MHC-I) restricted epitopes of TAAs is a highly desirable goal in cancer therapy as it would allow the treatment of tumors that may have already metastasized. The PDT killed tumor cells may be phagocytosed by dendritic cells (DC) that then migrate to draining lymph nodes and prime naÃve T-cells that recognize TAA epitopes. We have carried out in vivo PDT with a BPD-mediated vascular regimen using a pair of BALB/c mouse colon carcinomas: CT26 wild type expressing the naturally occurring retroviral antigen gp70 and CT26.CL25 additionally expressing beta-galactosidase (b-gal) as a model tumor rejection antigen. PDT of CT26.CL25 cured 100% of tumors but none of the CT26WT tumors (all recurred). Cured CT26.CL25 mice were resistant to rechallenge. Moreover mice with two bilateral CT26.CL25 tumors that had only one treated with PDT demonstrated spontaneous regression of 70% of untreated contralateral tumors. T-lymphocytes were isolated from lymph nodes of PDT cured mice that recognized a particular peptide specific to b-gal antigen. T-lymphocytes from LN were able to kill CT26.CL25 target cells in vitro but not CT26WT cells as shown by a chromium release assay. CT26.CL25 tumors treated with PDT and removed five days later had higher levels of Th1 cytokines than CT26 WT tumors showing a higher level of immune response. When mice bearing CT26WT tumors were treated with a regimen of low dose cyclophosphamide (CY) 2 days before, PDT led to 100% of cures (versus 0% without CY) and resistance to rechallenge. Low dose CY is thought to deplete regulatory T-cells (Treg, CD4+CD25+foxp

Efficient induction of anti-tumor immunity by a TAT-CEA fusion protein vaccine with poly(I:C) in a murine colorectal tumor model.

PubMed

Park, Jung-Sun; Kim, Hye-Sung; Park, Hye-Mi; Kim, Chang-Hyun; Kim, Tai-Gyu

2011-11-03

Protein vaccines may be a useful strategy for cancer immunotherapy because recombinant tumor antigen proteins can be produced on a large scale at relatively low cost and have been shown to be safe for clinical application. However, protein vaccines have historically exhibited poor immunogenicity; thus, an improved strategy is needed for successful induction of immune responses. TAT peptide is a protein transduction domain composed of an 11-amino acid peptide (TAT(47-57): YGRKKRRQRRR). The positive charge of this peptide allows protein antigen fused with it to improve cell penetration. Poly(I:C) is a synthetic double-stranded RNA that is negatively charged and favors interaction with the cationic TAT peptide. Poly(I:C) has been reported on adjuvant role in tumor vaccine through promotion of immune responses. Therefore, we demonstrated that vaccine with a mixture of TAT-CEA fusion protein and poly(I:C) can induce anti-tumor immunity in a murine colorectal tumor model. Splenocytes from mice vaccinated with a mixture of TAT-CEA fusion protein and poly(I:C) effectively induced CEA-specific IFN-γ-producing T cells and showed cytotoxic activity specific for MC-38-cea2 tumor cells expressing CEA. Vaccine with a mixture of TAT-CEA fusion protein and poly(I:C) delayed tumor growth in MC-38-cea-2 tumor-bearing mice. Depletion of CD8(+) T cells and NK cells reversed the inhibition of tumor growth in an MC-38-cea2-bearing mice, indicating that CD8(+) T cells and NK cells are responsible for anti-tumor immunity by vaccine with a mixture of TAT-CEA fusion protein and poly(I:C). Taken together, these results suggest that poly(I:C) could be used as a potent adjuvant to induce the anti-tumor immunity of a TAT-CEA fusion protein vaccine in a murine colorectal tumor model. Copyright © 2011 Elsevier Ltd. All rights reserved.

Ferulic acid prevents liver injury and increases the anti-tumor effect of diosbulbin B in vivo.

PubMed

Wang, Jun-ming; Sheng, Yu-chen; Ji, Li-li; Wang, Zheng-tao

2014-06-01

The present study is designed to investigate the protection by ferulic acid against the hepatotoxicity induced by diosbulbin B and its possible mechanism, and further observe whether ferulic acid augments diosbulbin B-induced anti-tumor activity. The results show that ferulic acid decreases diosbulbin B-increased serum alanine transaminase/aspartate transaminase (ALT/AST) levels. Ferulic acid also decreases lipid peroxide (LPO) levels which are elevated in diosbulbin B-treated mice. Histological evaluation of the liver demonstrates hydropic degeneration in diosbulbin B-treated mice, while ferulic acid reverses this injury. Moreover, the activities of copper- and zinc-containing superoxide dismutase (CuZn-SOD) and catalase (CAT) are decreased in the livers of diosbulbin B-treated mice, while ferulic acid reverses these decreases. Further results demonstrate that the mRNA expressions of CuZn-SOD and CAT in diosbulbin B-treated mouse liver are significantly decreased, while ferulic acid prevents this decrease. In addition, ferulic acid also augments diosbulbin B-induced tumor growth inhibition compared with diosbulbin B alone. Taken together, the present study shows that ferulic acid prevents diosbulbin B-induced liver injury via ameliorating diosbulbin B-induced liver oxidative stress injury and augments diosbulbin B-induced anti-tumor activity.

Altered Hepa1-6 cells by dimethyl sulfoxide (DMSO)-treatment induce anti-tumor immunity in vivo.

PubMed

Jiang, Zhengyu; Zhang, Hongxia; Wang, Ye; Yu, Bin; Wang, Chen; Liu, Changcheng; Lu, Juan; Chen, Fei; Wang, Minjun; Yu, Xinlu; Lin, Jiahao; Pan, Xinghua; Wang, Pin; Zhu, Haiying

2016-02-23

Cancer immunotherapy is the use of the immune system to treat cancer. Our current research proposed an optional strategy of activating immune system involving in cancer immunotherapy. When being treated with 2% DMSO in culture medium, Hepa1-6 cells showed depressed proliferation with no significant apoptosis or decreased viability. D-hep cells, Hepa1-6 cells treated with DMSO for 7 days, could restore to the higher proliferation rate in DMSO-free medium, but alteration of gene expression profile was irreversible. Interestingly, tumors from D-hep cells, not Hepa1-6 cells, regressed in wild-type C57BL/6 mice whereas D-hep cells exhibited similar tumorigenesis as Hep1-6 cells in immunodeficient mice. As expected, additional Hepa1-6 cells failed to form tumors in the D-hep-C57 mice in which D-hep cells were eliminated. Further research confirmed that D-hep-C57 mice established anti-tumor immunity against Hepa1-6 cells. Our research proposed viable tumor cells with altered biological features by DMSO-treatment could induce anti-tumor immunity in vivo.

Drainage alone or combined with anti-tumor therapy for treatment of obstructive jaundice caused by recurrence and metastasis after primary tumor resection.

PubMed

Xu, Chuan; Huang, Xin-En; Wang, Shu-Xiang; Lv, Peng-Hua; Sun, Ling; Wang, Fu-An; Wang, Li-Fu

2014-01-01

To compare drainage alone or combined with anti-tumor therapy for treatment of obstructive jaundice caused by recurrence and metastasis after primary tumor resection. We collect 42 patients with obstructive jaundice caused by recurrence and metastasis after tumor resection from January 2008 - August 2012, for which percutaneous transhepatic catheter drainage (pTCD)/ percutaneous transhepatic biliary stenting (pTBS) were performed. In 25 patients drainage was combined with anti-tumor treatment, antineoplastic therapy including intra/postprodure local treatment and postoperative systemic chemotherapy, the other 17 undergoing drainage only. We assessed the two kinds of treatment with regard to patient prognosis. Both treatments demonstrated good effects in reducing bilirubin levels in the short term and promoting liver function. The time to reobstruction was 125 days in the combined group and 89 days in the drainage only group; the mean survival times were 185 and 128 days, the differences being significant. Interventional drainage in the treatment of the obstructive jaundice caused by recurrence and metastasis after tumor resection can decrease bilirubin level quickly in a short term and promote the liver function recovery. Combined treatment prolongs the survival time and period before reobstruction as compared to drainage only.

Integrin β1 activation induces an anti-melanoma host response

PubMed Central

Sole, Xavier; Salony; Chowdhury, Joeeta; Ross, Kenneth N.; Ramaswamy, Sridhar

2017-01-01

TGF-β is a cytokine thought to function as a tumor promoter in advanced malignancies. In this setting, TGF-β increases cancer cell proliferation, survival, and migration, and orchestrates complex, pro-tumorigenic changes in the tumor microenvironment. Here, we find that in melanoma, integrin β1-mediated TGF-β activation may also produce tumor suppression via an altered host response. In the A375 human melanoma cell nu/nu xenograft model, we demonstrate that cell surface integrin β1-activation increases TGF-β activity, resulting in stromal activation, neo-angiogenesis and, unexpectedly for this nude mouse model, increase in the number of intra-tumoral CD8+ T lymphocytes within the tumor microenvironment. This is associated with attenuation of tumor growth and long-term survival benefit. Correspondingly, in human melanomas, TGF-β1 correlates with integrin β1/TGF-β1 activation and the expression of markers for vasculature and stromal activation. Surprisingly, this integrin β1/TGF-β1 transcriptional footprint also correlates with the expression of markers for tumor-infiltrating lymphocytes, multiple immune checkpoints and regulatory pathways, and, importantly, better long-term survival of patients. These correlations are unique to melanoma, in that we do not observe similar associations between β1 integrin/TGF-β1 activation and better long-term survival in other human tumor types. These results suggest that activation of TGF-β1 in melanoma may be associated with the generation of an anti-tumor host response that warrants further study. PMID:28448494

Colloidally stable surface-modified iron oxide nanoparticles: Preparation, characterization and anti-tumor activity

NASA Astrophysics Data System (ADS)

Macková, Hana; Horák, Daniel; Donchenko, Georgiy Viktorovich; Andriyaka, Vadim Ivanovich; Palyvoda, Olga Mikhailovna; Chernishov, Vladimir Ivanovich; Chekhun, Vasyl Fedorovich; Todor, Igor Nikolaevich; Kuzmenko, Oleksandr Ivanovich

2015-04-01

Maghemite (γ-Fe2O3) nanoparticles were obtained by co-precipitation of Fe(II) and Fe(III) chlorides and subsequent oxidation with sodium hypochlorite and coated with poly(N,N-dimethylacrylamide-co-acrylic acid) [P(DMAAm-AA)]. They were characterized by a range of methods including transmission electron microscopy (TEM), elemental analysis, dynamic light scattering (DLS) and zeta potential measurements. The effect of superparamagnetic P(DMAAm-AA)-γ-Fe2O3 nanoparticles on oxidation of blood lipids, glutathione and proteins in blood serum was detected using 2-thiobarbituric acid and the ThioGlo fluorophore. Finally, mice received magnetic nanoparticles administered per os and the antitumor activity of the particles was tested on Lewis lung carcinoma (LLC) in male mice line C57BL/6 as an experimental in vivo metastatic tumor model; the tumor size was measured and the number of metastases in lungs was determined. Surface-modified γ-Fe2O3 nanoparticles showed higher antitumor and antimetastatic activities than commercial CuFe2O4 particles and the conventional antitumor agent cisplatin.

Syntheses and anti-MRSA activities of the C3 analogs of mansonone F, a potent anti-bacterial sesquiterpenoid: insights into its structural requirements for anti-MRSA activity.

PubMed

Shin, Dong-Yun; Kim, Sun Nam; Chae, Jung-Hyun; Hyun, Soon-Sil; Seo, Seung-Yong; Lee, Yong-Sil; Lee, Kwang-Ok; Kim, Seok-Ho; Lee, Yun-Sang; Jeong, Jae Min; Choi, Nam-Song; Suh, Young-Ger

2004-09-06

Syntheses and excellent anti-MRSA activities of the mansonone F analogs are reported. In addition, the minimal structural requirements for its anti-MRSA activities as well as its structure-activity relationship including the C3 substituents effects on anti-MRSA activity are also described. In particular, this study revealed that both ortho-quinone and tricyclic systems of mansonone F are essential for anti-MRSA activities.

Anti-collagenase, anti-elastase and anti-oxidant activities of extracts from 21 plants

PubMed Central

Thring, Tamsyn SA; Hili, Pauline; Naughton, Declan P

2009-01-01

.05%) and rose aqueous (73.86%). Conclusion From a panel of twenty three plant extracts, some one dozen exhibit high or satisfactory anti-collagenase or anti-elastase activities, with nine having inhibitory activity against both enzymes. These included white tea which was found to have very high phenolic content, along with high TEAC and SOD activities. PMID:19653897

[Construction of a new oncolytic virus oHSV2hGM-CSF and its anti-tumor effects].

PubMed

Shi, Gui-Lan; Zhuang, Xiu-Fen; Han, Xiang-Ping; Li, Jie; Zhang, Yu; Zhang, Shu-Ren; Liu, Bin-Lei

2012-02-01

survival over 110 days after tumor cells inoculation whereas all the mice in the PBS group died by day 22 (P < 0.01). The anti-tumor mechanism of the newly constructed oHSV2hGM-CSF against B16R cell tumor appeared to include the directly oncolytic activity and the induction of anti-tumor immunity to some degree. The findings of our study demonstrate that the newly constructed oHSV2hGM-CSF has potent anti-tumor activity in vitro to many tumor cell lines and in vive to the transplanted B16R tumor models.

Anti-CEA-functionalized superparamagnetic iron oxide nanoparticles for examining colorectal tumors in vivo

NASA Astrophysics Data System (ADS)

Huang, Kai-Wen; Chieh, Jen-Jie; Lin, In-Tsang; Horng, Herng-Er; Yang, Hong-Chang; Hong, Chin-Yih

2013-10-01

Although the biomarker carcinoembryonic antigen (CEA) is expressed in colorectal tumors, the utility of an anti-CEA-functionalized image medium is powerful for in vivo positioning of colorectal tumors. With a risk of superparamagnetic iron oxide nanoparticles (SPIONPs) that is lower for animals than other material carriers, anti-CEA-functionalized SPIONPs were synthesized in this study for labeling colorectal tumors by conducting different preoperatively and intraoperatively in vivo examinations. In magnetic resonance imaging (MRI), the image variation of colorectal tumors reached the maximum at approximately 24 h. However, because MRI requires a nonmetal environment, it was limited to preoperative imaging. With the potentiality of in vivo screening and intraoperative positioning during surgery, the scanning superconducting-quantum-interference-device biosusceptometry (SSB) was adopted, showing the favorable agreement of time-varied intensity with MRI. Furthermore, biological methodologies of different tissue staining methods and inductively coupled plasma (ICP) yielded consistent results, proving that the obtained in vivo results occurred because of targeted anti-CEA SPIONPs. This indicates that developed anti-CEA SPIONPs owe the utilities as an image medium of these in vivo methodologies.

Two photon microscopy intravital study of DC-mediated anti-tumor response of NK cells

NASA Astrophysics Data System (ADS)

Caccia, Michele; Gorletta, Tatiana; Sironi, Laura; Zanoni, Ivan; Salvetti, Cristina; Collini, Maddalena; Granucci, Francesca; Chirico, Giuseppe

2010-02-01

Recent studies have demonstrated that dendritic cells (DCs) play a crucial role in the activation of Natural Killer cells (NKs) that are responsible for anti-tumor innate immune responses. The focus of this report is on the role of pathogen associated molecular pattern (PAMP) activated-DCs in inducing NK cell-mediated anti-tumor responses. Mice transplanted sub-cute (s.c.) with AK7 cells, a mesothelioma cell line sensitive to NK cell responses, are injected with fluorescent NK cells and DC activation is then induced by s.c. injection of Lipopolysaccharide (LPS). Using 4 dimensional tracking we follow the kinetic behavior of NK cells at the Draining Lymph-Node (DLN). As control, noninflammatory conditions are also evaluated. Our data suggest that NK cells are recruited to the DLN where they can interact with activated-DCs with a peculiar kinetic behavior: short lived interactions interleaved by rarer longer ones. We also found that the changes in the NK dynamic behavior in inflammatory conditions clearly affect relevant motility parameters such as the instantaneous and average velocity and the effective diffusion coefficient. This observation suggests that NK cells and activated-DCs might efficiently interact in the DLN, where cells could be activated. Therefore the interaction between activated-DCs and NK cells in DLN is not only a reality but it may be also crucial for the start of the immune response of the NKs.

Effects of anti-tumor necrosis factor-alpha and anti-intercellular adhesion molecule-1 antibodies on ischemia/reperfusion lung injury.

PubMed

Chiang, Chi-Huei

2006-10-31

Inhibition of neutrophil activation and adherence to endothelium by antibodies to tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecules (ICAM-1), respectively, might attenuate ischemia-reperfusion injury (I/R). I/R was conducted in an isolated rat lung model. Anti-TNF-alpha antibody and/or anti-ICAM-1 antibody were added before ischemia or after reperfusion. Hemodynamic changes, lung weight gain (LWG), capillary filtration coefficients (Kfc), and pathologic changes were assessed to evaluate the severity of I/R. The LWG, Kfc, pathological changes and lung injury score of treatment groups with anti-TNF-alpha antibody treatment, either pre-ischemia or during reperfusion, were less than those observed in control groups. Similar findings were found in group treated with anti-ICAM-1 antibody or combination therapy during reperfusion. In contrast, pre-I/R treatment with anti-ICAM-1 antibody induced severe lung edema and failure to complete the experimental procedure. No additional therapeutic effect was found in combination therapy. We conclude that TNF-alpha and ICAM-1 play important roles in I/R. Anti-TNF-alpha antibody has therapeutic and preventive effects on I/R. However, combined therapy with anti-TNF-alpha antibody and anti-ICAM-1 antibody may have no additive effect and need further investigation.

Combination of Anti-angiogenesis with Chemotherapy for More Effective Cancer Treatment*

PubMed Central

Ma, Jie; Waxman, David J.

2008-01-01

Angiogenesis is a hallmark of tumor development and metastasis and is now a validated target for cancer treatment. Overall, however, the survival benefits of anti-angiogenic drugs have, thus far, been rather modest, stimulating interest in developing more effective ways to combine anti-angiogenic drugs with established chemotherapies. This review discusses recent progress and emerging challenges in this field; interactions between anti-angiogenic drugs and conventional chemotherapeutic agents are examined, and strategies for the optimization of combination therapies are discussed. Anti-angiogenic drugs such as the anti-VEGF antibody bevacizumab can induce a functional normalization of the tumor vasculature that is transient and can potentiate the activity of co-administered chemoradiotherapies. However, chronic angiogenesis inhibition typically reduces tumor uptake of co-administered chemotherapeutics, indicating a need to explore new approaches, including intermittent treatment schedules and provascular strategies to increase chemotherapeutic drug exposure. In cases where anti-angiogenesis-induced tumor cell starvation augments the intrinsic cytotoxic effects of a conventional chemotherapeutic drug, combination therapy may increase anti-tumor activity despite a decrease in cytotoxic drug exposure. As new angiogenesis inhibitors enter the clinic, reliable surrogate markers are needed to monitor the progress of anti-angiogenic therapies and to identify responsive patients. New targets for anti-angiogenesis continue to be discovered, increasing the opportunities to interdict tumor angiogenesis and circumvent resistance mechanisms that may emerge with chronic use of these drugs. PMID:19074844

Anti-Tumor Effect of Steamed Codonopsis lanceolata in H22 Tumor-Bearing Mice and Its Possible Mechanism

PubMed Central

Li, Wei; Xu, Qi; He, Yu-Fang; Liu, Ying; Yang, Shu-Bao; Wang, Zi; Zhang, Jing; Zhao, Li-Chun

2015-01-01

Although previous studies confirmed that steaming and the fermentation process could significantly improve the cognitive-enhancement and neuroprotective effects of Codonopsis lanceolata, the anti-tumor efficacy of steamed C. lanceolata (SCL) and what mechanisms are involved remain largely unknown. The present study was designed to evaluate the anti-tumor effect in vivo of SCL in H22 tumor-bearing mice. The results clearly indicated that SCL could not only inhibit the tumor growth, but also prolong the survival time of H22 tumor-bearing mice. Besides, the serum levels of cytokines, such as interferon gamma (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-2 (IL-2), were enhanced by SCL administration. The observations of Hoechst 33258 staining demonstrated that SCL was able to induce tumor cell apoptosis. Finally, immunohistochemical analysis revealed that SCL treatment significantly increased Bax expression and decreased Bcl-2 and vascular endothelial growth factor (VEGF) expression of H22 tumor tissues in a dose-dependent manner. Moreover, LC/MS analysis of SCL indicated that it mainly contained lobetyolin and six saponins. Taken all together, the findings in the present study clearly demonstrated that SCL inhibited the H22 tumor growth in vivo at least partly via improving the immune functions, inducing apoptosis and inhibiting angiogenesis. PMID:26426041

Synergy of anti-CD40, CpG and MPL in activation of mouse macrophages

PubMed Central

Shi, Yongyu; Felder, Mildred A.R.; Sondel, Paul M.; Rakhmilevich, Alexander L.

2015-01-01

Activation of macrophages is a prerequisite for their antitumor effects. Several reagents, including agonistic anti-CD40 monoclonal antibody (anti-CD40), CpG oligodeoxynucleotides (CpG) and monophosphoryl lipid A (MPL), can stimulate activation of macrophages. Our previous studies showed synergy between anti-CD40 and CpG and between anti-CD40 and MPL in macrophage activation and antitumor efficacy in mice. In the present study, we asked whether there was synergy among these three reagents. The activation of adherent peritoneal exudate cells (PEC) obtained from mice injected with anti-CD40 and then treated with CpG and/or MPL in vitro was determined by their ability to suppress proliferation of tumor cells and to produce various cytokines and chemokines in vitro. Cell sorting and histology followed by functional testing showed that macrophages were the main cell population in PEC activated by CD40 ligation in vivo. A combination of anti-CD40, CpG or MPL activated PEC to suppress proliferation of B16 cells and produce nitric oxide far greater than the single reagents or any of the double combinations of these reagents. In addition, the combination of all three reagents activated PEC to secrete IL-12, IFN-γ and MCP-1 to a greater degree than any single reagent or any two combined reagents. These results demonstrate that macrophages can be synergistically activated by anti-CD40, CpG and MPL, suggesting that this novel combined approach might be further investigated as potential cancer therapy. PMID:25829245

Synergy of anti-CD40, CpG and MPL in activation of mouse macrophages.

PubMed

Shi, Yongyu; Felder, Mildred A R; Sondel, Paul M; Rakhmilevich, Alexander L

2015-08-01

Activation of macrophages is a prerequisite for their antitumor effects. Several reagents, including agonistic anti-CD40 monoclonal antibody (anti-CD40), CpG oligodeoxynucleotides (CpG) and monophosphoryl lipid A (MPL), can stimulate activation of macrophages. Our previous studies showed synergy between anti-CD40 and CpG and between anti-CD40 and MPL in macrophage activation and antitumor efficacy in mice. In the present study, we asked whether there was synergy among these three reagents. The activation of adherent peritoneal exudate cells (PEC) obtained from mice injected with anti-CD40 and then treated with CpG and/or MPL in vitro was determined by their ability to suppress proliferation of tumor cells and to produce various cytokines and chemokines in vitro. Cell sorting and histology followed by functional testing showed that macrophages were the main cell population in PEC activated by CD40 ligation in vivo. A combination of anti-CD40, CpG or MPL activated PEC to suppress proliferation of B16 cells and produce nitric oxide far greater than the single reagents or any of the double combinations of these reagents. In addition, the combination of all three reagents activated PEC to secrete IL-12, IFN-γ and MCP-1 to a greater degree than any single reagent or any two combined reagents. These results demonstrate that macrophages can be synergistically activated by anti-CD40, CpG and MPL, suggesting that this novel combined approach might be further investigated as potential cancer therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Anti-inflammatory activity of traditional Chinese medicinal herbs.

PubMed

Pan, Min-Hsiung; Chiou, Yi-Shiou; Tsai, Mei-Ling; Ho, Chi-Tang

2011-10-01

Accumulating epidemiological and clinical evidence shows that inflammation is an important risk factor for various human diseases. Thus, suppressing chronic inflammation has the potential to delay, prevent, and control various chronic diseases, including cerebrovascular, cardiovascular, joint, skin, pulmonary, blood, lymph, liver, pancreatic, and intestinal diseases. Various natural products from traditional Chinese medicine (TCM) have been shown to safely suppress proinflammatory pathways and control inflammation-associated disease. In vivo and/or in vitro studies have demonstrated that anti-inflammatory effects of TCM occur by inhibition of the expression of master transcription factors (for example, nuclear factor-κB (NF-κB)), pro-inflammatory cytokines (for example, tumor necrosis factor-α (TNF-α), chemokines (for example, chemokine (C-C motif) ligand (CCL)-24), intercellular adhesion molecule expression and pro-inflammatory mediators (for example, inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2)). However, a handful of review articles have focused on the anti-inflammatory activities of TCM and explore their possible mechanisms of action. In this review, we summarize recent research attempting to identify the anti-inflammatory constituents of TCM and their molecular targets that may create new opportunities for innovation in modern pharmacology.

Prime-boost immunization by both DNA vaccine and oncolytic adenovirus expressing GM-CSF and shRNA of TGF-β2 induces anti-tumor immune activation

PubMed Central

Choi, Hye Jin; Joo, Yeonsoo; Kim, Joo-Hang; Song, Jae J.

2017-01-01

A successful DNA vaccine for the treatment of tumors should break established immune tolerance to tumor antigen. However, due to the relatively low immunogenicity of DNA vaccines, compared to other kinds of vaccines using live virus or protein, a recombinant viral vector was used to enhance humoral and cellular immunity. In the current study, we sought to develop a novel anti-cancer agent as a complex of DNA and oncolytic adenovirus for the treatment of malignant melanoma in the C57BL/6 mouse model. MART1, a human melanoma-specific tumor antigen, was used to induce an increased immune reaction, since a MART1-protective response is required to overcome immune tolerance to the melanoma antigen MelanA. Because GM-CSF is a potent inducer of anti-tumor immunity and TGF-β2 is involved in tumor survival and host immune suppression, mouse GM-CSF (mGM-CSF) and shRNA of mouse TGF-β2 (shmTGF-β2) genes were delivered together with MART1 via oncolytic adenovirus. MART1 plasmid was also used for antigen-priming. To compare the anti-tumor effect of oncolytic adenovirus expressing both mGM-CSF and shmTGF-β2 (AdGshT) with that of oncolytic adenovirus expressing mGM-CSF only (AdG), each virus was intratumorally injected into melanoma-bearing C57BL/6 mice. As a result, mice that received AdGshT showed delayed tumor growth than those that received AdG. Heterologous prime-boost immunization was combined with oncolytic AdGshT and MART1 expression to result in further delayed tumor growth. This regression is likely due to the following 4 combinations: MART1-derived mouse melanoma antigen-specific immune reaction, immune stimulation by mGM-CSF/shmTGF-β2, tumor growth inhibition by shmTGF-β2, and tumor cell-specific lysis via an oncolytic adenovirus. Immune activation was mainly induced by mature tumor-infiltrating dendritic cell (TIDC) and lowered regulatory T cells in tumor-infiltrating lymphocytes (TIL). Taken together, these findings demonstrate that human MART1 induces a mouse

Prime-boost immunization by both DNA vaccine and oncolytic adenovirus expressing GM-CSF and shRNA of TGF-β2 induces anti-tumor immune activation.

PubMed

Kim, So Young; Kang, Dongxu; Choi, Hye Jin; Joo, Yeonsoo; Kim, Joo-Hang; Song, Jae J

2017-02-28

A successful DNA vaccine for the treatment of tumors should break established immune tolerance to tumor antigen. However, due to the relatively low immunogenicity of DNA vaccines, compared to other kinds of vaccines using live virus or protein, a recombinant viral vector was used to enhance humoral and cellular immunity. In the current study, we sought to develop a novel anti-cancer agent as a complex of DNA and oncolytic adenovirus for the treatment of malignant melanoma in the C57BL/6 mouse model. MART1, a human melanoma-specific tumor antigen, was used to induce an increased immune reaction, since a MART1-protective response is required to overcome immune tolerance to the melanoma antigen MelanA. Because GM-CSF is a potent inducer of anti-tumor immunity and TGF-β2 is involved in tumor survival and host immune suppression, mouse GM-CSF (mGM-CSF) and shRNA of mouse TGF-β2 (shmTGF-β2) genes were delivered together with MART1 via oncolytic adenovirus. MART1 plasmid was also used for antigen-priming. To compare the anti-tumor effect of oncolytic adenovirus expressing both mGM-CSF and shmTGF-β2 (AdGshT) with that of oncolytic adenovirus expressing mGM-CSF only (AdG), each virus was intratumorally injected into melanoma-bearing C57BL/6 mice. As a result, mice that received AdGshT showed delayed tumor growth than those that received AdG. Heterologous prime-boost immunization was combined with oncolytic AdGshT and MART1 expression to result in further delayed tumor growth. This regression is likely due to the following 4 combinations: MART1-derived mouse melanoma antigen-specific immune reaction, immune stimulation by mGM-CSF/shmTGF-β2, tumor growth inhibition by shmTGF-β2, and tumor cell-specific lysis via an oncolytic adenovirus. Immune activation was mainly induced by mature tumor-infiltrating dendritic cell (TIDC) and lowered regulatory T cells in tumor-infiltrating lymphocytes (TIL). Taken together, these findings demonstrate that human MART1 induces a mouse

Anti-tumor response induced by immunologically modified carbon nanotubes and laser irradiation using rat mammary tumor model

NASA Astrophysics Data System (ADS)

Acquaviva, Joseph T.; Hasanjee, Aamr M.; Bahavar, Cody F.; Zhou, Fefian; Liu, Hong; Howard, Eric W.; Bullen, Liz C.; Silvy, Ricardo P.; Chen, Wei R.

2015-03-01

Laser immunotherapy (LIT) is being developed as a treatment modality for metastatic cancer which can destroy primary tumors and induce effective systemic anti-tumor responses by using a targeted treatment approach in conjunction with the use of a novel immunoadjuvant, glycated chitosan (GC). In this study, Non-invasive Laser Immunotherapy (NLIT) was used as the primary treatment mode. We incorporated single-walled carbon nanotubes (SWNTs) into the treatment regimen to boost the tumor-killing effect of LIT. SWNTs and GC were conjugated to create a completely novel, immunologically modified carbon nanotube (SWNT-GC). To determine the efficacy of different laser irradiation durations, 5 minutes or 10 minutes, a series of experiments were performed. Rats were inoculated with DMBA-4 cancer cells, a highly aggressive metastatic cancer cell line. Half of the treatment group of rats receiving laser irradiation for 10 minutes survived without primary or metastatic tumors. The treatment group of rats receiving laser irradiation for 5 minutes had no survivors. Thus, Laser+SWNT-GC treatment with 10 minutes of laser irradiation proved to be effective at reducing tumor size and inducing long-term anti-tumor immunity.

Proton pump inhibitors while belonging to the same family of generic drugs show different anti-tumor effect.

PubMed

Lugini, Luana; Federici, Cristina; Borghi, Martina; Azzarito, Tommaso; Marino, Maria Lucia; Cesolini, Albino; Spugnini, Enrico Pierluigi; Fais, Stefano

2016-08-01

Tumor acidity represents a major cause of chemoresistance. Proton pump inhibitors (PPIs) can neutralize tumor acidity, sensitizing cancer cells to chemotherapy. To compare the anti-tumor efficacy of different PPIs in vitro and in vivo. In vitro experiments PPIs anti-tumor efficacy in terms of cell proliferation and cell death/apoptosis/necrosis evaluation were performed. In vivo PPIs efficacy experiments were carried out using melanoma xenograft model in SCID mice. Lansoprazole showed higher anti-tumor effect when compared to the other PPIs. The lansoprazole effect lasted even upon drug removal from the cell culture medium and it was independent from the lipophilicity of the PPIs formulation. These PPIs have shown different anti-tumoral efficacy, and the most effective at low dose was lansoprazole. The possibility to contrast tumor acidity by off-label using PPIs opens a new field of oncology investigation.

Assessment of the in vitro cytotoxicity and in vivo anti-tumor activity of the alcoholic stem bark extract/fractions of Mimusops elengi Linn.

PubMed

Kumar, Harish; Savaliya, Mihir; Biswas, Subhankar; Nayak, Pawan G; Maliyakkal, Naseer; Manjunath Setty, M; Gourishetti, Karthik; Pai, K Sreedhara Ranganath

2016-08-01

Various parts of Mimusops elengi Linn. (Sapotaceae) have been used widely in traditional Indian medicine for the treatment of pain, inflammation and wounds. The study was conducted to explore the use of stem bark of M. elengi on pharmacological grounds and to evaluate the scientific basis of cytotoxic and anti-tumor activity. Extract/fractions were prepared and in vitro cytotoxicity was assessed using SRB assay. Most effective fractions were subjected to fluorescence microscopy based acridine orange/ethidium bromide (AO/EB) and Hoechst 33342 staining to determine apoptosis induction and DNA fragmentation assay. Comet and micronuclei assay were performed to assess genotoxicity. Cell cycle analysis was also performed. In vivo anti-tumor potential was evaluated by Ehrlich ascites carcinoma (EAC) model in mice. The alcoholic stem bark extract of M. elengi along with four fractions showed potential in vitro cytotoxicity in SRB assay. Of these, dichloromethane and ethyl acetate fractions were selected for further studies. The fractions revealed apoptosis inducing potential in AO/EB and Hoechst 33342 staining, which was further confirmed by DNA fragmentation assay. Genotoxic potential was revealed by comet and micronuclei assay. Fractions also exhibited specific cell cycle inhibition in G0/G1 phase. In EAC model, ethyl acetate fraction along with the standard (cisplatin) effectively reduced the increase in body weight compared to control and improved mean survival time. Both fractions were able to restore the altered hematological and biochemical parameters. Hence, M. elengi stem bark may be a possible therapeutic candidate having cytotoxic and anti-tumor potential.

Methanol extract of Xanthium strumarium L. possesses anti-inflammatory and anti-nociceptive activities.

PubMed

Kim, In-Tae; Park, Young-Mi; Won, Jong-Heon; Jung, Hyun-Ju; Park, Hee-Juhn; Choi, Jong-Won; Lee, Kyung-Tae

2005-01-01

As an attempt to identify bioactive natural products with anti-inflammatory activity, we evaluated the effects of the methanol extract of the semen of Xanthium strumarium L. (MEXS) on lipopolysaccharide (LPS)-induced nitric oxide (NO), prostaglandin E2 (PGE2) and tumor necrosis factor-alpha (TNF-alpha) production in RAW 264.7 cells. Our data indicate that MEXS is a potent inhibitor of NO, PGE2 and TNF-alpha production. Consistent with these findings, the expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein and iNOS, COX-2 and TNF-alpha mRNA were down-regulated in a concentration-dependent manner. Furthermore, MEXS inhibited nuclear factor kappa B (NF-kappaB) DNA binding activity and the translocation of NF-kappaB to the nucleus by blocking the degradation of inhibitor of kappa B-alpha (IkappaB-alpha). We further evaluated the anti-inflammatory and anti-nociceptive activities of MEXS in vivo. MEXS (100, 200 mg/kg/d, p.o.) reduced acute paw edema induced by carrageenin in rats, and showed analgesic activities in an acetic acid-induced abdominal constriction test and a hot plate test in mice. Thus, our study suggests that the inhibitions of iNOS, COX-2 expression, and TNF-alpha release by the methanol extract of the semen of Xanthium strumarium L. are achieved by blocking NF-kappaB activation, and that this is also responsible for its anti-inflammatory effects.

The anti-fibrotic agent pirfenidone synergizes with cisplatin in killing tumor cells and cancer-associated fibroblasts.

PubMed

Mediavilla-Varela, Melanie; Boateng, Kingsley; Noyes, David; Antonia, Scott J

2016-03-02

Anti-fibrotic drugs such as pirfenidone have been developed for the treatment of idiopathic pulmonary fibrosis. Because activated fibroblasts in inflammatory conditions have similar characteristics as cancer-associated fibroblasts (CAFs) and CAFs contribute actively to the malignant phenotype, we believe that anti-fibrotic drugs have the potential to be repurposed as anti-cancer drugs. The effects of pirfenidone alone and in combination with cisplatin on human patient-derived CAF cell lines and non-small cell lung cancer (NSCLC) cell lines were examined. The impact on cell death in vitro as well as tumor growth in a mouse model was determined. Annexin V/PI staining and Western blot analysis were used to characterize cell death. Synergy was assessed with the combination index method using Calcusyn software. Pirfenidone alone induced apoptotic cell death in lung CAFs at a high concentration (1.5 mg/mL). However, co-culture in vitro experiments and co-implantation in vivo experiments showed that the combination of low doses of cisplatin (10 μM) and low doses of pirfenidone (0.5 mg/mL), in both CAFs and tumors, lead to increased cell death and decreased tumor progression, respectively. Furthermore, the combination of cisplatin and pirfenidone in NSCLC cells (A549 and H157 cells) leads to increased apoptosis and synergistic cell death. Our studies reveal for the first time that the combination of cisplatin and pirfenidone is active in preclinical models of NSCLC and therefore may be a new therapeutic approach in this disease.

Ferulic acid prevents liver injury and increases the anti-tumor effect of diosbulbin B in vivo *

PubMed Central

Wang, Jun-ming; Sheng, Yu-chen; Ji, Li-li; Wang, Zheng-tao

2014-01-01

The present study is designed to investigate the protection by ferulic acid against the hepatotoxicity induced by diosbulbin B and its possible mechanism, and further observe whether ferulic acid augments diosbulbin B-induced anti-tumor activity. The results show that ferulic acid decreases diosbulbin B-increased serum alanine transaminase/aspartate transaminase (ALT/AST) levels. Ferulic acid also decreases lipid peroxide (LPO) levels which are elevated in diosbulbin B-treated mice. Histological evaluation of the liver demonstrates hydropic degeneration in diosbulbin B-treated mice, while ferulic acid reverses this injury. Moreover, the activities of copper- and zinc-containing superoxide dismutase (CuZn-SOD) and catalase (CAT) are decreased in the livers of diosbulbin B-treated mice, while ferulic acid reverses these decreases. Further results demonstrate that the mRNA expressions of CuZn-SOD and CAT in diosbulbin B-treated mouse liver are significantly decreased, while ferulic acid prevents this decrease. In addition, ferulic acid also augments diosbulbin B-induced tumor growth inhibition compared with diosbulbin B alone. Taken together, the present study shows that ferulic acid prevents diosbulbin B-induced liver injury via ameliorating diosbulbin B-induced liver oxidative stress injury and augments diosbulbin B-induced anti-tumor activity. PMID:24903991

Anti-tumor angiogenesis effect of aminopeptidase inhibitor bestatin against B16-BL6 melanoma cells orthotopically implanted into syngeneic mice.

PubMed

Aozuka, Yasushi; Koizumi, Keiichi; Saitoh, Yurika; Ueda, Yasuji; Sakurai, Hiroaki; Saiki, Ikuo

2004-12-08

We investigated the effect of bestatin, an inhibitor of aminopeptidase N (APN)/CD13 and aminopeptidase B, on the angiogenesis induced by B16-BL6 melanoma cells. Oral administration of bestatin (100-200 mg/kg/day) was found to significantly inhibit the melanoma cell-induced angiogenesis in a mouse dorsal air sac assay. Additionally, anti-APN/CD13 mAb (WM15), which neutralizes the aminopeptidase activity in tumor cells, as well as bestatin inhibited the tube-like formation of human umbilical vein endothelial cells (HUVECs) in vitro. Furthermore, the intraperitoneal administration of bestatin (50-100 mg/kg/day) after the orthotopic implantation of B16-BL6 melanoma cells into mice reduced the number of vessels oriented towards the established primary tumor mass on the dorsal side of mice. These findings suggest that bestatin is an active anti-angiogenic agent that may inhibit tumor angiogenesis in vivo and tube-like formation of endothelial cells in vitro through its inhibition of APN/CD13 activity.

Subchronic toxicity, immunoregulation and anti-breast tumor effect of Nordamnacantal, an anthraquinone extracted from the stems of Morinda citrifolia L.

PubMed

Abu, Nadiah; Zamberi, Nur Rizi; Yeap, Swee Keong; Nordin, Noraini; Mohamad, Nurul Elyani; Romli, Muhammad Firdaus; Rasol, Nurulfazlina Edayah; Subramani, Tamilselvan; Ismail, Nor Hadiani; Alitheen, Noorjahan Banu

2018-01-27

Morinda citrifolia L. that was reported with immunomodulating and cytotoxic effects has been traditionally used to treat multiple illnesses including cancer. An anthraquinone derived from fruits of Morinda citrifolia L., nordamnacanthal, is a promising agent possessing several in vitro biological activities. However, the in vivo anti-tumor effects and the safety profile of nordamnacanthal are yet to be evaluated. In vitro cytotoxicity of nordamnacanthal was tested using MTT, cell cycle and Annexin V/PI assays on human MCF-7 and MDA-MB231 breast cancer cells. Mice were orally fed with nordamnacanthal daily for 28 days for oral subchronic toxicity study. Then, the in vivo anti-tumor effect was evaluated on 4T1 murine cancer cells-challenged mice. Changes of tumor size and immune parameters were evaluated on the untreated and nordamnacanthal treated mice. Nordamnacanthal was found to possess cytotoxic effects on MDA-MB231, MCF-7 and 4T1 cells in vitro. Moreover, based on the cell cycle and Annexin V results, nordamnacanthal managed to induce cell death in both MDA-MB231 and MCF-7 cells. Additionally, no mortality, signs of toxicity and changes of serum liver profile were observed in nordamnacanthal treated mice in the subchronic toxicity study. Furthermore, 50 mg/kg body weight of nordamncanthal successfully delayed the progression of 4T1 tumors in Balb/C mice after 28 days of treatment. Treatment with nordamnacanthal was also able to increase tumor immunity as evidenced by the immunophenotyping of the spleen and YAC-1 cytotoxicity assays. Nordamnacanthal managed to inhibit the growth and induce cell death in MDA-MB231 and MCF-7 cell lines in vitro and cease the tumor progression of 4T1 cells in vivo. Overall, nordamnacanthal holds interesting anti-cancer properties that can be further explored.

Anti-tumor effects of peptide analogs targeting neuropeptide hormone receptors on mouse pheochromocytoma cells.

PubMed

Ziegler, C G; Ullrich, M; Schally, A V; Bergmann, R; Pietzsch, J; Gebauer, L; Gondek, K; Qin, N; Pacak, K; Ehrhart-Bornstein, M; Eisenhofer, G; Bornstein, S R

2013-05-22

Pheochromocytoma is a rare but potentially lethal chromaffin cell tumor with currently no effective treatment. Peptide hormone receptors are frequently overexpressed on endocrine tumor cells and can be specifically targeted by various anti-tumor peptide analogs. The present study carried out on mouse pheochromocytoma cells (MPCs) and a more aggressive mouse tumor tissue-derived (MTT) cell line revealed that these cells are characterized by pronounced expression of the somatostatin receptor 2 (sst2), growth hormone-releasing hormone (GHRH) receptor and the luteinizing hormone-releasing hormone (LHRH) receptor. We further demonstrated significant anti-tumor effects mediated by cytotoxic somatostatin analogs, AN-162 and AN-238, by LHRH antagonist, Cetrorelix, by the cytotoxic LHRH analog, AN-152, and by recently developed GHRH antagonist, MIA-602, on MPC and for AN-152 and MIA-602 on MTT cells. Studies of novel anti-tumor compounds on these mouse cell lines serve as an important basis for mouse models of metastatic pheochromocytoma, which we are currently establishing. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Drug insight: Anti-tumor necrosis factor therapy for inflammatory arthropathies during reproduction, pregnancy and lactation.

PubMed

Skomsvoll, Johan F; Wallenius, Marianne; Koksvik, Hege S; Rødevand, Erik; Salvesen, Kjell A; Spigset, Olav; Kvien, Tore K

2007-03-01

Tumor necrosis factor (TNF) antagonists are widely used to reduce disease activity and joint damage, and to improve health-related quality of life in patients suffering from rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis. To date, no increased risk of embryotoxicity or teratogenicity, or adverse pregnancy outcome (such as birth defects, premature birth, and low birth weight) has been reported in patients with inflammatory arthropathies treated with anti-TNF therapy, compared with the general population. However, the available data are limited, and methotrexate, which is commonly used in combination with anti-TNF drugs, is teratogenic. Until more data are available, no firm conclusions can be reached regarding the safety of anti-TNF therapy in pregnancy. Nevertheless, in selected cases where there is high disease activity, anti-TNF therapy might be recommended, depending on the results of individual risk-benefit analyses. Fully informed consent from the mother is needed in such cases. Anti-TNF agents are not usually used during lactation, although the risk of toxicity is probably negligible.

Establishment of anti-tumor memory in humans using in vitro-educated CD8+ T cells

PubMed Central

Butler, Marcus O.; Friedlander, Philip; Milstein, Matthew I.; Mooney, Mary M.; Metzler, Genita; Murray, Andrew P.; Tanaka, Makito; Berezovskaya, Alla; Imataki, Osamu; Drury, Linda; Brennan, Lisa; Flavin, Marisa; Neuberg, Donna; Stevenson, Kristen; Lawrence, Donald; Hodi, F. Stephen; Velazquez, Elsa F.; Jaklitsch, Michael T.; Russell, Sara E.; Mihm, Martin; Nadler, Lee M.; Hirano, Naoto

2013-01-01

While advanced stage melanoma patients have a median survival of less than a year, adoptive T cell therapy can induce durable clinical responses in some patients. Successful adoptive T cell therapy to treat cancer requires engraftment of anti-tumor T lymphocytes that not only retain specificity and function in vivo but also display an intrinsic capacity to survive. To date, adoptively transferred anti-tumor CD8+ T lymphocytes (CTL) have had limited life spans unless the host has been manipulated. To generate CTL that possess an intrinsic capacity to persist in vivo, we developed a human artificial antigen presenting cell system that can educate anti-tumor CTL to acquire both a central memory and effector memory phenotype as well as the capacity to survive in culture for prolonged periods of time. In the present report, we examined whether anti-tumor CTL generated using this system could function and persist in patients. Here, we showed that MART1-specific CTL, educated and expanded using our artificial antigen presenting cell system, could survive for prolonged periods in advanced stage melanoma patients without previous conditioning or cytokine treatment. Moreover, these CTL trafficked to the tumor, mediated biological and clinical responses, and established anti-tumor immunologic memory. Therefore, this approach may broaden the availability of adoptive cell therapy to patients both alone and in combination with other therapeutic modalities. PMID:21525398

Analgesic, anti-inflammatory and anti-pyretic activities of Caesalpinia decapetala

PubMed Central

Parveen, Amna; Sajid Hamid Akash, Muhammad; Rehman, Kanwal; Mahmood, Qaisar; Qadir, Muhammad Imran

2014-01-01

Introduction: In many pathological conditions, pain, inflammation and fever are interdependent to each other. Due to the use of synthetic drugs, many unwanted effects usually appear. Various studies have been conducted on Caesalpinia decapetala (C. decapetala) to evaluate its effects in the treatment of various diseases but no sufficient scientific literature is available online to prove its analgesic, anti-inflammatory and anti-pyretic activities. Methods: The analgesic, anti-inflammatory and anti-pyretic activities of 70% aqueous methanolic and n-hexane extracts of C. decapetala was evaluated using Swiss albino mice (20-30 g). Results: The results showed that aqueous methanolic extract of C. decapetala at the dose of 100 mg/kg exhibited significant (p< 0.05) activities in various pain models including acetic acid-induced writhing (18.4 ± 0.53), formalin-induced licking (275 ± 4.18) and hot plate method (2.3 ± 0.0328); whereas,  n-hexane extract showed its effects in acetic acid-induced writhing (20 ± 0.31), formalin-induced licking (293 ± 1.20) and hot plate method (2.224 ± 0.029) compared to the effects observed in control group animals. Similarly, the aqueous methanolic extract of C. decapetala after 2 h of treatment exhibited more significant anti-inflammatory (0.66 ± 0.06) and anti-pyretic (38.81 ± 0.05) activities compared to the control group animals. Conclusion: From the findings of our present study, we concluded that the aqueous methanolic extract of C. decapetala has stronger analgesic, anti-inflammatory and anti-pyretic effects than its n-hexane extract. Further studies are required to investigate the active constituents of C. decapetala that exhibit analgesic, anti-inflammatory and anti-pyretic activities. PMID:24790898

Up-regulation of tumor suppressor genes by exogenous dhC16-Cer contributes to its anti-cancer activity in primary effusion lymphoma

PubMed Central

Lin, Zhen; Zabaleta, Jovanny; Dai, Lu; Qin, Zhiqiang

2017-01-01

Primary effusion lymphoma (PEL) is a rare and highly aggressive B-cell malignancy with Kaposi's sarcoma-associated herpesvirus (KSHV) infection, while lack of effective therapies. Our recent data indicated that targeting the sphingolipid metabolism by either sphingosine kinase inhibitor or exogenous ceramide species induces PEL cell apoptosis and suppresses tumor progression in vivo. However, the underlying mechanisms for these exogenous ceramides “killing” PEL cells remain largely unknown. Based on the microarray analysis, we found that exogenous dhC16-Cer treatment affected the expression of many cellular genes with important functions within PEL cells such as regulation of cell cycle, cell survival/proliferation, and apoptosis/anti-apoptosis. Interestingly, we found that a subset of tumor suppressor genes (TSGs) was up-regulated from dhC16-Cer treated PEL cells. One of these elevated TSGs, Thrombospondin-1 (THBS1) was required for dhC16-Cer induced PEL cell cycle arrest. Moreover, dhC16-Cer up-regulation of THBS1 was through the suppression of multiple KSHV microRNAs expression. Our data demonstrate that exogenous ceramides display anti-cancer activities for PEL through regulation of both host and oncogenic virus factors. PMID:28146424

Up-regulation of tumor suppressor genes by exogenous dhC16-Cer contributes to its anti-cancer activity in primary effusion lymphoma.

PubMed

Cao, Yueyu; Qiao, Jing; Lin, Zhen; Zabaleta, Jovanny; Dai, Lu; Qin, Zhiqiang

2017-02-28

Primary effusion lymphoma (PEL) is a rare and highly aggressive B-cell malignancy with Kaposi's sarcoma-associated herpesvirus (KSHV) infection, while lack of effective therapies. Our recent data indicated that targeting the sphingolipid metabolism by either sphingosine kinase inhibitor or exogenous ceramide species induces PEL cell apoptosis and suppresses tumor progression in vivo. However, the underlying mechanisms for these exogenous ceramides "killing" PEL cells remain largely unknown. Based on the microarray analysis, we found that exogenous dhC16-Cer treatment affected the expression of many cellular genes with important functions within PEL cells such as regulation of cell cycle, cell survival/proliferation, and apoptosis/anti-apoptosis. Interestingly, we found that a subset of tumor suppressor genes (TSGs) was up-regulated from dhC16-Cer treated PEL cells. One of these elevated TSGs, Thrombospondin-1 (THBS1) was required for dhC16-Cer induced PEL cell cycle arrest. Moreover, dhC16-Cer up-regulation of THBS1 was through the suppression of multiple KSHV microRNAs expression. Our data demonstrate that exogenous ceramides display anti-cancer activities for PEL through regulation of both host and oncogenic virus factors.

Collaboration between tumor-specific CD4+ T cells and B cells in anti-cancer immunity.

PubMed

Guy, Thomas V; Terry, Alexandra M; Bolton, Holly A; Hancock, David G; Zhu, Erhua; Brink, Robert; McGuire, Helen M; Shklovskaya, Elena; Fazekas de St. Groth, Barbara

2016-05-24

The role of B cells and antibodies in anti-tumor immunity is controversial, with both positive and negative effects reported in animal models and clinical studies. We developed a murine B16.F10 melanoma model to study the effects of collaboration between tumor-specific CD4+ T cells and B cells on tumor control. By incorporating T cell receptor transgenic T cells and B cell receptor isotype switching B cells, we were able to track the responses of tumor-reactive T and B cells and the development of anti-tumor antibodies in vivo. In the presence of tumor-specific B cells, the number of tumor-reactive CD4+ T cells was reduced in lymphoid tissues and the tumor itself, and this correlated with poor tumor control. B cells had little effect on the Th1 bias of the CD4+ T cell response, and the number of induced FoxP3+ regulatory cells (iTregs) generated from within the original naive CD4+ T cell inoculum was unrelated to the degree of B cell expansion. In response to CD4+ T cell help, B cells produced a range of isotype-switched anti-tumor antibodies, principally IgG1, IgG2a/c and IgG2b. In the absence of CD4+ T cells, B cells responded to agonistic anti-CD40 administration by switching to production of IgG2a/c and, to a lesser extent, IgG1, IgG3, IgA and IgE, which reduced the number of lung metastases after i.v. tumor inoculation but had no effect on the growth of subcutaneous tumors.

Type I Interferons as Stimulators of DC-Mediated Cross-Priming: Impact on Anti-Tumor Response.

PubMed

Schiavoni, Giovanna; Mattei, Fabrizio; Gabriele, Lucia

2013-12-25

Induction of potent tumor-specific cytotoxic T-cell responses is a fundamental objective in anticancer therapeutic strategies. This event requires that antigen-presenting cells present tumor-associated antigens (Ag) on their MHC class-I molecule, in a process termed cross-presentation. Dendritic cells (DC) are particularly keen on this task and can induce the cross-priming of CD8(+) T cells, when exposed to danger or inflammatory signals that stimulate their activation. Type I interferons (IFN-I), a family of long-known immunostimulatory cytokines, have been proven to produce optimal activation signal for DC-induced cross-priming. Recent in vitro and in vivo evidences have suggested that IFN-I-stimulated cross-priming by DC against tumor-associated Ag is a key mechanism for cancer immunosurveillance and may be usefully exploited to boost anti-tumor CD8(+) T-cell responses. Here, we will review the cross-presentation properties of different DC subsets, with special focus on cell-associated and tumor Ag, and discuss how IFN-I can modify this function, with the aim of identifying more specific and effective strategies for improving anticancer responses.

Withaferin A, a natural compound with anti-tumor activity, is a potent inhibitor of transcription factor C/EBPβ.

PubMed

Falkenberg, Kim D; Jakobs, Anke; Matern, Julian C; Dörner, Wolfgang; Uttarkar, Sagar; Trentmann, Amke; Steinmann, Simone; Coulibaly, Anna; Schomburg, Caroline; Mootz, Henning D; Schmidt, Thomas J; Klempnauer, Karl-Heinz

2017-07-01

Recent work has shown that deregulation of the transcription factor Myb contributes to the development of leukemia and several other human cancers, making Myb and its cooperation partners attractive targets for drug development. By employing a myeloid Myb-reporter cell line we have identified Withaferin A (WFA), a natural compound that exhibits anti-tumor activities, as an inhibitor of Myb-dependent transcription. Analysis of the inhibitory mechanism of WFA showed that WFA is a significantly more potent inhibitor of C/EBPβ, a transcription factor cooperating with Myb in myeloid cells, than of Myb itself. We show that WFA covalently modifies specific cysteine residues of C/EBPβ, resulting in the disruption of the interaction of C/EBPβ with the co-activator p300. Our work identifies C/EBPβ as a novel direct target of WFA and highlights the role of p300 as a crucial co-activator of C/EBPβ. The finding that WFA is a potent inhibitor of C/EBPβ suggests that inhibition of C/EBPβ might contribute to the biological activities of WFA. Copyright © 2017 Elsevier B.V. All rights reserved.

Novel histone deacetylase inhibitor N25 exerts anti-tumor effects and induces autophagy in human glioma cells by inhibiting HDAC3

PubMed Central

Sun, Xin-Yuan; Qu, Yue; Ni, An-Ran; Wang, Gui-Xiang; Huang, Wei-Bin; Chen, Zhong-Ping; Lv, Zhu-Fen; Zhang, Song; Lindsay, Holly; Zhao, Sibo; Li, Xiao-Nan; Feng, Bing-Hong

2017-01-01

N25, a novel histone deacetylase inhibitor, was created through structural modification of suberoylanilide hydroxamic acid. To evaluate the anti-tumor activity of N25 and clarify its molecular mechanism of inducing autophagy in glioma cells, we investigated its in vitro anti-proliferative effect and in vivo anticancer effect. Moreover, we detected whether N25 induces autophagy in glioma cells by transmission electron microscope and analyzed the protein expression level of HDAC3, Tip60, LC3 in glioma samples by western blot. We additionally analyzed the protein expression level of HDAC3, Tip60, ULK1 (Atg1), and Beclin-1 (Atg6) after treatment with N25 in glioma cells. Our results showed that the anti-tumor activity of N25 in glioma cells is slightly stronger than SAHA both in vitro and in vivo. We found that N25 induced autophagy, and HDAC3 was significantly elevated and Tip60 and LC3 significantly decreased in glioma samples compared with normal brain tissues. Nevertheless, N25 inhibited HDAC3 and up-regulated the protein expression of Tip60, ULK1 (Atg1), and Beclin-1 (Atg6) after treatment of glioma cells with N25. In conclusion, these data suggest that N25 has striking anti-tumor activity in part due to inhibition of HDAC3. Additionally, N25 may induce autophagy through inhibiting HDAC3. PMID:29088860

A phase 1/2 dose-finding, safety, and activity study of cabazitaxel in pediatric patients with refractory solid tumors including tumors of the central nervous system.

PubMed

Manley, Peter E; Trippett, Tanya; Smith, Amy A; Macy, Margaret E; Leary, Sarah E S; Boklan, Jessica; Cohen, Kenneth J; Goldman, Stewart; Kilburn, Lindsay B; Dhall, Girish; Devin, Jeanne; Herzog, Cynthia E; Partap, Sonia; Fauchet, Floris; Badreddine, Emmy; Bernard, John P; Chi, Susan N

2018-05-11

This phase 1/2 study (NCT01751308) evaluated cabazitaxel in pediatric patients. Phase 1 determined the maximum tolerated dose (MTD) in patients with recurrent/refractory solid tumors, including central nervous system (CNS) tumors. Phase 2 evaluated activity in pediatric recurrent high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). In phase 1, a 3 + 3 dose-escalation study design was followed. Cabazitaxel was administered at a starting dose of 20 mg/m 2 . Dose-limiting toxicities (DLTs) during cycle 1 were assessed to determine the MTD. Tumor response and cabazitaxel pharmacokinetics were also assessed. In phase 2, patients received cabazitaxel at the MTD determined in phase 1. Tumor responses were assessed every 9 weeks (modified Response Assessment in Neuro-oncology criteria). Progression-free survival and cabazitaxel pharmacokinetics were evaluated, and overall survival was estimated. In phase 1, 23 patients were treated, including 19 with CNS tumors. One patient had a partial response; five had stable disease for >3 cycles. Common adverse events included fatigue, diarrhea, nausea and vomiting, febrile neutropenia, and hypersensitivity reactions. Two of three DLTs (febrile neutropenia) occurred with a dose of 35 mg/m 2 ; the MTD was 30 mg/m 2 . Slightly higher cabazitaxel clearance was observed compared with adult trials. In phase 2, 16 patients (eight HGG and eight DIPG) were enrolled; 11 were evaluable for response and five withdrew (three due to anaphylaxis). All 11 patients progressed within four cycles. No responses were observed; the study was stopped due to futility. The safety profile of cabazitaxel was consistent with previous studies. The MTD (30 mg/m 2 ) was higher than the adult MTD. Cabazitaxel did not demonstrate activity in recurrent/refractory HGG or DIPG. © 2018 Wiley Periodicals, Inc.

Anti-proliferative and anti-secretory effects of everolimus on human pancreatic neuroendocrine tumors primary cultures: is there any benefit from combination with somatostatin analogs?

PubMed

Mohamed, Amira; Romano, David; Saveanu, Alexandru; Roche, Catherine; Albertelli, Manuela; Barbieri, Federica; Brue, Thierry; Niccoli, Patricia; Delpero, Jean-Robert; Garcia, Stephane; Ferone, Diego; Florio, Tullio; Moutardier, Vincent; Poizat, Flora; Barlier, Anne; Gerard, Corinne

2017-06-20

Therapeutic management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is challenging. The mammalian target of rapamycin (mTOR) inhibitor everolimus recently obtained approval from the Food and Drug Administration for the treatment of patients with advanced pancreatic neuroendocrine tumors (pNETs). Despite its promising antitumor efficacy observed in cell lines, clinical benefit for patients is unsatisfactory. The limited therapeutic potential of everolimus in cancer cells has been attributed to Akt activation due to feedback loops relief following mTOR inhibition. Combined inhibition of Akt might then improve everolimus antitumoral effect. In this regard, the somatostatin analog (SSA) octreotide has been shown to repress the PI3K/Akt pathway in some tumor cell lines. Moreover, SSAs are well tolerated and routinely used to reduce symptoms caused by peptide release in patients carrying functional GEP-NETs. We have recently established and characterized primary cultures of human pNETs and demonstrated the anti-proliferative effects of both octreotide and pasireotide. In this study, we aim at determining the antitumor efficacy of everolimus alone or in combination with the SSAs octreotide and pasireotide in primary cultures of pNETs. Everolimus reduced both Chromogranin A secretion and cell viability and upregulated Akt activity in single treatment. Its anti-proliferative and anti-secretory efficacy was not improved combined with the SSAs. Both SSAs did not overcome everolimus-induced Akt upregulation. Furthermore, caspase-dependent apoptosis induced by SSAs was lost in combined treatments. These molecular events provide the first evidence supporting the lack of marked benefit in patients co-treated with everolimus and SSA.

Anti-proliferative and anti-secretory effects of everolimus on human pancreatic neuroendocrine tumors primary cultures: is there any benefit from combination with somatostatin analogs?

PubMed Central

Mohamed, Amira; Romano, David; Saveanu, Alexandru; Roche, Catherine; Albertelli, Manuela; Barbieri, Federica; Brue, Thierry; Niccoli, Patricia; Delpero, Jean-Robert; Garcia, Stephane; Ferone, Diego; Florio, Tullio; Moutardier, Vincent; Gerard, Corinne

2017-01-01

Therapeutic management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is challenging. The mammalian target of rapamycin (mTOR) inhibitor everolimus recently obtained approval from the Food and Drug Administration for the treatment of patients with advanced pancreatic neuroendocrine tumors (pNETs). Despite its promising antitumor efficacy observed in cell lines, clinical benefit for patients is unsatisfactory. The limited therapeutic potential of everolimus in cancer cells has been attributed to Akt activation due to feedback loops relief following mTOR inhibition. Combined inhibition of Akt might then improve everolimus antitumoral effect. In this regard, the somatostatin analog (SSA) octreotide has been shown to repress the PI3K/Akt pathway in some tumor cell lines. Moreover, SSAs are well tolerated and routinely used to reduce symptoms caused by peptide release in patients carrying functional GEP-NETs. We have recently established and characterized primary cultures of human pNETs and demonstrated the anti-proliferative effects of both octreotide and pasireotide. In this study, we aim at determining the antitumor efficacy of everolimus alone or in combination with the SSAs octreotide and pasireotide in primary cultures of pNETs. Everolimus reduced both Chromogranin A secretion and cell viability and upregulated Akt activity in single treatment. Its anti-proliferative and anti-secretory efficacy was not improved combined with the SSAs. Both SSAs did not overcome everolimus-induced Akt upregulation. Furthermore, caspase-dependent apoptosis induced by SSAs was lost in combined treatments. These molecular events provide the first evidence supporting the lack of marked benefit in patients co-treated with everolimus and SSA. PMID:28454119

Parthenolide, a sesquiterpene lactone, expresses multiple anti-cancer and anti-inflammatory activities.

PubMed

Mathema, Vivek Bhakta; Koh, Young-Sang; Thakuri, Balkrishna Chand; Sillanpää, Mika

2012-04-01

Parthenolide, a naturally occurring sesquiterpene lactone derived from feverfew (Tanacetum parthenium), exhibits exceptional anti-cancer and anti-inflammatory properties, making it a prominent candidate for further studies and drug development. In this review, we briefly investigate molecular events and cell-specific activities of this chemical in relation to cytochrome c, nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), signal transduction and activation of transcription (STAT), reactive oxygen species (ROS), TCP, HDACs, microtubules, and inflammasomes. This paper reports that parthenolide shows strong NF-κB- and STAT-inhibition-mediated transcriptional suppression of pro-apoptotic genes. This compound acts both at the transcriptional level and by direct inhibition of associated kinases (IKK-β). Similarly, this review discusses parthenolide-induced ROS-mediated apoptosis of tumor cells via the intrinsic apoptotic signaling pathway. The unique ability of this compound to not harm normal cells but at the same time induce sensitization to extrinsic as well as intrinsic apoptosis signaling in cancer cells provides an important, novel therapeutic strategy for treatment of cancer and inflammation-related disorders.

BPIC: A novel anti-tumor lead capable of inhibiting inflammation and scavenging free radicals.

PubMed

Li, Shan; Wang, Yuji; Zhao, Ming; Wu, Jianhui; Peng, Shiqi

2015-03-01

Inflammation has a critical role in the tumor progression, free radical damage can worse the status of patients in cancer condition. The anti-cancer agents capable of inhibiting inflammation and scavenging free radicals attract a lot of our interest. Aimed at the discovery of such anti-tumor agent, a novel intercalator, benzyl 1-[4-hydroxy-3-(methoxycarbonyl)-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate (BPIC) was presented. The docking investigation of BPIC and doxorubicin towards the DNA (PDB ID: 1NAB) gave equal score and similar feature. The anti-proliferation assay of 8 cancer cells identified S180 cells had equal sensitivity to BPIC and doxorubicin. The anti-tumor assay defined the efficacy of BPIC been 2 folds higher than that of doxorubicin. At 1μmol/kg of dose BPIC effectively inhibited xylene-induced ear edema and decreased the plasma TNF-α and IL-8 of the mice. BPIC scavenged ∙OH, ∙O2(-) and NO free radicals in a concentration dependent manner and NO free radicals had the highest sensitivity. BPIC could be a novel anti-tumor lead capable of simultaneously inhibiting inflammation and scavenging free radicals. Copyright © 2015 Elsevier Ltd. All rights reserved.

Triterpenoids Amplify Anti-Tumoral Effects of Mistletoe Extracts on Murine B16.F10 Melanoma In Vivo

PubMed Central

Strüh, Christian M.; Jäger, Sebastian; Kersten, Astrid; Schempp, Christoph M.; Scheffler, Armin; Martin, Stefan F.

2013-01-01

Purpose Mistletoe extracts are often used in complementary cancer therapy although the efficacy of that therapy is controversially discussed. Approved mistletoe extracts contain mainly water soluble compounds of the mistletoe plant, i.e. mistletoe lectins. However, mistletoe also contains water-insoluble triterpenoids (mainly oleanolic acid) that have anti-tumorigenic effects. To overcome their loss in watery extracts we have solubilized mistletoe triterpenoids with cyclodextrins, thus making them available for in vivo cancer experiments. Experimental design B16.F10 subcutaneous melanoma bearing C57BL/6 mice were treated with new mistletoe extracts containing both water soluble compounds and solubilized triterpenoids. Tumor growth and survival was monitored. In addition, histological examinations of the tumor material and tumor surrounding tissue were performed. Results Addition of solubilized triterpenoids increased the anti-tumor effects of the mistletoe extracts, resulting in reduced tumor growth and prolonged survival of the mice. Histological examination of the treated tumors showed mainly tumor necrosis and some apoptotic cells with active caspase-3 and TUNEL staining. A significant decrease of CD31-positive tumor blood vessels was observed after treatment with solubilized triterpenoids and different mistletoe extracts. Conclusion We conclude that the addition of solubilized mistletoe triterpenoids to conventional mistletoe extracts improves the efficacy of mistletoe treatment and may represent a novel treatment option for malignant melanoma. PMID:23614029

Risk of Lymphoma in Patients With Inflammatory Bowel Disease Treated With Anti-Tumor Necrosis Factor Alpha Agents: A Systematic Review and Meta-analysis.

PubMed

Yang, Chen; Huang, Junlin; Huang, Xiaowen; Huang, Shaozhuo; Cheng, Jiaxin; Liao, Weixin; Chen, Xuewen; Wang, Xueyi; Dai, Shixue

2018-05-12

The association between anti-tumor necrosis factor alpha agents and the risk of lymphoma in patients with inflammatory bowel disease has already been sufficiently reported. However, the results of these studies are inconsistent. Hence, this analysis was conducted to investigate whether anti-tumor necrosis factor alpha agents can increase the risk of lymphoma in inflammatory bowel disease patients. MEDLINE, EMBASE and the Cochrane Library were searched to identify relevant studies which evaluated the risk of lymphoma in inflammatory bowel disease patients treated with anti-tumor necrosis factor alpha agents. A random-effects meta-analysis was performed to calculate the pooled incidence rate ratios as well as risk ratios. Twelve studies comprising 285811 participants were included. The result showed that there was no significantly increased risk of lymphoma between anti-tumor necrosis factor alpha agents exposed and anti-tumor necrosis factor alpha agents unexposed groups (random effects: incidence rate ratio [IRR], 1.43 95%CI, 0.91-2.25, p= 0.116; random effects: risk ratio [RR], 0.83 95%CI, 0.47-1.48, p=0.534). However, monotherapy of anti-tumor necrosis factor alpha agents (random effects: IRR=1.65, 95%CI, 1.16-2.35; p=0.006; random effects: RR=1.00, 95%CI, 0.39-2.59; p=0.996) or combination therapy (random effects: IRR=3.36, 95%CI, 2.23-5.05; p< 0.001; random effects: RR=1.90, 95%CI, 0.66-5.44; p=0.233) can significantly increase the risk of lymphoma. Exposition of anti-tumor necrosis factor alpha agents in patients with inflammatory bowel disease is not associated with a higher risk of lymphoma. Combination therapy and anti-tumor necrosis factor alpha agents monotherapy can significantly increase the risk of lymphoma in patients with inflammatory bowel disease.

A dimeric form of a small-sized protein binder exhibits enhanced anti-tumor activity through prolonged blood circulation.

PubMed

Kim, Tae Yoon; Seo, Hyo-Deok; Lee, Joong-Jae; Kang, Jung Ae; Kim, Woo Sik; Kim, Hye-Min; Song, Ha-Yeon; Park, Ji Min; Lee, Dong-Eun; Kim, Hak-Sung

2018-06-10

Small-sized non-antibody scaffolds have attracted considerable interest as alternatives to immunoglobulin antibodies. However, their short half-life is considered a drawback in the development of therapeutic agents. Here we demonstrate that a homo-dimeric form of a repebody enhances the anti-tumor activity than a monomeric form through prolonged blood circulation. Spytag and spycatcher were genetically fused to the C-terminus of a respective human IL-6-specific repebody, and the resulting two repebody constructs were mixed at an equimolar ratio to produce a homo-dimeric form through interaction between spytag and spycatcher. The homo-dimeric repebody was detected as a single band in the SDS-PAGE analysis with an expected molecular size (78 kDa), showing high stability and homogeneity. The dimeric repebody was shown to simultaneously accommodate two hIL-6 molecules, and its binding affinity for hIL-6 was estimated to be comparable to a monomeric repebody. The serum concentration of the dimeric repebody was observed to be about 5.5 times higher than a monomeric repebody, consequently leading to considerably higher tumor suppression effect in human tumor xenograft mice. The present approach can be effectively used for prolonging the blood half-life of small-sized protein binders, resulting in enhanced therapeutic efficacy. Copyright © 2018 Elsevier B.V. All rights reserved.

Anti-Fas Antibody Conjugated Nanoparticles Enhancing the Antitumor Effect of Camptothecin by Activating the Fas-FasL Apoptotic Pathway.

PubMed

Yu, Hongliang; He, Jian; Lu, Qian; Huo, Da; Yuan, Shanmei; Zhou, Zhengyang; Xu, Peipei; Hu, Yong

2016-11-09

Emerging evidence suggest that the introduction of Fas ligand (FasL) can enhance the Fas-dependent apoptosis and induce durable immune responses against tumor. However, selective triggering of apoptosis in tumor cells while sparing normal cells remains a great challenge for the application of FasL-based therapeutic strategies. Herein, smart nanoparticles (NPs) with a sandwich structure were fabricated. These NPs consist of a matrix metalloproteinase (MMP) cleavable PEG outer layer, an anti-Fas antibody middle layer, and a camptothecin (CPT)-loaded inner core. They could accumulate at a tumor site by the enhanced permeability and retention (EPR) effect. The removable PEG layer protects the cytotoxic anti-Fas antibody from premature contact with normal tissues, thus avoiding the unexpected lethal side effect before they reach the tumor site. Due to the high level of MMP expressed by tumor cells inside the tumor tissue, these NPs would shed their PEG layers, resulting in the exposure of anti-Fas antibody to bind the Fas receptor and triggering the apoptosis of tumor cells. Results of Western blot confirmed that these NPs could mimic the function of activated cytotoxic lymphocyte (CTL) to activate the Fas-FasL apoptosis pathway of tumor cells. With the aid of CPT payload, these anti-Fas antibody conjugated NPs achieved a high tumor inhibition in the B16 allograft tumor animal model. The design of these NPs provides a method for delivering cytotoxic ligand to targeting tissue, which may be valuable in cancer therapy.

Ganoderma lucidum exerts anti-tumor effects on ovarian cancer cells and enhances their sensitivity to cisplatin.

PubMed

Zhao, Sufen; Ye, Gang; Fu, Guodong; Cheng, Jian-Xin; Yang, Burton B; Peng, Chun

2011-05-01

Ganoderma lucidum is a herbal mushroom known to have many health benefits, including the inhibition of tumor cell growth. However, the effect of Ganoderma lucidum on epithelial ovarian cancer (EOC), the most fatal gynecological malignancy, has not yet been reported. In this study, we determined whether Ganoderma lucidum regulates EOC cell activity. Using several cell lines derived from EOC, we found that Ganoderma lucidum strongly decreased cell numbers in a dose-dependent manner. Ganoderma lucidum also inhibited colony formation, cell migration and spheroid formation. In particular, Ganoderma lucidum was effective in inhibiting cell growth in both chemosensitive and chemoresistant cells and the treatment with Ganoderma lucidum significantly enhanced the effect of cisplatin on EOC cells. Furthermore, Ganoderma lucidum induced cell cycle arrest at the G2/M phase and also induced apoptosis by activating caspase 3. Finally, Ganoderma lucidum increased p53 but inhibited Akt expression. Taken together, these findings suggest that Ganoderma lucidum exerts multiple anti-tumor effects on ovarian cancer cells and can enhance the sensitivity of EOC cells to cisplatin.

Drug Delivery Systems For Anti-Cancer Active Complexes of Some Coinage Metals.

PubMed

Zhang, Ming; Saint-Germain, Camille; He, Guiling; Sun, Raymond Wai-Yin

2018-02-12

Although cisplatin and a number of platinum complexes have widely been used for the treatment of neoplasia, patients receiving these treatments have frequently suffered from their severe toxic side effects, the development of resistance with consequent relapse. In the recent decades, numerous complexes of coinage metals including that of gold, copper and silver have been reported to display promising in vitro and/or in vivo anti-cancer activities as well as potent activities towards cisplatin-resistant tumors. Nevertheless, the medical development of these metal complexes has been hampered by their instability in aqueous solutions and the nonspecific binding in biological systems. One of the approaches to overcome these problems is to design and develop adequate drug delivery systems (DDSs) for the transport of these complexes. By functionalization, encapsulation or formulation of the metal complexes, several types of DDSs have been reported to improve the desired pharmacological profile of the metal complexes, improving their overall stability, bioavailability, anti-cancer activity and reducing their toxicity towards normal cells. In this review, we summarized the recent findings for different DDSs for various anti- cancer active complexes of some coinage metals. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Adoptive transfer of natural killer cells promotes the anti-tumor efficacy of T cells.

PubMed

Goding, Stephen R; Yu, Shaohong; Bailey, Lisa M; Lotze, Michael T; Basse, Per H

2017-04-01

The density of NK cells in tumors correlates positively with prognosis in many types of cancers. The average number of infiltrating NK cells is, however, quite modest (approximately 30 NK cells/sq.mm), even in tumors deemed to have a "high" density of infiltrating NK cells. It is unclear how such low numbers of tumor-infiltrating NK cells can influence outcome. Here, we used ovalbumin-expressing tumor cell lines and TCR transgenic, OVA-specific cytotoxic T lymphocytes (OT-I-CTLs) to determine whether the simultaneous attack by anti-tumor CTLs and IL-2-activated NK (A-NK) cells synergistically increases the overall tumor cell kill and whether upregulation of tumor MHC class-I by NK cell-derived interferon-gamma (IFNγ) improves tumor-recognition and kill by anti-tumor CTLs. At equal E:T ratios, A-NK cells killed OVA-expressing tumor cells better than OT-I-CTLs. The cytotoxicity against OVA-expressing tumor cells increased by combining OT-I-CTLs and A-NK cells, but the increase was additive rather than synergistic. A-NK cells adenovirally-transduced to produce IL-12 (A-NK IL-12 ) produced high amounts of IFNγ. The addition of a low number of A-NK IL-12 cells to OT-I-CTLs resulted in a synergistic, albeit modest, increase in overall cytotoxicity. Pre-treatment of tumor cells with NK cell-conditioned medium increased tumor MHC expression and sensitivity to CTL-mediated killing. Pre-treatment of CTLs with NK cell-conditioned medium had no effect on CTL cytotoxicity. In vivo, MHC class-I expression by OVA-expressing B16 melanoma lung metastases increased significantly within 24-48h after adoptive transfer of A-NK IL-12 cells. OT-I-CTLs and A-NK IL-12 cells localized selectively and equally well into OVA-expressing B16 lung metastases and treatment of mice bearing 7-days-old OVA-B16 lung metastases with both A-NK IL-12 cells and OT-I-CTLs lead to a significant prolongation of survival. Thus, an important function of tumor-infiltrating NK cells may be to increase tumor

Anti-inflammatory and anti-granuloma activity of Berberis aristata DC. in experimental models of inflammation

PubMed Central

Kumar, Rohit; Gupta, Yogendra Kumar; Singh, Surender

2016-01-01

Objective: Berberis aristata (Berberidaceae) is an important medicinal plant used in traditional system of medicine for the treatment of rheumatoid arthritis and other inflammatory disorders. The aim of the present study is to scientifically validate the traditional use of BA in the treatment of inflammatory disorders. Materials and Methods: Anti-inflammatory and anti-granuloma activity of BA hydroalcoholic extract (BAHE) were evaluated in experimental models, viz., carrageenan-induced paw edema, cotton pellet-induced granuloma formation, and complete Freund's adjuvant-induced stimulation of peritoneal macrophages in rats. Expression of inflammatory mediators, viz., tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10, TNF-R1, and cyclooxygenase-2 (COX-2) was carried out in serum and peritoneal macrophages to derive the plausible mechanism of BAHE in activated peritoneal macrophages. Results: Pretreatment with BAHE produced a dose-dependent reduction (P < 0.01) in carrageenan-induced paw edema and cotton pellet-induced granuloma model. BAHE treatment produced significant (P < 0.01) reduction in serum inflammatory cytokine levels as compared to control. Protein expression of pro-inflammatory markers, IL-1β, IL-6, TNF-R1, and COX-2, was found to be reduced in stimulated macrophages whereas anti-inflammatory cytokine, IL-10, was upregulated in peritoneal macrophages. Conclusion: The result of the present study thus demonstrates the anti-inflammatory and anti-granuloma activity of BAHE which may be attributed to its inhibitory activity on macrophage-derived cytokine and mediators. PMID:27114638

Anti-Tumor Effects of Ganoderma lucidum (Reishi) in Inflammatory Breast Cancer in In Vivo and In Vitro Models

PubMed Central

Suarez-Arroyo, Ivette J.; Rosario-Acevedo, Raysa; Aguilar-Perez, Alexandra; Clemente, Pedro L.; Cubano, Luis A.; Serrano, Juan; Schneider, Robert J.; Martínez-Montemayor, Michelle M.

2013-01-01

The medicinal mushroom Ganoderma lucidum (Reishi) was tested as a potential therapeutic for Inflammatory Breast Cancer (IBC) using in vivo and in vitro IBC models. IBC is a lethal and aggressive form of breast cancer that manifests itself without a typical tumor mass. Studies show that IBC tissue biopsies overexpress E-cadherin and the eukaryotic initiation factor 4GI (eIF4GI), two proteins that are partially responsible for the unique pathological properties of this disease. IBC is treated with a multimodal approach that includes non-targeted systemic chemotherapy, surgery, and radiation. Because of its non-toxic and selective anti-cancer activity, medicinal mushroom extracts have received attention for their use in cancer therapy. Our previous studies demonstrate these selective anti-cancer effects of Reishi, where IBC cell viability and invasion, as well as the expression of key IBC molecules, including eIF4G is compromised. Thus, herein we define the mechanistic effects of Reishi focusing on the phosphoinositide-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, a regulator of cell survival and growth. The present study demonstrates that Reishi treated IBC SUM-149 cells have reduced expression of mTOR downstream effectors at early treatment times, as we observe reduced eIF4G levels coupled with increased levels of eIF4E bound to 4E-BP, with consequential protein synthesis reduction. Severe combined immunodeficient mice injected with IBC cells treated with Reishi for 13 weeks show reduced tumor growth and weight by ∼50%, and Reishi treated tumors showed reduced expression of E-cadherin, mTOR, eIF4G, and p70S6K, and activity of extracellular regulated kinase (ERK1/2). Our results provide evidence that Reishi suppresses protein synthesis and tumor growth by affecting survival and proliferative signaling pathways that act on translation, suggesting that Reishi is a potential natural therapeutic for breast and other cancers. PMID:23468988

Anti-tumor effects of Ganoderma lucidum (reishi) in inflammatory breast cancer in in vivo and in vitro models.

PubMed

Suarez-Arroyo, Ivette J; Rosario-Acevedo, Raysa; Aguilar-Perez, Alexandra; Clemente, Pedro L; Cubano, Luis A; Serrano, Juan; Schneider, Robert J; Martínez-Montemayor, Michelle M

2013-01-01

The medicinal mushroom Ganoderma lucidum (Reishi) was tested as a potential therapeutic for Inflammatory Breast Cancer (IBC) using in vivo and in vitro IBC models. IBC is a lethal and aggressive form of breast cancer that manifests itself without a typical tumor mass. Studies show that IBC tissue biopsies overexpress E-cadherin and the eukaryotic initiation factor 4GI (eIF4GI), two proteins that are partially responsible for the unique pathological properties of this disease. IBC is treated with a multimodal approach that includes non-targeted systemic chemotherapy, surgery, and radiation. Because of its non-toxic and selective anti-cancer activity, medicinal mushroom extracts have received attention for their use in cancer therapy. Our previous studies demonstrate these selective anti-cancer effects of Reishi, where IBC cell viability and invasion, as well as the expression of key IBC molecules, including eIF4G is compromised. Thus, herein we define the mechanistic effects of Reishi focusing on the phosphoinositide-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, a regulator of cell survival and growth. The present study demonstrates that Reishi treated IBC SUM-149 cells have reduced expression of mTOR downstream effectors at early treatment times, as we observe reduced eIF4G levels coupled with increased levels of eIF4E bound to 4E-BP, with consequential protein synthesis reduction. Severe combined immunodeficient mice injected with IBC cells treated with Reishi for 13 weeks show reduced tumor growth and weight by ∼50%, and Reishi treated tumors showed reduced expression of E-cadherin, mTOR, eIF4G, and p70S6K, and activity of extracellular regulated kinase (ERK1/2). Our results provide evidence that Reishi suppresses protein synthesis and tumor growth by affecting survival and proliferative signaling pathways that act on translation, suggesting that Reishi is a potential natural therapeutic for breast and other cancers.

The Yin/Yan of CCL2: a minor role in neutrophil anti-tumor activity in vitro but a major role on the outgrowth of metastatic breast cancer lesions in the lung in vivo.

PubMed

Lavender, Nicole; Yang, Jinming; Chen, Sheau-Chiann; Sai, Jiqing; Johnson, C Andrew; Owens, Philip; Ayers, Gregory D; Richmond, Ann

2017-01-31

The role of the chemokine CCL2 in breast cancer is controversial. While CCL2 recruits and activates pro-tumor macrophages, it is also reported to enhance neutrophil-mediated anti-tumor activity. Moreover, loss of CCL2 in early development enhances breast cancer progression. To clarify these conflicting findings, we examined the ability of CCL2 to alter naïve and tumor entrained neutrophil production of ROS, release of granzyme-B, and killing of tumor cells in multiple mouse models of breast cancer. CCL2 was delivered intranasally in mice to elevate CCL2 levels in the lung and effects on seeding and growth of breast tumor cells were evaluated. The TCGA data base was queried for relationship between CCL2 expression and relapse free survival of breast cancer patients and compared to subsets of breast cancer patients. Even though each of the tumor cell lines studied produced approximately equal amounts of CCL2, exogenous delivery of CCL2 to co-cultures of breast tumor cells and neutrophils enhanced the ability of tumor-entrained neutrophils (TEN) to kill the less aggressive 67NR variant of 4T1 breast cancer cells. However, exogenous CCL2 did not enhance naïve or TEN neutrophil killing of more aggressive 4T1 or PyMT breast tumor cells. Moreover, this anti-tumor activity was not observed in vivo. Intranasal delivery of CCL2 to BALB/c mice markedly enhanced seeding and outgrowth of 67NR cells in the lung and increased the recruitment of CD4+ T cells and CD8+ central memory T cells into lungs of tumor bearing mice. There was no significant increase in the recruitment of CD19+ B cells, or F4/80+, Ly6G+ and CD11c + myeloid cells. CCL2 had an equal effect on CD206+ and MHCII+ populations of macrophages, thus balancing the pro- and anti-tumor macrophage cell population. Analysis of the relationship between CCL2 levels and relapse free survival in humans revealed that overall survival is not significantly different between high CCL2 expressing and low CCL2 expressing

Anti-granuloma activity of Coriandrum sativum in experimental models

PubMed Central

Nair, Vinod; Singh, Surender; Gupta, Yogendra Kumar

2013-01-01

Background: Coriandrum sativum has been used in the traditional systems of medicine for management of arthritis and other inflammatory disorders. Objectives: In this study, we have evaluated the anti-inflammatory and anti-granuloma activities of Coriandrum sativum hydroalcoholic extract (CSHE) in experimental models. Materials and Methods: The anti-inflammatory activity of CSHE was evaluated using carrageenan-induced paw edema model and the anti-granuloma activity of CSHE was evaluated using the subcutaneous cotton pellet implantation-induced granuloma formation and stimulation of peritoneal macrophages with complete Freund's adjuvant. Serum tumor necrosis factor-α (TNF-α), IL-6, IL-1 β levels, and peritoneal macrophage expression of TNF-R1 were evaluated as markers of global inflammation. Results: CSHE at the highest dose tested (32 mg/kg) produced a significant reduction (P < 0.05) in paw edema after carrageenan administration. CSHE treatment also reduced dry granuloma weight in all treated animals. Serum IL-6 and IL-1 β levels were significantly (P < 0.05) lower in the CSHE (32 mg/kg)-treated group as compared to control. Although there was an increase in serum TNF-α level in the CSHE-treated group as compared to control, TNF-R1 expression on peritoneal macrophages was found to be reduced. Conclusion: Thus, the result of this study demonstrates the anti-inflammatory and anti-granuloma activities of CSHE in experimental models, and validates its traditional use for the management of arthritis and other inflammatory disorders. PMID:23741156

Enhancement of anti-tumor effect of particulate vaccine delivery system by 'bacteriomimetic' CpG functionalization of poly-lactic-co-glycolic acid nanoparticles.

PubMed

Kokate, Rutika A; Thamake, Sanjay I; Chaudhary, Pankaj; Mott, Brittney; Raut, Sangram; Vishwanatha, Jamboor K; Jones, Harlan P

2015-01-01

Low immunogenicity remains a major obstacle in realizing the full potential of cancer vaccines. In this study, we evaluated CpG-coated tumor antigen (Tag)-encapsulating 'bacteriomimetic' nanoparticles (CpG-nanoparticle [NP]-Tag NPs) as an approach to enhance anti-tumor immunity. CpG-NP-Tag NPs were synthesized, characterized for their physicochemical properties and tested in vivo. We found CpG predosing followed by intraperitoneal (IP) immunization with CpG-NP-Tag NPs significantly attenuated tumor growth in female BALB/c mice compared with respective controls. Histopathological and Immunofluorescence data revealed CpG-NP-Tag tumors had lower proliferation, higher apoptotic activity, greater CD4(+) and CD8(+) T cell infiltration as well as higher IFN-γ levels as compared with control groups. Our findings suggest CpG-NP-Tag NPs can enhance anti-tumor effect of nanoparticulate tumor vaccination system.

Synthesis, Characterization, and Anti-Inflammatory Activities of Methyl Salicylate Derivatives Bearing Piperazine Moiety.

PubMed

Li, Jingfen; Yin, Yong; Wang, Lisheng; Liang, Pengyun; Li, Menghua; Liu, Xu; Wu, Lichuan; Yang, Hua

2016-11-23

In this study, a new series of 16 methyl salicylate derivatives bearing a piperazine moiety were synthesized and characterized. The in vivo anti-inflammatory activities of target compounds were investigated against xylol-induced ear edema and carrageenan-induced paw edema in mice. The results showed that all synthesized compounds exhibited potent anti-inflammatory activities. Especially, the anti-inflammatory activities of compounds M15 and M16 were higher than that of aspirin and even equal to that of indomethacin at the same dose. In addition, the in vitro cytotoxicity activities and anti-inflammatory activities of four target compounds were performed in RAW264.7 macrophages, and compound M16 was found to significantly inhibit the release of lipopolysaccharide (LPS)-induced interleukin (IL)-6 and tumor necrosis factor (TNF)-α in a dose-dependent manner. In addition, compound M16 was found to attenuate LPS induced cyclooxygenase (COX)-2 up-regulation. The current preliminary study may provide information for the development of new and safe anti-inflammatory agents.

Cryo-thermal therapy elicits potent anti-tumor immunity by inducing extracellular Hsp70-dependent MDSC differentiation

NASA Astrophysics Data System (ADS)

Zhu, Jun; Zhang, Yan; Zhang, Aili; He, Kun; Liu, Ping; Xu, Lisa X.

2016-06-01

Achieving control of metastatic disease is a long-sought goal in cancer therapy. Treatments that encourage a patient’s own immune system are bringing new hopes in reaching such a goal. In clinic, local hyperthermia and cryoablation have been explored to induce anti-tumor immune responses against tumors. We have also developed a novel therapeutic modality of cryo-thermal treatment by alternating liquid nitrogen (LN2) cooling and radio frequency (RF) heating, and better therapeutic effect was achieved in treating metastatic cancer in animal model. In this study, we investigated the mechanism of systemic immune response elicited by cryo-thermal therapy. In the 4T1 murine mammary carcinoma model, we found that local cryo-thermal therapy resulted in a considerable reduction of distant lung metastases, and improved long-term survival. Moreover, results of tumor re-challenge experiments indicated generation of a strong tumor-specific immune memory after the local treatment of primary tumors. Our further study indicated that cryo-thermal therapy caused an elevated extracellular release of Hsp70. Subsequently, Hsp70 induced differentiation of MDSCs into mature DCs, contributing to the relief of MDSCs-mediated immunosuppression and ultimately the activation of strong anti-tumor immune response. Our findings reveal new insight into the mechanism of robust therapeutic effects of cryo-thermal therapy against metastatic cancers.

Lectins with anti-HIV activity: a review.

PubMed

Akkouh, Ouafae; Ng, Tzi Bun; Singh, Senjam Sunil; Yin, Cuiming; Dan, Xiuli; Chan, Yau Sang; Pan, Wenliang; Cheung, Randy Chi Fai

2015-01-06

Lectins including flowering plant lectins, algal lectins, cyanobacterial lectins, actinomycete lectin, worm lectins, and the nonpeptidic lectin mimics pradimicins and benanomicins, exhibit anti-HIV activity. The anti-HIV plant lectins include Artocarpus heterophyllus (jacalin) lectin, concanavalin A, Galanthus nivalis (snowdrop) agglutinin-related lectins, Musa acuminata (banana) lectin, Myrianthus holstii lectin, Narcissus pseudonarcissus lectin, and Urtica diocia agglutinin. The anti-HIV algal lectins comprise Boodlea coacta lectin, Griffithsin, Oscillatoria agardhii agglutinin. The anti-HIV cyanobacterial lectins are cyanovirin-N, scytovirin, Microcystis viridis lectin, and microvirin. Actinohivin is an anti-HIV actinomycete lectin. The anti-HIV worm lectins include Chaetopterus variopedatus polychaete marine worm lectin, Serpula vermicularis sea worm lectin, and C-type lectin Mermaid from nematode (Laxus oneistus). The anti-HIV nonpeptidic lectin mimics comprise pradimicins and benanomicins. Their anti-HIV mechanisms are discussed.

Anti-inflammatory and antinociceptive activities of azadirachtin in mice.

PubMed

Soares, Darly G; Godin, Adriana M; Menezes, Raquel R; Nogueira, Rafaela D; Brito, Ana Mercy S; Melo, Ivo S F; Coura, Giovanna Maria E; Souza, Danielle G; Amaral, Flávio A; Paulino, Tony P; Coelho, Márcio M; Machado, Renes R

2014-06-01

Azadirachta indica (Meliaceae) extracts have been reported to exhibit anti-inflammatory and antinociceptive properties. However, the activities of azadirachtin, a limonoid and the major bioactive compound found in the extracts, have been poorly investigated in animal models. In the present study, we investigated the effects induced by azadirachtin in experimental models of pain and inflammation in mice. Carrageenan-induced paw edema and fibrovascular tissue growth induced by subcutaneous cotton pellet implantation were used to investigate the anti-inflammatory activity of azadirachtin in mice. Zymosan-induced writhing and hot plate tests were employed to evaluate the antinociceptive activity. To explore putative mechanisms of action, the level of tumor necrosis factor-α in inflammatory tissue was measured and the effect induced by opioidergic and serotonergic antagonists was evaluated. Previous per os (p. o.) administration of azadirachtin (120 mg/kg) significantly reduced the acute paw edema induced by carrageenan. However, the concomitant increase of the paw concentration of tumor necrosis factor-α induced by this inflammatory stimulus was not reduced by azadirachtin. In addition to inhibiting the acute paw edema induced by carrageenan, azadirachtin (6, 60, and 120 mg/kg) inhibited the proliferative phase of the inflammatory response, as demonstrated by the reduced formation of fibrovascular tissue growth. Azadirachtin (120 mg/kg) also inhibited the nociceptive response in models of nociceptive (hot plate) and inflammatory (writhing induced by zymosan) pain. The activity of azadirachtin (120 mg/kg) in the model of nociceptive pain was attenuated by a nonselective opioid antagonist, naltrexone (10 mg/kg, i. p.), but not by a nonselective serotonergic antagonist, cyproheptadine. In conclusion, this study demonstrates the activity of azadirachtin in experimental models of nociceptive and inflammatory pain, and also in models of acute and chronic inflammation

[Design of new anti-tumor agents interrupting deregulated signaling pathways induced by tyrosine kinase proteins. Inhibition of protein-protein interaction involving Grb2].

PubMed

Vidal, Michel; Liu, Wang Qing; Gril, Brunile; Assayag, Franck; Poupon, Marie-France; Garbay, Christiane

2004-01-01

Cellular signaling pathways induced by growth-factor receptors are frequently deregulated in cancer. Anti-tumor agents that inhibit their enzymatic tyrosine kinase activity have been designed and are now used in human chemotherapy. We propose here an alternative way to interrupt over-expressed signaling by inhibiting protein-protein interactions that involve either the over-expressed proteins or proteins located downstream. The adaptor protein Grb2 over-expressed in connection with HER2/ErbB2/neu in Ras signaling pathway was chosen as a target. Peptides with very high affinity for Grb2 were rationally designed from structural data. Their capacity to interrupt the signaling pathway, their anti-proliferative activity as well as their potential anti-tumor properties are described.

Repeated cycles of 5-fluorouracil chemotherapy impaired anti-tumor functions of cytotoxic T cells in a CT26 tumor-bearing mouse model.

PubMed

Wu, Yanhong; Deng, Zhenling; Wang, Huiru; Ma, Wenbo; Zhou, Chunxia; Zhang, Shuren

2016-09-20

Recently, the immunostimulatory roles of chemotherapeutics have been increasingly revealed, although bone marrow suppression is still a common toxicity of chemotherapy. While the numbers and ratios of different immune subpopulations are analyzed after chemotherapy, changes to immune status after each cycle of treatment are less studied and remain unclear. To determine the tumor-specific immune status and functions after different cycles of chemotherapy, we treated CT26 tumor-bearing mice with one to four cycles of 5-fluorouracil (5-FU). Overall survival was not improved when more than one cycle of 5-FU was administered. Here we present data concerning the immune statuses after one and three cycles of chemotherapy. We analyzed the amount of spleen cells from mice treated with one and three cycles of 5-FU as well as assayed their proliferation and cytotoxicity against the CT26 tumor cell line. We found that the absolute numbers of CD8 T-cells and NK cells were not influenced significantly after either one or three cycles of chemotherapy. However, after three cycles of 5-FU, proliferated CD8 T-cells were decreased, and CT26-specific cytotoxicity and IFN-γ secretion of spleen cells were impaired in vitro. After one cycle of 5-FU, there was a greater percentage of tumor infiltrating CD8 T-cells. In addition, more proliferated CD8 T-cells, enhanced tumor-specific cytotoxicity as well as IFN-γ secretion of spleen cells against CT26 in vitro were observed. Given the increased expression of immunosuppressive factors, such as PD-L1 and TGF-β, we assessed the effect of early introduction of immunotherapy in combination with chemotherapy. We found that mice treated with cytokine induced killer cells and PD-L1 monoclonal antibodies after one cycle of 5-FU had a better anti-tumor performance than those treated with chemotherapy or immunotherapy alone. These data suggest that a single cycle of 5-FU treatment promoted an anti-tumor immune response, whereas repeated chemotherapy

Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis.

PubMed

Mathew, R M; Vandenberghe, R; Garcia-Merino, A; Yamamoto, T; Landolfi, J C; Rosenfeld, M R; Rossi, J E; Thiessen, B; Dropcho, E J; Dalmau, J

2007-03-20

To report the presence of microscopic neoplasms of the testis in men with anti-Ma2-associated encephalitis (Ma2-encephalitis) and to discuss the clinical implications. Orchiectomy specimens were examined using immunohistochemistry with Ma2 and Oct4 antibodies. Among 25 patients with Ma2-encephalitis younger than 50 years, 19 had germ-cell tumors, and 6 had no evidence of cancer. These 6 patients underwent orchiectomy because they fulfilled five criteria: 1) demonstration of anti-Ma2 antibodies in association with MRI or clinical features compatible with Ma2-encephalitis, 2) life-threatening or progressive neurologic deficits, 3) age < 50 years, 4) absence of other tumors, and 5) new testicular enlargement or risk factors for germ-cell tumors, mainly cryptorchidism or ultrasound evidence of testicular microcalcifications. All orchiectomy specimens showed intratubular-germ cell neoplasms unclassified type (IGCNU) and other abnormalities including microcalcifications, atrophy, fibrosis, inflammatory infiltrates, or hypospermatogenesis. Ma2 was expressed by neoplastic cells in three of three patients examined. Even though most patients had severe neurologic deficits at the time of orchiectomy (median progression of symptoms, 10 months), 4 had partial improvement and prolonged stabilization (8 to 84 months, median 22.5 months) and two did not improve after the procedure. In young men with Ma2-encephalitis, 1) the disorder should be attributed to a germ-cell neoplasm of the testis unless another Ma2-expressing tumor is found, 2) negative tumor markers, ultrasound, body CT, or PET do not exclude an intratubular germ-cell neoplasm of the testis, and 3) if no tumor is found, the presence of the five indicated criteria should prompt consideration of orchiectomy.

Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis

PubMed Central

Mathew, R.M.; Vandenberghe, R.; Garcia-Merino, A.; Yamamoto, T.; Landolfi, J.C.; Rosenfeld, M.R.; Rossi, J.E.; Thiessen, B.; Dropcho, E.J.; Dalmau, J.

2007-01-01

Objective: To report the presence of microscopic neoplasms of the testis in men with anti-Ma2-associated encephalitis (Ma2-encephalitis) and to discuss the clinical implications. Methods: Orchiectomy specimens were examined using immunohistochemistry with Ma2 and Oct4 antibodies. Results: Among 25 patients with Ma2-encephalitis younger than 50 years, 19 had germ-cell tumors, and 6 had no evidence of cancer. These 6 patients underwent orchiectomy because they fulfilled five criteria: 1) demonstration of anti-Ma2 antibodies in association with MRI or clinical features compatible with Ma2-encephalitis, 2) life-threatening or progressive neurologic deficits, 3) age < 50 years, 4) absence of other tumors, and 5) new testicular enlargement or risk factors for germ-cell tumors, mainly cryptorchidism or ultrasound evidence of testicular microcalcifications. All orchiectomy specimens showed intratubular-germ cell neoplasms unclassified type (IGCNU) and other abnormalities including microcalcifications, atrophy, fibrosis, inflammatory infiltrates, or hypospermatogenesis. Ma2 was expressed by neoplastic cells in three of three patients examined. Even though most patients had severe neurologic deficits at the time of orchiectomy (median progression of symptoms, 10 months), 4 had partial improvement and prolonged stabilization (8 to 84 months, median 22.5 months) and two did not improve after the procedure. Conclusions: In young men with Ma2-encephalitis, 1) the disorder should be attributed to a germ-cell neoplasm of the testis unless another Ma2-expressing tumor is found, 2) negative tumor markers, ultrasound, body CT, or PET do not exclude an intratubular germ-cell neoplasm of the testis, and 3) if no tumor is found, the presence of the five indicated criteria should prompt consideration of orchiectomy. PMID:17151337

An evaluation of the anti-tumor efficacy of oleanolic acid-loaded PEGylated liposomes

NASA Astrophysics Data System (ADS)

Tang, Shengnan; Gao, Dawei; Zhao, Tingting; Zhou, Jing; Zhao, Xiaoning

2013-06-01

The effective delivery of oleanolic acid (OA) to the target site has several benefits in therapy for different pathologies. However, the delivery of OA is challenging due to its poor aqueous solubility. The study aims to evaluate the tumor inhibition effect of the PEGylated OA nanoliposome on the U14 cervical carcinoma cell line. In our previous study, OA was successfully encapsulated into PEGylated liposome with the modified ethanol injection method. Oral administration of PEGylated OA liposome was demonstrated to be more efficient in inhibiting xenograft tumors. The results of organ index indicated that PEG liposome exhibited higher anti-tumor activity and lower cytotoxicity. It was also found that OA and OA liposomes induced tumor cell apoptosis detected by flow cytometry. Furthermore, effects of OA on the morphology of tumor and other tissues were observed by hematoxylin and eosin staining. The histopathology sections did not show pathological changes in kidney or liver in tested mice. In contrast, there was a significant difference in tumor tissues between treatment groups and the negative control group. These observations imply that PEGylated liposomes seem to have advantages for cancer therapy in terms of effective delivery of OA.

Predictors of response to anti-tumor necrosis factor therapy in ulcerative colitis.

PubMed

Zampeli, Evanthia; Gizis, Michalis; Siakavellas, Spyros I; Bamias, Giorgos

2014-08-15

Ulcerative colitis (UC) is an immune-mediated, chronic inflammatory disease of the large intestine. Its course is characterized by flares of acute inflammation and periods of low-grade chronic inflammatory activity or remission. Monoclonal antibodies against tumor necrosis factor (anti-TNF) are part of the therapeutic armamentarium and are used in cases of moderate to severe UC that is refractory to conventional treatment with corticosteroids and/or immunosuppressants. Therapeutic response to these agents is not uniform and a large percentage of patients either fail to improve (primary non-response) or lose response after a period of improvement (secondary non-response/loss of response). In addition, the use of anti-TNF agents has been related to uncommon but potentially serious adverse effects that preclude their administration or lead to their discontinuation. Finally, use of these medications is associated with a considerable cost for the health system. The identification of parameters that may predict response to anti-TNF drugs in UC would help to better select for patients with a high probability to respond and minimize risk and costs for those who will not respond. Analysis of the major clinical trials and the accumulated experience with the use of anti-TNF drugs in UC has resulted to the report of such prognostic factors. Included are clinical and epidemiological characteristics, laboratory markers, endoscopic indicators and molecular (immunological/genetic) signatures. Such predictive parameters of long-term outcomes may either be present at the commencement of treatment or determined during the early period of therapy. Validation of these prognostic markers in large cohorts of patients with variable characteristics will facilitate their introduction into clinical practice and the best selection of UC patients who will benefit from anti-TNF therapy.

Anti-hepatoma activity and mechanism of corn silk polysaccharides in H22 tumor-bearing mice.

PubMed

Yang, Jingyue; Li, Xiao; Xue, Yan; Wang, Nan; Liu, Wenchao

2014-03-01

Corn silk is a well known traditional Chinese herbal medicine and corn silk polysaccharides (CSP) possess multiple pharmacological activities. However, the antitumor effect of CSP on hepatocarcinoma has not been studied. This study aimed to investigate the effects of CSP on tumor growth and immune functions in H22 hepatocarcinoma tumor-bearing mice. The results demonstrated that CSP could not only inhibit the tumor growth, but also extended the survival time of H22 tumor-bearing mice. Besides, CSP administration could increase the body weight, peripheral white blood cells (WBC) count, thymus index and spleen index of H22 tumor-bearing mice. Furthermore, the production of serum cytokines in H22 tumor-bearing mice, such as IL-2, IL-6 and TNF-α, was enhanced by CSP treatment. In addition, no toxicological effects were observed on hepatic function and renal function in CSP-treated mice transplanted H22 tumor cells. In summary, this experimental finding indicated that CSP could elevate the immune functions in H22 tumor-bearing mice to enhance its antitumor activity and CSP seems to be a safe and effective agent for the treatment of hepatocellular carcinoma. Copyright © 2013 Elsevier B.V. All rights reserved.

PET Imaging of 64Cu-DOTA-scFv-Anti-PSMA Lipid Nanoparticles (LNPs): Enhanced Tumor Targeting over Anti-PSMA scFv or Untargeted LNPs

PubMed Central

Wong, Patty; Li, Lin; Chea, Junie; Delgado, Melissa K.; Crow, Desiree; Poku, Erasmus; Szpikowska, Barbara; Bowles, Nicole; Channappa, Divya; Colcher, David; Wong, Jeffrey Y.C.; Shively, John E.; Yazaki, Paul J.

2017-01-01

Introduction Single chain (scFv) antibodies are ideal targeting ligands due to their modular structure, high antigen specificity and affinity. These monovalent ligands display rapid tumor targeting but have limitations due to their fast urinary clearance. Methods An anti-prostate membrane antigen (PSMA) scFv with a site-specific cysteine was expressed and evaluated in a prostate cancer xenograft model by Cu-64 PET imaging. To enhance tumor accumulation, the scFv-cys was conjugated to the co-polymer DSPE-PEG-maleimide that spontaneously assembled into a homogeneous multivalent lipid nanoparticle (LNP). Results The targeted LNP exhibited a 2-fold increase in tumor uptake compared to the scFv alone using two different thiol ester chemistries. The anti-PSMA scFv-LNP exhibited a 1.6 fold increase in tumor targeting over the untargeted LNP. Conclusions The targeted anti-PSMA scFv-LNP showed enhanced tumor accumulation over the scFv alone or the untargeted DOTA-micelle providing evidence for the development of this system for drug delivery. Advances in Knowledge and implications for patient care Anti-tumor scFv antibody fragments have not achieved their therapeutic potential due to their fast blood clearance. Conjugation to a LNP enables multivalency to the tumor antigen as well as increased molecular size for chemotherapy drug delivery. PMID:28126683

Anti-Tumor Activity of a Novel Compound-CDF Is Mediated by Regulating miR-21, miR-200, and PTEN in Pancreatic Cancer

PubMed Central

Kong, Dejuan; Sarkar, Sanila H.; Wang, Zhiwei; Banerjee, Sanjeev; Aboukameel, Amro; Padhye, Subhash; Philip, Philip A.; Sarkar, Fazlul H.

2011-01-01

Background The existence of cancer stem cells (CSCs) or cancer stem-like cells in a tumor mass is believed to be responsible for tumor recurrence because of their intrinsic and extrinsic drug-resistance characteristics. Therefore, targeted killing of CSCs would be a newer strategy for the prevention of tumor recurrence and/or treatment by overcoming drug-resistance. We have developed a novel synthetic compound-CDF, which showed greater bioavailability in animal tissues such as pancreas, and also induced cell growth inhibition and apoptosis, which was mediated by inactivation of NF-κB, COX-2, and VEGF in pancreatic cancer (PC) cells. Methodology/Principal Findings In the current study we showed, for the first time, that CDF could significantly inhibit the sphere-forming ability (pancreatospheres) of PC cells consistent with increased disintegration of pancreatospheres, which was associated with attenuation of CSC markers (CD44 and EpCAM), especially in gemcitabine-resistant (MIAPaCa-2) PC cells containing high proportion of CSCs consistent with increased miR-21 and decreased miR-200. In a xenograft mouse model of human PC, CDF treatment significantly inhibited tumor growth, which was associated with decreased NF-κB DNA binding activity, COX-2, and miR-21 expression, and increased PTEN and miR-200 expression in tumor remnants. Conclusions/Significance These results strongly suggest that the anti-tumor activity of CDF is associated with inhibition of CSC function via down-regulation of CSC-associated signaling pathways. Therefore, CDF could be useful for the prevention of tumor recurrence and/or treatment of PC with better treatment outcome in the future. PMID:21408027

A ketogenic diet supplemented with medium-chain triglycerides enhances the anti-tumor and anti-angiogenic efficacy of chemotherapy on neuroblastoma xenografts in a CD1-nu mouse model.

PubMed

Aminzadeh-Gohari, Sepideh; Feichtinger, René Günther; Vidali, Silvia; Locker, Felix; Rutherford, Tricia; O'Donnel, Maura; Stöger-Kleiber, Andrea; Mayr, Johannes Adalbert; Sperl, Wolfgang; Kofler, Barbara

2017-09-12

Neuroblastoma (NB) is a pediatric malignancy characterized by a marked reduction in aerobic energy metabolism. Recent preclinical data indicate that targeting this metabolic phenotype by a ketogenic diet (KD), especially in combination with calorie restriction, slows tumor growth and enhances metronomic cyclophosphamide (CP) therapy of NB xenografts. Because calorie restriction would be contraindicated in most cancer patients, the aim of the present study was to optimize the KD such that the tumors are sensitized to CP without the need of calorie restriction. In a NB xenograft model, metronomic CP was combined with KDs of different triglyceride compositions and fed to CD1-nu mice ad libitum . Metronomic CP in combination with a KD containing 8-carbon medium-chain triglycerides exerted a robust anti-tumor effect, suppressing growth and causing a significant reduction of tumor blood-vessel density and intratumoral hemorrhage, accompanied by activation of AMP-activated protein kinase in NB cells. Furthermore, the KDs caused a significant reduction in the serum levels of essential amino acids, but increased those of serine, glutamine and glycine. Our data suggest that targeting energy metabolism by a modified KD may be considered as part of a multimodal treatment regimen to improve the efficacy of classic anti-NB therapy.

Microencapsulation of anti-tumor, antibiotic and thrombolytic drugs in microgravity

NASA Technical Reports Server (NTRS)

Morrison, Dennis R.; Mosier, Benjamin; Cassanto, John

1994-01-01

Encapsulation of cytotoxic or labile drugs enables targeted delivery and sustained release kinetics that are not available with intravenous injection. A new liquid-liquid diffusion process has been developed for forming unique microcapsules that contain both aqueous and hydrocarbon soluble drugs. Microgravity experiments, on sounding rockets (1989-92) and Shuttle missions STS-52 (1992) and STS-56 (1993) using an automated Materials Dispersion Apparatus, produced multi-lamellar microcapsules containing both Cis-platinum (anti-tumor drug) and iodinated poppy seed oil (a radiocontrast medium), surrounded by a polyglyceride skin. Microcapsules formed with amoxicillin (antibiotic) or urokinase (a clot dissolving enzyme), co-encapsulated with IPO, are still intact after two years. Microcapsules were formed with the drug so concentrated that crystals formed inside. Multi-layered microspheres, with both hydrophobic drug compartments, can enable diffusion of complementary drugs from the same microcapsule, e.g. antibiotics and immuno-stimulants to treat resistant infections or multiple fibrinolytic drugs to dissolve emboli. Co-encapsulation of enough radio-contrast medium enables oncologists to monitor the delivery of anti-tumor microcapsules to target tumors using computerized tomography and radiography that would track the distribution of microcapsules after release from the intra-arterial catheter. These microcapsules could have important applications in chemotheraphy of certain liver, kidney, brain and other tumors.

In vitro and in vivo anti-glioma activity of a chalcone-quinoxaline hybrid.

PubMed

Loch-Neckel, Gecioni; Bicca, Maíra Assunção; Leal, Paulo César; Mascarello, Alessandra; Siqueira, Jarbas Mota; Calixto, João B

2015-01-27

Chalcones are important compounds that exhibit multiple biological activities, including anti-inflammatory, antimitotic and antibacterial properties. In the present study, we have analyzed the potential anti-cancer activity of a chalcone named N9 (a hybrid chalcone-quinoxaline compound) using in vitro and in vivo experimental glioma models. Here, we report N9-induced inhibition of cell proliferation and also N9-induced cell death in a concentration-dependent manner in U87-MG glioma cells. These effects of N9 appear to be associated with its ability to inhibit the expression of cell cycle-associated proteins, and also the augmentation in the expression of the p21 (p21/Cip1) protein, a cyclin-dependent kinase inhibitor. Additionally, N9 also potentiates the production of the pro-apoptotic markers Bax and p53 via inhibition of MDM2. Moreover, our results show that N9 also significantly enhanced apoptosis of U87-MG cells with disruption of mitochondrial membrane potential, generation of ROS and caspase-9 activation. In vivo experiments carried out in a murine xenograft model of U87-MG revealed that N9 produced a significant reduction of tumors volume when compared to vehicle treated mice. Collectively, data demonstrate that N9 possess in vitro and in vivo anti-cancer activity, an effect that seems to involve the induction of p53 and p21 proteins, as well as, the activation of mitochondrial apoptosis pathway associated with the inhibition of protein MDM2. Overall, this study suggests N9 is affecting a variety of intracellular pathways related to tumor apoptosis. Perhaps N9 or derivate molecules could represent new potential drugs for cancer therapeutics. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Anti-tumor Study of Chondroitin Sulfate-Methotrexate Nanogels

NASA Astrophysics Data System (ADS)

Wang, Jinyu; Zhao, Weibo; Chen, Haixiao; Qin, An; Zhu, Peizhi

2017-10-01

Self-assembly nanogels (NGs) were formed by bioconjugating methotrexate (MTX) with chondroitin sulfate (CS). MTX-CS NGs can greatly enhance the solubility and improve the delivery efficacy of MTX due to the CD44 binding property of CS. Vivo experiments revealed that MTX-CS NGs showed less toxicity than MTX. MTX-CS NGs can improve the anti-tumor effect while reducing the side effects of MTX. Due to their CD44 binding property, chondroitin sulfate-drug conjugates could be a promising and efficient platform for improving the solubility of sparingly soluble drug molecules as well as targeted delivery to cancer cells and tumor tissues.

Type I Interferons as Stimulators of DC-Mediated Cross-Priming: Impact on Anti-Tumor Response

PubMed Central

Schiavoni, Giovanna; Mattei, Fabrizio; Gabriele, Lucia

2013-01-01

Induction of potent tumor-specific cytotoxic T-cell responses is a fundamental objective in anticancer therapeutic strategies. This event requires that antigen-presenting cells present tumor-associated antigens (Ag) on their MHC class-I molecule, in a process termed cross-presentation. Dendritic cells (DC) are particularly keen on this task and can induce the cross-priming of CD8+ T cells, when exposed to danger or inflammatory signals that stimulate their activation. Type I interferons (IFN-I), a family of long-known immunostimulatory cytokines, have been proven to produce optimal activation signal for DC-induced cross-priming. Recent in vitro and in vivo evidences have suggested that IFN-I-stimulated cross-priming by DC against tumor-associated Ag is a key mechanism for cancer immunosurveillance and may be usefully exploited to boost anti-tumor CD8+ T-cell responses. Here, we will review the cross-presentation properties of different DC subsets, with special focus on cell-associated and tumor Ag, and discuss how IFN-I can modify this function, with the aim of identifying more specific and effective strategies for improving anticancer responses. PMID:24400008

Tumor-Associated Neutrophils in Human Lung Cancer

DTIC Science & Technology

2017-10-01

tumor inflammation, anti-tumor neutrophils, anti-tumor innate immune response. anti-tumor adaptive immune response, neutrophil and T cell interaction...Ottonello, 1992; van Egmond and Bakema, 2013) and by producing factors to recruit and acti- vate cells of the innate and adaptive immune system...dependent cell -mediated cytotoxicity (ADCC) [16], (iii) produce factors to recruit and activate cells of the innate and adaptive immune systems [17], and

Superior anti-tumor activity of the MDM2 antagonist idasanutlin and the Bcl-2 inhibitor venetoclax in p53 wild-type acute myeloid leukemia models.

PubMed

Lehmann, Christian; Friess, Thomas; Birzele, Fabian; Kiialainen, Anna; Dangl, Markus

2016-06-28

Venetoclax, a small molecule BH3 mimetic which inhibits the anti-apoptotic protein Bcl-2, and idasanutlin, a selective MDM2 antagonist, have both shown activity as single-agent treatments in pre-clinical and clinical studies in acute myeloid leukemia (AML). In this study, we deliver the rationale and molecular basis for the combination of idasanutlin and venetoclax for treatment of p53 wild-type AML. The effect of idasanutlin and venetoclax combination on cell viability, apoptosis, and cell cycle progression was investigated in vitro using established AML cell lines. In vivo efficacy was demonstrated in subcutaneous and orthotopic xenograft models generated in female nude or non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Mode-of-action analyses were performed by means of cell cycle kinetic studies, RNA sequencing as well as western blotting experiments. Combination treatment with venetoclax and idasanutlin results in synergistic anti-tumor activity compared with the respective single-agent treatments in vitro, in p53 wild-type AML cell lines, and leads to strongly superior efficacy in vivo, in subcutaneous and orthotopic AML models. The inhibitory effects of idasanutlin were cell-cycle dependent, with cells arresting in G1 in consecutive cycles and the induction of apoptosis only evident after cells had gone through at least two cell cycles. Combination treatment with venetoclax removed this dependency, resulting in an acceleration of cell death kinetics. As expected, gene expression studies using RNA sequencing showed significant alterations to pathways associated with p53 signaling and cell cycle arrest (CCND1 pathway) in response to idasanutlin treatment. Only few gene expression changes were observed for venetoclax treatment and combination treatment, indicating that their effects are mediated mainly at the post-transcriptional level. Protein expression studies demonstrated that inhibition of the anti-apoptotic protein Mcl-1 contributed to

JS-K has Potent Anti-Angiogenic Activity in vitro and Inhibits Tumor Angiogenesis in a Multiple Myeloma Model in vivo

PubMed Central

Kaur, Gurmeet; Kiziltepe, Tanyel; Anderson, Kenneth C.; Kutok, Jeffery L.; Jia, Lee; Boucher, Kenneth M.; Saavedra, Joseph E.; Keefer, Larry K.; Shami, Paul J.

2009-01-01

Glutathione S-Transferases (GST) play an important role in multidrug resistance and are upregulated in multiple cancers. We have designed a prodrug class that releases NO on metabolism by GST. O2-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, a member of this class) has potent anti-neoplastic activity. We studied the effect of JS-K on angiogenesis. JS-K inhibited the proliferation of HUVEC’s with a 50% inhibitory concentration (IC50) of 0.432, 0.466, and 0.505 µM at 24, 48, and 72 hours, respectively. In the cord formation assay, JS-K led to a decrease in the number of cord junctions and cord length with an IC50 of 0.637 and 0.696 µM, respectively. JS-K inhibited cell migration at 5 hours using VEGF as a chemoattractant. Migration inhibition occurred with an IC50 of 0.493 µM. In the chick aortic ring assay using VEGF or FGF-b for vessel growth stimulation, 0.5 µM JS-K completely inhibited vessel growth. JS-K inhibited tumor angiogenesis in vivo in NIH III mice implanted subcutaneously with OPM1 multiple myeloma cells. JS-K is a potent inhibitor of angiogenesis in vitro and tumor vessel growth in vivo. As such, it establishes a new class of anti-neoplastic agents that target the malignant cells directly as well as their microenvironment. PMID:20723011

Reversible inhibition of lysine specific demethylase 1 is a novel anti-tumor strategy for poorly differentiated endometrial carcinoma.

PubMed

Theisen, Emily R; Gajiwala, Snehal; Bearss, Jared; Sorna, Venkataswamy; Sharma, Sunil; Janat-Amsbury, Margit

2014-10-09

Endometrial cancer is the most common gynecologic malignancy. Type II endometrial carcinoma is often poorly differentiated and patients diagnosed with Type II disease (~11%) are disproportionately represented in annual endometrial cancer deaths (48%). Recent genomic studies highlight mutations in chromatin regulators as drivers in Type II endometrial carcinoma tumorigenesis, suggesting the use of epigenetic targeted therapies could provide clinical benefit to these patients. We investigated the anti-tumor efficacy of the LSD1 inhibitor HCI2509 in two poorly differentiated Type II endometrial cancer cell lines AN3CA and KLE. The effects of HCI2509 on viability, proliferation, anchorage-independent growth, global histone methylation, LSD1 target gene induction, cell cycle, caspase activation and TUNEL were assayed. KLE cells were used in an orthotopic xenograft model to assess the anti-tumor activity of HCI2509. Both AN3CA and KLE cells were sensitive to HCI2509 treatment with IC50s near 500 nM for cell viability. Inhibition of LSD1 with HCI2509 caused decreased proliferation and anchorage independent growth in soft agar, elevated global histone methylation, and perturbed the cell cycle in both cell lines. These effects were largely dose-dependent. HCI2509 treatment also caused apoptotic cell death. Orthotopic implantation of KLE cells resulted in slow-growing and diffuse tumors throughout the abdomen. Tumor burden was distributed log-normally. Treatment with HCI2509 resulted 5/9 tumor regressions such that treatment and regressions were significantly associated (p=0.034). Our findings demonstrate the anti-cancer properties of the LSD1 inhibitor HCI2509 on poorly differentiated endometrial carcinoma cell lines, AN3CA and KLE. HCI2509 showed single-agent efficacy in orthotopic xenograft studies. Continued studies are needed to preclinically validate LSD1 inhibition as a therapeutic strategy for endometrial carcinoma.

Pivotal roles of CD4+ effector T cells in mediating agonistic anti-GITR mAb-induced-immune activation and tumor immunity in CT26 tumors.

PubMed

Zhou, Pengfei; L'italien, Lawrence; Hodges, Douglas; Schebye, Xiao Min

2007-12-01

Glucocorticoid-induced TNF receptor family related protein (GITR) is a member of the TNFR superfamily. Previous studies have shown that in vivo administration of a GITR agonistic Ab (DTA-1) is able to overcome tolerance and induce tumor rejection in several murine syngeneic tumor models. However, little is known about the in vivo targets and the mechanisms of how this tolerance is overcome in a tumor-bearing host, nor is much known about how the immune network is regulated to achieve this antitumor response. In this study, we demonstrate that the in vivo ligation of GITR on CD4(+) effector T cells renders them refractory to suppression by regulatory T (T(reg)) cells in the CT26 tumor-bearing mouse. GITR engagement on T(reg) cells does not appear to directly abrogate their suppressive function; rather, it increases the expansion of T(reg) cells and promotes IL-10 production, a cytokine important for their suppressive function. Moreover, CD4(+) effector T cells play a crucial role in mediating DTA-1-induced immune activation and expansion of CD8(+), NK, and B cells in the tumor-draining lymph nodes. This includes increased CD69 expression on all of these subsets. In addition, NK and tumor-specific CD8(+) T cells are generated that are cytolytic, which show increased intracellular IFN-gamma production and CD107a mobilization, the latter a hallmark of cytolytic activities that lead to tumor killing.

Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis.

PubMed

Sonveaux, Pierre; Copetti, Tamara; De Saedeleer, Christophe J; Végran, Frédérique; Verrax, Julien; Kennedy, Kelly M; Moon, Eui Jung; Dhup, Suveera; Danhier, Pierre; Frérart, Françoise; Gallez, Bernard; Ribeiro, Anthony; Michiels, Carine; Dewhirst, Mark W; Feron, Olivier

2012-01-01

Switching to a glycolytic metabolism is a rapid adaptation of tumor cells to hypoxia. Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating tumor cells, it also creates a gradient of lactate that mirrors the gradient of oxygen in tumors. More than a metabolic waste, the lactate anion is known to participate to cancer aggressiveness, in part through activation of the hypoxia-inducible factor-1 (HIF-1) pathway in tumor cells. Whether lactate may also directly favor HIF-1 activation in endothelial cells (ECs) thereby offering a new druggable option to block angiogenesis is however an unanswered question. In this study, we therefore focused on the role in ECs of monocarboxylate transporter 1 (MCT1) that we previously identified to be the main facilitator of lactate uptake in cancer cells. We found that blockade of lactate influx into ECs led to inhibition of HIF-1-dependent angiogenesis. Our demonstration is based on the unprecedented characterization of lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in vascular endothelial growth factor receptor 2 (VEGFR2) and basic fibroblast growth factor (bFGF) expression. Furthermore, using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of tumor angiogenesis through intravital microscopy and immunohistochemistry, we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects. Together with the previous demonstration of MCT1 being a key regulator of lactate exchange between tumor cells, the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities.

Targeting the Lactate Transporter MCT1 in Endothelial Cells Inhibits Lactate-Induced HIF-1 Activation and Tumor Angiogenesis

PubMed Central

Sonveaux, Pierre; Copetti, Tamara; De Saedeleer, Christophe J.; Végran, Frédérique; Verrax, Julien; Kennedy, Kelly M.; Moon, Eui Jung; Dhup, Suveera; Danhier, Pierre; Frérart, Françoise; Gallez, Bernard; Ribeiro, Anthony; Michiels, Carine

2012-01-01

Switching to a glycolytic metabolism is a rapid adaptation of tumor cells to hypoxia. Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating tumor cells, it also creates a gradient of lactate that mirrors the gradient of oxygen in tumors. More than a metabolic waste, the lactate anion is known to participate to cancer aggressiveness, in part through activation of the hypoxia-inducible factor-1 (HIF-1) pathway in tumor cells. Whether lactate may also directly favor HIF-1 activation in endothelial cells (ECs) thereby offering a new druggable option to block angiogenesis is however an unanswered question. In this study, we therefore focused on the role in ECs of monocarboxylate transporter 1 (MCT1) that we previously identified to be the main facilitator of lactate uptake in cancer cells. We found that blockade of lactate influx into ECs led to inhibition of HIF-1-dependent angiogenesis. Our demonstration is based on the unprecedented characterization of lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in vascular endothelial growth factor receptor 2 (VEGFR2) and basic fibroblast growth factor (bFGF) expression. Furthermore, using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of tumor angiogenesis through intravital microscopy and immunohistochemistry, we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects. Together with the previous demonstration of MCT1 being a key regulator of lactate exchange between tumor cells, the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities. PMID:22428047

Influence of tumors on protective anti-tumor immunity and the effects of irradiation

PubMed Central

Foulds, Gemma A.; Radons, Jürgen; Kreuzer, Mira; Multhoff, Gabriele; Pockley, Alan G.

2012-01-01

Innate and adaptive immunity plays important roles in the development and progression of cancer and it is becoming apparent that tumors can influence the induction of potentially protective responses in a number of ways. The prevalence of immunoregulatory T cell populations in the circulation and tumors of patients with cancer is increased and the presence of these cells appears to present a major barrier to the induction of tumor immunity. One aspect of tumor-mediated immunoregulation which has received comparatively little attention is that which is directed toward natural killer (NK) cells, although evidence that the phenotype and function of NK cell populations are modified in patients with cancer is accumulating. Although the precise mechanisms underlying these localized and systemic immunoregulatory effects remain unclear, tumor-derived factors appear, in part at least, to be involved. The effects could be manifested by an altered function and/or via an influence on the migratory properties of individual cell subsets. A better insight into endogenous immunoregulatory mechanisms and the capacity of tumors to modify the phenotype and function of innate and adaptive immune cells might assist the development of new immunotherapeutic approaches and improve the management of patients with cancer. This article reviews current knowledge relating to the influence of tumors on protective anti-tumor immunity and considers the potential influence that radiation-induced effects might have on the prevalence, phenotype, and function of innate and adaptive immune cells in patients with cancer. PMID:23378947

Plantamajoside, a potential anti-tumor herbal medicine inhibits breast cancer growth and pulmonary metastasis by decreasing the activity of matrix metalloproteinase-9 and -2.

PubMed

Pei, Shimin; Yang, Xu; Wang, Huanan; Zhang, Hong; Zhou, Bin; Zhang, Di; Lin, Degui

2015-12-16

Metastasis is the major cause of death in breast cancers. MMPs play a key role in tumor microenvironment that facilitates metastasis. The existing researches suggest that the high expression of gelatinase A and B (MMP2 and MMP9) promote the metastasis of breast cancer. Therefore, gelatinase inhibitor can effectively suppress tumor metastasis. However, at present, there is no dramatically effective gelatinase inhibitor against breast cancer. We screened gelatinase inhibitor among Chinese herbal medicine by molecular docking technology; investigated the proliferation, migration and invasion of MDA-MB-231 human breast cancer cell line and 4T1 mouse breast cancer cell line in response to the treatment with the screened inhibitor by wound assay, invasion assay and gelatin zymography; then further examined the effects of inhibitor on allograft mammary tumors of mice by immunohistochemistry. We successfully screened an Chinese herbal medicine-Plantamajoside(PMS)-which can reduce the gelatinase activity of MMP9 and MMP2. In vitro, PMS can inhibit the proliferation, migration and invasion of MDA-MB-231 human breast cancer cell line and 4T1 mouse breast cancer cell line by decreasing MMP9 and MMP2 activity. In vivo, oral administration of PMS to the mice bearing 4T1 cells induced tumors resulted in significant reduction in allograft tumor volume and weights, significant decrease in microvascular density and significant lower lung metastasis rate. Our results indicate that as a promising anti-cancer agent, PMS may inhibit growth and metastasis of breast cancer by inhibiting the activity of MMP9 and MMP2.

Targeted delivery of doxorubicin into tumor cells by nanostructured lipid carriers conjugated to anti-EGFRvIII monoclonal antibody.

PubMed

Abdolahpour, Saeideh; Toliyat, Tayebeh; Omidfar, Kobra; Modjtahedi, Helmout; Wong, Albert J; Rasaee, Mohammad Javad; Kashanian, Susan; Paknejad, Maliheh

2018-02-01

Epidermal growth factor receptor variant III (EGFRvIII) is the most common variant of the EGF receptor in many human tumors. This variant is tumor specific and highly immunogenic, thus, it can be used as a target for targeted drug delivery toward tumor cells. The major aim of this study was to develop an EGFRvIII-mediated drug delivery system by anti-EGFRvIII monoclonal antibody (MAb) conjugated to doxorubicin (Dox)-loaded nanostructured lipid carriers (NLC) to enhance the targeting specificity and cytotoxic effect of Dox on EGFRvIII-overexpressing cell line. In our study, Dox was chosen as a hydrophobic cytotoxic drug and drug-loaded nanostructured lipid carriers (Dox-NLC) was prepared by solvent emulsification/evaporation method. In order to conjugate anti-EGFRvIII MAb to Dox-NLC, DSPE-PEG2000-NHS (1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000-NHS) was used as a linker. Physicochemical characteristics of antibody conjugated Dox-NLC (MAb-Dox-NLC), including particle size, zeta potential, entrapment efficiency and in vitro Dox release were investigated. Cytotoxicity of MAb-Dox-NLC against NIH-3T3 and HC2 20d2/c (EGFRvIII-transfected NIH-3T3) cell lines was evaluated. The MAb-Dox-NLC appeared to enhance the cytotoxic activity of targeted NLC against HC2 20d2/c cells. The cellular uptake percentage of targeted NLC by HC2 20d2/c cells was higher than that of NIH-3T3 cells, indicating that EGFRvIII can specifically target HC2 20d2/c cells. In conclusion, anti-EGFRvIII MAb-targeted NLC may be considered as an effective nanocarrier for targeted drug delivery.

Modeling Protective Anti-Tumor Immunity via Preventative Cancer Vaccines Using a Hybrid Agent-based and Delay Differential Equation Approach

PubMed Central

Kim, Peter S.; Lee, Peter P.

2012-01-01

A next generation approach to cancer envisions developing preventative vaccinations to stimulate a person's immune cells, particularly cytotoxic T lymphocytes (CTLs), to eliminate incipient tumors before clinical detection. The purpose of our study is to quantitatively assess whether such an approach would be feasible, and if so, how many anti-cancer CTLs would have to be primed against tumor antigen to provide significant protection. To understand the relevant dynamics, we develop a two-compartment model of tumor-immune interactions at the tumor site and the draining lymph node. We model interactions at the tumor site using an agent-based model (ABM) and dynamics in the lymph node using a system of delay differential equations (DDEs). We combine the models into a hybrid ABM-DDE system and investigate dynamics over a wide range of parameters, including cell proliferation rates, tumor antigenicity, CTL recruitment times, and initial memory CTL populations. Our results indicate that an anti-cancer memory CTL pool of 3% or less can successfully eradicate a tumor population over a wide range of model parameters, implying that a vaccination approach is feasible. In addition, sensitivity analysis of our model reveals conditions that will result in rapid tumor destruction, oscillation, and polynomial rather than exponential decline in the tumor population due to tumor geometry. PMID:23133347

IL-15 superagonist/IL-15RαSushi-Fc fusion complex (IL-15SA/IL-15RαSu-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8+ T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas.

PubMed

Kim, Peter S; Kwilas, Anna R; Xu, Wenxin; Alter, Sarah; Jeng, Emily K; Wong, Hing C; Schlom, Jeffrey; Hodge, James W

2016-03-29

Interleukin (IL)-15-N72D superagonist-complexed with IL-15RαSushi-Fc fusion protein (IL-15SA/IL-15RαSu-Fc; ALT-803) has been reported to exhibit significant anti-tumor activity in murine myeloma, rat bladder cancer, and murine glioblastoma models. In this study, we examined the immunomodulatory and anti-tumor effects of IL-15SA/IL-15RαSu-Fc in tumor-free and highly metastatic tumor-bearing mice. Here, IL-15SA/IL-15RαSu-Fc significantly expanded natural killer (NK) and CD8+ T cells. In examining NK cell subsets, the greatest significant increase was in highly cytotoxic and migrating (CD11b+, CD27hi; high effector) NK cells, leading to enhanced function on a per-cell basis. CD8+ T cell subset analysis determined that IL-15SA/IL-15RαSu-Fc significantly increased IL-15 responding memory (CD122+, CD44+) CD8+ T cells, in particular those having the innate (NKG2D+, PD1-) phenotype. In 4T1 breast tumor-bearing mice, IL-15SA/IL-15RαSu-Fc induced significant anti-tumor activity against spontaneous pulmonary metastases, depending on CD8+ T and NK cells, and resulting in prolonged survival. Similar anti-tumor activity was seen in the experimental pulmonary metastasis model of CT26 colon carcinoma cells, particularly when IL-15SA/IL-15RαSu-Fc was combined with a cocktail of checkpoint inhibitors, anti-CTLA-4 and anti-PD-L1. Altogether, these studies showed for the first time that IL-15SA/IL-15RαSu-Fc (1) promoted the development of high effector NK cells and CD8+ T cell responders of the innate phenotype, (2) enhanced function of NK cells, and (3) played a vital role in reducing tumor metastasis and ultimately survival, especially in combination with checkpoint inhibitors.

Mechanisms Underlying the Anti-Aging and Anti-Tumor Effects of Lithocholic Bile Acid

PubMed Central

Arlia-Ciommo, Anthony; Piano, Amanda; Svistkova, Veronika; Mohtashami, Sadaf; Titorenko, Vladimir I.

2014-01-01

Bile acids are cholesterol-derived bioactive lipids that play essential roles in the maintenance of a heathy lifespan. These amphipathic molecules with detergent-like properties display numerous beneficial effects on various longevity- and healthspan-promoting processes in evolutionarily distant organisms. Recent studies revealed that lithocholic bile acid not only causes a considerable lifespan extension in yeast, but also exhibits a substantial cytotoxic effect in cultured cancer cells derived from different tissues and organisms. The molecular and cellular mechanisms underlying the robust anti-aging and anti-tumor effects of lithocholic acid have emerged. This review summarizes the current knowledge of these mechanisms, outlines the most important unanswered questions and suggests directions for future research. PMID:25238416

Anti-tumor and Anti-angiogenic Effects of Aspirin-PC in Ovarian Cancer

PubMed Central

Huang, Yan; Lichtenberger, Lenard M.; Taylor, Morgan; Bottsford-Miller, Justin N.; Haemmerle, Monika; Wagner, Michael J.; Lyons, Yasmin; Pradeep, Sunila; Hu, Wei; Previs, Rebecca A.; Hansen, Jean M.; Fang, Dexing; Dorniak, Piotr L.; Filant, Justyna; Dial, Elizabeth J.; Shen, Fangrong; Hatakeyama, Hiroto; Sood, Anil K.

2016-01-01

To determine the efficacy of a novel and safer (for gastrointestinal tract) aspirin (aspirin-PC) in preclinical models of ovarian cancer, in vitro dose-response studies were performed to compare the growth-inhibitory effect of aspirin-PC vs. aspirin on 3 human (A2780, SKOV3ip1, HeyA8), and a mouse (ID8) ovarian cancer cell line over an 8-day culture period. In the in vivo studies, the aspirin test drugs were studied alone and in the presence of a VEGF-A inhibitor (bevacizumab or B20), due to an emerging role for platelets in tumor growth following anti-angiogenic therapy, and we examined their underlying mechanisms. Aspirin-PC was more potent (vs. aspirin) in blocking the growth of both human and mouse ovarian cancer cells in monolayer culture. Using in vivo model systems of ovarian cancer, we found that aspirin-PC significantly reduced ovarian cancer growth by 50–90% (depending on the ovarian cell line/density). The efficacy was further enhanced in combination with Bevacizumab or B20. The growth-inhibitory effect on ovarian tumor mass and number of tumor nodules was evident, but less pronounced for aspirin and the VEGF inhibitors alone. There was no detectable gastrointestinal toxicity. Both aspirin and aspirin-PC also inhibited cell proliferation, angiogenesis and increased apoptosis of ovarian cancer cells. In conclusion, PC-associated aspirin markedly inhibits the growth of ovarian cancer cells, which exceeds that of the parent drug, in both cell culture and in mouse model systems. We also found that both aspirin-PC and aspirin have robust anti-neoplastic action in the presence of VEGF blocking drugs. PMID:27638860

Tumor Necrosis Factor-α Sensitizes Breast Cancer Cells to Natural Products with Proteasome-Inhibitory Activity Leading to Apoptosis

PubMed Central

Lu, Li; Shi, Wenli; Deshmukh, Rahul R.; Long, Jie; Cheng, Xiaoli; Ji, Weidong; Zeng, Guohua; Chen, Xianliang; Zhang, Yajie; Dou, Q. Ping

2014-01-01

The inflammatory microenvironment plays an important role in the process of tumor development. Tumor necrosis factor-α (TNF-α), a key pro-inflammatory cytokine, has a significant role in this process. Natural medicinal products such as Withaferin A (WA) and Celastrol (Cel) have shown anti-cancer and anti-inflammatory properties that can be attributed to multiple mechanisms including, but not limited to, apoptosis induction due to the inhibition of proteasomal activities. This study aimed to investigate the effects of TNF-α in combination with WA or Cel in vitro in MDA-MB-231 breast cancer cells. TNF-α, when combined with WA or Cel, activated caspase-3 and -9 and downregulated XIAP in a dose-dependent manner, leading to induction of apoptosis in MDA-MB-231 breast cancer cells. The combination also caused accumulation of the proteasomal target protein IκBα, resulting in inhibition of the nuclear translocation of nuclear factor-κB (NF-κB). Taken together, these results suggest that TNF-α could sensitize breast cancer cells MDA-MB-231 to WA and Cel, at least in part, through inhibiting the activation of NF-κB signaling, leading to XIAP inhibition with subsequent upregulation of caspase-3 and -9 activities. Thus, the anti-cancer activities of TNF-α are enhanced when combined with the natural proteasome inhibitors, WA or Cel. PMID:25419573

Anti-tumor Effects of Plasma Activated Media and Correlation with Hydrogen Peroxide Concentration

NASA Astrophysics Data System (ADS)

Laroussi, Mounir; Mohades, Soheila; Barekzi, Nazir; Maruthamuthu, Venkat; Razavi, Hamid

2016-09-01

Plasma activated media (PAM) can induce death in cancer cells. In our research, PAM is produced by exposing liquid culture medium to a helium plasma pencil. Reactive oxygen and nitrogen species in the aqueous state are known factors in anti-tumor effects of PAM. The duration of plasma exposure determines the concentrations of reactive species produced in PAM. Stability of the plasma generated reactive species and their lifetime depend on parameters such as the chemical composition of the medium. Here, a complete cell culture medium was employed to make PAM. Later, PAM was used to treat SCaBER cancer cells either as an immediate PAM (right after exposure) or as an aged-PAM (after storage). SCaBER (ATCC®HTB-3™) is an epithelial cell line from a human bladder with the squamous carcinoma disease. A normal epithelial cell line from a kidney tissue of a dog - MDCK (ATCC®CCL-34™) - was used to analyze the selective effect of PAM. Correspondingly, we measured the concentration of hydrogen peroxide- as a stable species with biological impact on cell viability- in both immediate PAM and aged-PAM. In addition, we report on the effect of serum supplemented in PAM on the H2O2 concentration measured by Amplex red assay kit. Finally, we evaluate the effects of PAM on growth and morphological changes in MDCK cells using fluorescence microscopy.

Progression of undiagnosed cutaneous lymphoma after anti-tumor necrosis factor-alpha therapy.

PubMed

Martinez-Escala, Maria Estela; Posligua, Alba L; Wickless, Heather; Rutherford, Audrey; Sable, Kimberly A; Rubio-Gonzalez, Belen; Zhou, Xiaolong A; Kaplan, Jason B; Pro, Barbara; Choi, Jaehyuk; Querfeld, Christiane; Rosen, Steven T; Guitart, Joan

2018-06-01

Cutaneous lymphoma diagnosed after anti-tumor necrosis factor-α therapy (anti-TNF-α) has been reported in the literature, yet a clear link between both events remains elusive. To review our experience with cutaneous lymphoma diagnosed during or after the use of anti-TNF-α therapies. This is a multicenter retrospective study and a literature review. A total of 22 cases, including 20 cutaneous T-cell lymphomas (CTCLs) and 2 cutaneous B-cell lymphomas, were identified. In the CTCL group, 75% of the patients received an anti-TNF-α agent for a presumed inflammatory skin condition. Mycosis fungoides and Sézary syndrome were the most common subtypes of CTCL diagnosed. Advanced disease (stage IIB to IVA) was commonly seen at time of diagnosis and required aggressive therapy, including stem cell transplant in 3 patients; 2 patients in whom cutaneous B-cell lymphomas was diagnosed had an indolent course. A total of 31 cases were gathered from a literature search. This is a retrospective study. Our findings suggest that the disease of most of the identified patients was misdiagnosed as psoriasis or eczema; therefore, a comprehensive morphologic and molecular review of skin biopsy specimens and peripheral blood samples should be considered before initiation of anti-TNF-α therapy in patients with poorly defined dermatitis or atypical presentations of psoriasis. Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

KML001 displays vascular disrupting properties and irinotecan combined antitumor activities in a murine tumor model.

PubMed

Moon, Chang Hoon; Lee, Seung Ju; Lee, Ho Yong; Lee, Jong Cheol; Cha, Heejeong; Cho, Wha Ja; Park, Jeong Woo; Park, Hyun Jin; Seo, Jin; Lee, Young Han; Song, Ho-Taek; Min, Young Joo

2013-01-01

KML001 is sodium metaarsenite, and has shown cytotoxic activity in human tumor cell lines. The anti-cancer mechanism of KML001 involves cancer cell destruction due to DNA damage at the telomeres of cancer cell chromosomes. In this study, we assessed the vascular disrupting properties of KML001 and investigated whether KML001 as VDA is able to increase anti-tumor activity in irinotecan combined treatment. We used a murine model of the CT26 colon carcinoma cell line. CT26 isograft mice treated intraperitoneally with 10 mg/kg KML001 displayed extensive central necrosis of tumor by 24 h. The vascular disrupting effects of KML001 were assessed by dynamic contrast enhanced magnetic resonance imaging. Gadopentetic acid-diethylene triaminepentaacetic acid contrast enhancement was markedly decreased in KML001-treated mice one day after treatment, whereas persistently high signal enhancement was observed in mice injected with saline. Rate constant K(ep) value representing capillary permeability was significantly decreased (p<0.05) in mice treated with KML001. Cytoskeletal changes of human umbilical vein endothelial cells (HUVECs) treated with 10 uM KML001 were assessed by immune blotting and confocal imaging. KML001 degraded tubulin protein in HUVECs, which may be related to vascular disrupting properties of KML001. Finally, in the mouse CT26 isograft model, KML001 combined with irinotecan significantly delayed tumor growth as compared to control and irinotecan alone. These results suggest that KML001 is a novel vascular disrupting agent, which exhibits significant vascular shut-down activity and enhances anti-tumor activity in combination with chemotherapy. These data further suggest an avenue for effective combination therapy in treating solid tumors.

KML001 Displays Vascular Disrupting Properties and Irinotecan Combined Antitumor Activities in a Murine Tumor Model

PubMed Central

Moon, Chang Hoon; Lee, Seung Ju; Lee, Ho Yong; Lee, Jong Cheol; Cha, HeeJeong; Cho, Wha Ja; Park, Jeong Woo; Park, Hyun Jin; Seo, Jin; Lee, Young Han; Song, Ho-Taek; Min, Young Joo

2013-01-01

KML001 is sodium metaarsenite, and has shown cytotoxic activity in human tumor cell lines. The anti-cancer mechanism of KML001 involves cancer cell destruction due to DNA damage at the telomeres of cancer cell chromosomes. In this study, we assessed the vascular disrupting properties of KML001 and investigated whether KML001 as VDA is able to increase anti-tumor activity in irinotecan combined treatment. We used a murine model of the CT26 colon carcinoma cell line. CT26 isograft mice treated intraperitoneally with 10 mg/kg KML001 displayed extensive central necrosis of tumor by 24 h. The vascular disrupting effects of KML001 were assessed by dynamic contrast enhanced magnetic resonance imaging. Gadopentetic acid-diethylene triaminepentaacetic acid contrast enhancement was markedly decreased in KML001-treated mice one day after treatment, whereas persistently high signal enhancement was observed in mice injected with saline. Rate constant Kep value representing capillary permeability was significantly decreased (p<0.05) in mice treated with KML001. Cytoskeletal changes of human umbilical vein endothelial cells (HUVECs) treated with 10 uM KML001 were assessed by immune blotting and confocal imaging. KML001 degraded tubulin protein in HUVECs, which may be related to vascular disrupting properties of KML001. Finally, in the mouse CT26 isograft model, KML001 combined with irinotecan significantly delayed tumor growth as compared to control and irinotecan alone. These results suggest that KML001 is a novel vascular disrupting agent, which exhibits significant vascular shut-down activity and enhances anti-tumor activity in combination with chemotherapy. These data further suggest an avenue for effective combination therapy in treating solid tumors. PMID:23326531

Anti-Ma2 paraneoplastic encephalitis associated with testicular germ cell tumor treated by carboplatin, etoposide and bleomycin.

PubMed

Kimura, Masaki; Onozawa, Mizuki; Fujisaki, Akira; Arakawa, Takashi; Takeda, Katsuhiko; Dalmau, Joseph; Hattori, Kazunori

2008-10-01

Anti-Ma2-associated encephalitis is a paraneoplastic disorder that predominantly affects the limbic system, diencephalon and brainstem, and is usually associated with tumors of the testis. We report a 35-year-old man with a right testicular mass who presented with multiple neurological complains, and clinical, serological and radiological features compatible with anti-Ma2-associated encephalitis. After three courses of carboplatin, etoposide and bleomycin for metastatic testicular germ-cell tumor, all elevated tumor markers normalized and the retroperitoneal metastases disappeared, but the neurological disorder deteriorated. To our knowledge, this is the first case in which orchiectomy followed by carboplatin, etoposide and bleomycin for a testicular tumor with anti-Ma2 encephalitis was performed.

Oleuropein potentiates anti-tumor activity of cisplatin against HepG2 through affecting proNGF/NGF balance.

PubMed

Sherif, Iman O; Al-Gayyar, Mohammed M H

2018-04-01

Oleuropein is considered as a new chemotherapeutic agent in human hepatocellular carcinoma (HCC) while, its exact underlying molecular mechanism still not yet explored. In addition, cisplatin is a standard anticancer drug against solid tumors with toxic side effects. Therefore, we conducted this study to assess antitumor activity of oleuropein either alone or in combination with cisplatin against HepG2, human HCC cell lines, via targeting pro-NGF/NGF signaling pathway. HepG2 cells were treated with cisplatin (20, 50, 100 μM) and oleuropein (100, 200, 300 and 400 μM) as well as some of the cells were treated with 50 μM cisplatin and different concentrations of oleuropein. Gene expressions of nerve growth factor (NGF), matrix metalloproteinase-7 (MMP-7) and caspase-3 were evaluated by real time-PCR. In addition, protein levels of NGF and pro-form of NGF (pro-NGF) were measured by ELISA while, nitric oxide (NO) content was determined colorimetrically. Cisplatin treatment showed a significant elevation of NO content and pro-NGF protein level with a marked reduction of NGF protein level in addition to the upregulation of caspase-3 along with downregulation of MMP-7 gene expressions in a dose-dependent manner. However, the combination of 50 μM cisplatin and 200 μM oleuropein showed the most potent effect on the molecular level when compared with oleuropein or cisplatin alone. Our results showed for the first time that the anti-tumor activity of oleuropein against HCC could be attributed to influencing the pro-NGF/NGF balance via affecting MMP-7 activity without affecting the gene expression of NGF. Concurrent treatment with both oleuropein and cisplatin could lead to more effective chemotherapeutic combination against HCC. Copyright © 2018 Elsevier Inc. All rights reserved.

Stat6 activity-related Th2 cytokine profile and tumor growth advantage of human colorectal cancer cells in vitro and in vivo.

PubMed

Li, Ben Hui; Xu, Shuang Bing; Li, Feng; Zou, Xiao Guang; Saimaiti, Abudukeyoumu; Simayi, Dilixia; Wang, Ying Hong; Zhang, Yan; Yuan, Jia; Zhang, Wen Jie

2012-03-01

Signal transducer and activator of transcription 6 (Stat6) is critical in Th2 polarization of immune cells and active Stat6 activity has been suggested in anti-tumor immunity in animal models. The present study aims at investigating the impact of natural Stat6 activity on tumor microenvironment in human colorectal cancer cells in vitro and in vivo. Using colorectal cancer cell lines HT-29 and Caco-2 whose IL-4/Stat6 activities were known and nude mice as a model, we examined correlative relationships between Stat6 activities and gene expression profiles together with cellular behaviors in vitro and in vivo. HT-29 cells carrying active Stat6 signaling displayed spontaneous expression profiles favoring Th2 cytokines, cell cycle promotion, anti-apoptosis and pro-metastasis with increased mRNA levels of IL-4, IL-13, GATA-3, CDK4, CD44v6 and S100A4 using RT-PCR. In contrast, Caco-2 cells carrying defective Stat6 signaling exhibited spontaneous expression profiles favoring Th1 and Th17 cytokines, cell cycle inhibition, pro-apoptosis and anti-metastasis with elevated mRNA expression of IFNγ, TNFα, IL-12A, IL-17, IL-23, T-bet, CDKN1A, CDKNIB, CDKN2A and NM23-H1. Xenograft tumors of Stat6-active HT-29 cells showed a growth advantage over those of Stat6-defective Caco-2 cells. Furthermore, mice bearing HT-29 tumors expressed increased levels of Th2 cytokines IL-4 and IL-5 in the blood and pro-growth and/or pro-metastasis proteins CDK4 and CD44v6 in the tumor. To the contrary, mice bearing Caco-2 tumors expressed heightened levels of Th1 cytokines IFNγ and TNF in the blood and pro-apoptosis and anti-metastatic proteins p53 and p27(kip1) in the tumor. Colorectal cancer cells carrying active Stat6 signaling may create a microenvironment favoring Th2 cytokines and promoting expression of genes related to pro-growth, pro-metastasis and anti-apoptosis, which leads to a tumor growth advantage in vivo. These findings may imply why Stat6 pathway is constitutively activated in a

Ginsenoside G-Rh2 synergizes with SMI-4a in anti-melanoma activity through autophagic cell death.

PubMed

Lv, Da-Lun; Chen, Lei; Ding, Wei; Zhang, Wei; Wang, He-Li; Wang, Shuai; Liu, Wen-Bei

2018-01-01

Melanoma is a leading cause of cancer death worldwide, and SMI-4a and G-Rh2 exert anti-tumor activity in multiple cancer. However, SMI-4a as well as a synergistic relationship between SMI-4a and G-Rh2 in anti-melanoma capacity are still unknown. Therefore, we investigated the effects of SMI-4a and combined SMI-4a with G-Rh2 on the viability, apoptosis and autophagy of melanoma, and to preliminarily explore the underlying mechanism of SMI-4a and combined SMI-4a with G-Rh2 in inhibiting tumor growth. Cell viability was examined with cell counting Kit 8 assay and colony formation assay; Apoptosis was evaluated by flow cytometry and Caspase 3/7 activity assay; Western blotting was used to test proteins related to autophagy and the AKT/mammalian target of rapamycin (mTOR) signaling pathway; Tumor xenograft model in BALB/c nude mice was performed to evaluate the effects of SMI-4a and combined SMI-4a with G-Rh2 in anti-melanoma in vivo. SMI-4a, a pharmacological inhibitor of PIM-1, could decrease cell viability, induce apoptosis, and promote Caspase 3/7 activity in both A375 and G361 melanoma cells, and SMI-4a inhibited tumor growth by inducing autophagy via down-regulating AKT/mTOR axis in melanoma cells. Furthermore, G-Rh2 amplified the anti-tumor activity of SMI-4a in melanoma cells via strengthening autophagy. Our results suggested that SMI-4a could enhance autophagy-inducing apoptosis by inhibiting AKT/mTOR signaling pathway in melanoma cells, and G-Rh2 could enhance the effects of SMI-4a against melanoma cancer via amplifying autophagy induction. This study demonstrates that combined SMI-4a and G-Rh2 might be a novel alternative strategy for melanoma treatment.

Anti-cancer, anti-diabetic and other pharmacologic and biological activities of penta-galloyl-glucose

PubMed Central

Zhang, Jinhui; Li, Li; Kim, Sung-Hoon; Hagerman, Ann E.; Lü, Junxuan

2010-01-01

1, 2, 3, 4, 6-penta-O-galloyl-β-D-glucose (PGG) is a polyphenolic compound highly enriched in a number of medicinal herbals. Several in vitro and a handful of in vivo studies have shown that PGG exhibits multiple biological activities which implicate a great potential for PGG in the therapy and prevention of several major diseases including cancer and diabetes. Chemically and functionally, PGG appears to be distinct from its constituent gallic acid or tea polyphenols. For anti-cancer activity, three published in vivo preclinical cancer model studies with PGG support promising efficacy to selectively inhibit malignancy without host toxicity. Potential mechanisms include anti-angiogenesis, anti-proliferative actions through inhibition of DNA replicative synthesis and S-phase arrest and also G1 arrest, induction of apoptosis, anti-inflammation and anti-oxidation. Putative molecular targets include p53, Stat3, Cox-2, VEGFR1, AP-1, SP-1, Nrf-2 and MMP-9. For anti-diabetic activity, PGG and analogues appear to improve glucose uptake. However, very little is known about the absorption, pharmacokinetics and metabolism of PGG, nor its toxicity profile. The lack of large quantity of highly pure PGG has been a bottleneck limiting in vivo validation of cancer preventive and therapeutic efficacies in clinically relevant models. PMID:19575286

Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP.

PubMed

Lev, Avital; Lulla, Amriti R; Wagner, Jessica; Ralff, Marie D; Kiehl, Joshua B; Zhou, Yan; Benes, Cyril H; Prabhu, Varun V; Oster, Wolfgang; Astsaturov, Igor; Dicker, David T; El-Deiry, Wafik S

2017-10-10

Pancreatic cancer is chemo-resistant and metastasizes early with an overall five-year survival of ∼8.2%. First-in-class imipridone ONC201 is a small molecule in clinical trials with anti-cancer activity. ONC212, a fluorinated-ONC201 analogue, shows preclinical efficacy in melanoma and hepatocellular-cancer models. We investigated efficacy of ONC201 and ONC212 against pancreatic cancer cell lines ( N =16 including 9 PDX-cell lines). We demonstrate ONC212 efficacy in 4 in-vivo models including ONC201-resistant tumors. ONC212 is active in pancreatic cancer as single agent or in combination with 5-fluorouracil, irinotecan, oxaliplatin or RTK inhibitor crizotinib. Based on upregulation of pro-survival IGF1-R in some tumors, we found an active combination of ONC212 with inhibitor AG1024, including in vivo . We show a rationale for targeting pancreatic cancer using ONC212 combined with targeting the unfolded-protein response and ER chaperones such as GRP78/BIP. Our results lay the foundation to test imipridones, anti-cancer agents, in pancreatic cancer, that is refractory to most drugs.

Anti-CD20 antibody induces the improvement of cytokine-induced killer cell activity via the STAT and MAPK/ERK signaling pathways

PubMed Central

DENG, QI; BAI, XUE; LV, HAI-RONG; XIAO, XIA; ZHAO, MING-FENG; LI, YU-MING

2015-01-01

There is a current requirement for novel therapeutic strategies for the treatment of hematopoietic tumors. Residual tumor cells are the main origin of tumor relapse. The aim of this study was to eliminate the residual tumor cells of hematopoietic tumors. Cytokine-induced killer (CIK) cells are used in immunotherapy to deplete the residual cells. However, it is necessary to increase the antitumor activity and clinical applicability of CIK cells. The present study investigated the antitumor activity of CIK cells to the SU-DHL2 human B-cell lymphoma and K562 human chronic myelogenous leukemia cell lines. CD3+CD56+ cells from healthy donors were expanded in culture with cytokines and anti-CD20 monoclonal antibody (mAb; rituximab) to generate CIK cells. A preliminary investigation of their mechanism was then performed. The increase in the cytotoxicity of the CIK cells induced by the anti-CD20 mAb was associated with an increase in the expression of cytotoxic factors. The expression of components of the signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways was found to increase. Upregulation of the expression of STAT1, STAT3 and STAT5 is important as these co-stimulatory molecules enhance T-cell proliferation. Activation of the MAPK signaling pathway is a possible mechanism for the anti-apoptosis effect on the proliferation of CIK cells. In conclusion, anti-CD20 mAb may play an important role in the improvement of CIK-mediated cytotoxicity to tumor cells. These observations may aid in the improvement of the effects of immunotherapy in depleting the residual cells of hematopoietic tumors. Thus, the use of CIK cells cultured with anti-CD20 mAb could be a novel therapeutic strategy for the depletion of chemotherapy-resistant or residual cells in anaplastic large and B-cell lymphoma. PMID:25780412

Bromelain inhibits COX-2 expression by blocking the activation of MAPK regulated NF-kappa B against skin tumor-initiation triggering mitochondrial death pathway.

PubMed

Bhui, Kulpreet; Prasad, Sahdeo; George, Jasmine; Shukla, Yogeshwer

2009-09-18

Chemoprevention impels the pursuit for either single targeted or cocktail of multi-targeted agents. Bromelain, potential agent in this regard, is a pharmacologically active compound, present in stems and fruits of pineapple (Ananas cosmosus), endowed with anti-inflammatory, anti-invasive and anti-metastatic properties. Herein, we report the anti tumor-initiating effects of bromelain in 2-stage mouse skin tumorigenesis model. Pre-treatment of bromelain resulted in reduction in cumulative number of tumors (CNT) and average number of tumors per mouse. Preventive effect was also comprehended in terms of reduction in tumor volume up to a tune of approximately 65%. Components of the cell signaling pathways, connecting proteins involved in cell death were targeted. Bromelain treatment resulted in upregulation of p53 and Bax and subsequent activation of caspase 3 and caspase 9 with concomitant decrease in Bcl-2. A marked inhibition in cyclooxygenase-2 (Cox-2) expression and inactivation of nuclear factor-kappa B (NF-kappaB) was recorded, as phosphorylation and consequent degradation of I kappa B alpha was blocked by bromelain. Also, bromelain treatment curtailed extracellular signal regulated protein kinase (ERK1/2), p38 mitogen-activated protein kinase (MAPK) and Akt activity. The basis of anti tumor-initiating activity of bromelain was revealed by its time dependent reduction in DNA nick formation and increase in percentage prevention. Thus, modulation of inappropriate cell signaling cascades driven by bromelain is a coherent approach in achieving chemoprevention.

Toll-like receptor 9 agonist enhances anti-tumor immunity and inhibits tumor-associated immunosuppressive cells numbers in a mouse cervical cancer model following recombinant lipoprotein therapy.

PubMed

Chang, Li-Sheng; Leng, Chih-Hsiang; Yeh, Yi-Chen; Wu, Chiao-Chieh; Chen, Hsin-Wei; Huang, Hai-Mei; Liu, Shih-Jen

2014-03-19

Although cytotoxic T lymphocytes (CTLs) play a major role in eradicating cancer cells during immunotherapy, the cancer-associated immunosuppressive microenvironment often limits the success of such therapies. Therefore, the simultaneous induction of cancer-specific CTLs and reversal of the immunosuppressive tumor microenvironment may be more effectively achieved through a single therapeutic vaccine. A recombinant lipoprotein with intrinsic Toll-like receptor 2 (TLR2) agonist activity containing a mutant form of E7 (E7m) and a bacterial lipid moiety (rlipo-E7m) has been demonstrated to induce robust CTL responses against small tumors. This treatment in combination with other TLR agonists is able to eliminate large tumors. Mouse bone marrow-derived dendritic cells (DCs) were employed to determine the synergistic production of pro-inflammatory cytokines upon combination of rlipo-E7m and other TLR agonists. Antigen-specific CTL responses were investigated using immunospots or in vivo cytolytic assays after immunization in mice. Mice bearing various tumor sizes were used to evaluate the anti-tumor effects of the formulation. Specific subpopulations of immunosuppressive cells in the tumor infiltrate were quantitatively determined by flow cytometry. We demonstrate that a TLR9 agonist (unmethylated CpG oligodeoxynucleotide, CpG ODN) enhances CTL responses and eradicates large tumors when combined with rlipo-E7m. Moreover, combined treatment with rlipo-E7m and CpG ODN effectively increases tumor infiltration by CTLs and reduces the numbers of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) in the tumor microenvironment. These findings suggest that the dramatic anti-tumor effects of the recombinant lipoprotein together with CpG ODN may reflect the amplification of CTL responses and the repression of the immunosuppressive environment. This promising approach could be applied for the development of additional

The Effects of Different Purifying Methods on the Chemical Properties, in Vitro Anti-Tumor and Immunomodulatory Activities of Abrus cantoniensis Polysaccharide Fractions

PubMed Central

Wu, Shaowei; Fu, Xiong; Brennan, Margaret A.; Brennan, Charles S.; Chun, Chen

2016-01-01

Abrus cantoniensis (Hance) is a popular Chinese vegetable consumed as a beverage, soup or folk medicine. To fully exploit the potential of the polysaccharide in Abrus cantoniensis, nine polysaccharide fractions of Abrus cantoniensis were isolated and purified (AP-AOH30-1, AP-AOH30-2, AP-AOH80-1, AP-AOH80-2, AP-ACl-1, AP-ACl-2, AP-ACl-3, AP-H and AP-L). Fourier-transform infrared spectroscopy (FT-IR) and gas chromatography (GC) were used to characterize these Abrus polysaccharides fractions (APF). In vitro anti-tumor and immunomodulatory activities were also investigated and compared using the rank-sum ratio (RSR) method. Results demonstrated significant differences in the structure and bioactivities among APF, which were associated to the process used for their purification. Among the APF, AP-ACl-3 yield was 613.5 mg/kg of product and consisted of rhamnose (9.8%), arabinose (8.9%), fructose (3.0%), galactose (9.9%), glucose (4.3%), galacturonic acid (3.0%) and glucuronic acid (61.1%) with a molecular weight of 4.4 × 104 Da. Furthermore, AP-ACl-3 exhibited considerable bioactivities significantly preventing the migration of MCF-7 cells and stimulating lymphocyte proliferation along with nitric oxide (NO) production of peritoneal macrophages. AP-ACl-3 could be explored as a novel potential anti-tumor and immunomodulatory agent. PMID:27058538

Abalone visceral extract inhibit tumor growth and metastasis by modulating Cox-2 levels and CD8+ T cell activity.

PubMed

Lee, Choong-Gu; Kwon, Ho-Keun; Ryu, Jae Ha; Kang, Sung Jin; Im, Chang-Rok; Ii Kim, Jae; Im, Sin-Hyeog

2010-10-20

Abalone has long been used as a valuable food source in East Asian countries. Although the nutritional importance of abalone has been reported through in vitro and in vivo studies, there is little evidence about the potential anti-tumor effects of abalone visceral extract. The aim of the present study is to examine anti-tumor efficacy of abalone visceral extract and to elucidate its working mechanism. In the present study, we used breast cancer model using BALB/c mouse-derived 4T1 mammary carcinoma and investigated the effect of abalone visceral extract on tumor development. Inhibitory effect against tumor metastasis was assessed by histopathology of lungs. Cox-2 productions by primary and secondary tumor were measured by real-time RT-PCR and immunoblotting (IB). Proliferation assay based on [3H]-thymidine incorporation and measurement of cytokines and effector molecules by RT-PCR were used to confirm tumor suppression efficacy of abalone visceral extract by modulating cytolytic CD8+ T cells. The cytotoxicity of CD8+ T cell was compared by JAM test. Oral administration of abalone visceral extract reduced tumor growth (tumor volume and weight) and showed reduced metastasis as confirmed by decreased level of splenomegaly (spleen size and weight) and histological analysis of the lung metastasis (gross analysis and histological staining). Reduced expression of Cox-2 (mRNA and protein) from primary tumor and metastasized lung was also detected. In addition, treatment of abalone visceral extract increased anti-tumor activities of CD8+ T cells by increasing the proliferation capacity and their cytolytic activity. Our results suggest that abalone visceral extract has anti-tumor effects by suppressing tumor growth and lung metastasis through decreasing Cox-2 expression level as well as promoting proliferation and cytolytic function of CD8+ T cells.

Abalone visceral extract inhibit tumor growth and metastasis by modulating Cox-2 levels and CD8+ T cell activity

PubMed Central

2010-01-01

Background Abalone has long been used as a valuable food source in East Asian countries. Although the nutritional importance of abalone has been reported through in vitro and in vivo studies, there is little evidence about the potential anti-tumor effects of abalone visceral extract. The aim of the present study is to examine anti-tumor efficacy of abalone visceral extract and to elucidate its working mechanism. Methods In the present study, we used breast cancer model using BALB/c mouse-derived 4T1 mammary carcinoma and investigated the effect of abalone visceral extract on tumor development. Inhibitory effect against tumor metastasis was assessed by histopathology of lungs. Cox-2 productions by primary and secondary tumor were measured by real-time RT-PCR and immunoblotting (IB). Proliferation assay based on [3H]-thymidine incorporation and measurement of cytokines and effector molecules by RT-PCR were used to confirm tumor suppression efficacy of abalone visceral extract by modulating cytolytic CD8+ T cells. The cytotoxicity of CD8+ T cell was compared by JAM test. Results Oral administration of abalone visceral extract reduced tumor growth (tumor volume and weight) and showed reduced metastasis as confirmed by decreased level of splenomegaly (spleen size and weight) and histological analysis of the lung metastasis (gross analysis and histological staining). Reduced expression of Cox-2 (mRNA and protein) from primary tumor and metastasized lung was also detected. In addition, treatment of abalone visceral extract increased anti-tumor activities of CD8+ T cells by increasing the proliferation capacity and their cytolytic activity. Conclusions Our results suggest that abalone visceral extract has anti-tumor effects by suppressing tumor growth and lung metastasis through decreasing Cox-2 expression level as well as promoting proliferation and cytolytic function of CD8+ T cells. PMID:20961430

Anti-Diabetic, Anti-Oxidant and Anti-Hyperlipidemic Activities of Flavonoids from Corn Silk on STZ-Induced Diabetic Mice.

PubMed

Zhang, Yan; Wu, Liying; Ma, Zhongsu; Cheng, Jia; Liu, Jingbo

2015-12-23

Corn silk is a well-known ingredient frequently used in traditional Chinese herbal medicines. This study was designed to evaluate the anti-diabetic, anti-oxidant and anti-hyperlipidemic activities of crude flavonoids extracted from corn silk (CSFs) on streptozotocin (STZ)-induced diabetic mice. The results revealed that treatment with 300 mg/kg or 500 mg/kg of CSFs significantly reduced the body weight loss, water consumption, and especially the blood glucose (BG) concentration of diabetic mice, which indicated their potential anti-diabetic activities. Serum total superoxide dismutase (SOD) and malondialdehyde (MDA) assays were also performed to evaluate the anti-oxidant effects. Besides, several serum lipid values including total cholesterol (TC), triacylglycerol (TG), low density lipoprotein cholesterol (LDL-C) were reduced and the high density lipoprotein cholesterol level (HDL-C) was increased. The anti-diabetic, anti-oxidant and anti-hyperlipidemic effect of the CSFs suggest a potential therapeutic treatment for diabetic conditions.

[Establishment of EL4 tumor-bearing mouse models and investigation on immunological mechanisms of anti-tumor effect of melphalan].

PubMed

Li, Mo-lin; Li, Chuan-gang; Shu, Xiao-hong; Jia, Yu-jie; Qin, Zhi-hai

2006-03-01

To establish mouse lymphoma EL4 tumor-bearing mouse models in wild type C57BL/6 mice and nude C57BL/6 mice respectively, and to further investigate the immunological mechanisms of anti-tumor effect of melphalan. Mouse lymphoma EL4 cells were inoculated subcutaneously into wild type C57BL/6 mice (immune-competent mice). Twelve days later, melphalan of different doses were administered intraperitoneally to treat these wild type C57BL/6 tuomr-bearing mice. Tumor sizes were observed and recorded subsequently to find out the minimal dose of melphalan that could cure the tuomr-bearing mice. Then the same amount of EL4 tumor cells were inoculated subcutaneously into wild type C57BL/6 mice and nude C57BL/6 mice (T cell-deficient mice) simultaneously, which had the same genetic background of C57BL/6. Twelve days later, melphalan of the minimal dose was given intraperitoneally to treat both the wild type and nude C57BL/6 tuomr-bearing mice. Tumor sizes were observed and recorded in these two different types of mice subsequently. A single dose of melphalan (7.5 mg/kg) could cure EL4 tumor-bearing wild type C57BL/6 mice, but could not induce tumor regression in EL4 tumor-bearing nude C57BL/6 mice. A single dose of melphalan has obvious anti-tumor effect on mouse lymphoma EL4 tumor-bearing wild type C57BL/6mice, which requires the involvement of T lymphocytes in the host probably related to their killing functions.

Combining Anti-ERBB3 Antibodies Specific for Domain I and Domain III Enhances the Anti-Tumor Activity over the Individual Monoclonal Antibodies

PubMed Central

D’Souza, Jimson W.; Shchaveleva, Irina; Marks, James D.; Litwin, Samuel; Robinson, Matthew K.

2014-01-01

Background Inappropriate signaling through the epidermal growth factor receptor family (EGFR1/ERBB1, ERBB2/HER2, ERBB3/HER3, and ERBB4/HER4) of receptor tyrosine kinases leads to unregulated activation of multiple downstream signaling pathways that are linked to cancer formation and progression. In particular, ERBB3 plays a critical role in linking ERBB signaling to the phosphoinositide 3-kinase and Akt signaling pathway and increased levels of ERBB3-dependent signaling is also increasingly recognized as a mechanism for acquired resistance to ERBB-targeted therapies. Methods We had previously reported the isolation of a panel of anti-ERBB3 single-chain Fv antibodies through use of phage-display technology. In the current study scFv specific for domain I (F4) and domain III (A5) were converted into human IgG1 formats and analyzed for efficacy. Results Treatment of cells with an oligoclonal mixture of the A5/F4 IgGs appeared more effective at blocking both ligand-induced and ligand-independent signaling through ERBB3 than either single IgG alone. This correlated with improved ability to inhibit the cell growth both as a single agent and in combination with other ERBB-targeted therapies. Treatment of NCI-N87 tumor xenografts with the A5/F4 oligoclonal led to a statistically significant decrease in tumor growth rate that was further enhanced in combination with trastuzumab. Conclusion These results suggest that an oligoclonal antibody mixture may be a more effective approach to downregulate ERBB3-dependent signaling. PMID:25386657

Novel biotransformation process of podophyllotoxin to 4 β-sulfur-substituted podophyllum derivates with anti-tumor activity by Penicillium purpurogenum Y.J. Tang.