Cisplatin and doxorubicin repress Vascular Endothelial Growth Factor expression and differentially down-regulate Hypoxia-inducible Factor I activity in human ovarian cancer cells

Duyndam, Monique C.A.; Berkel, Maria P.A. van; Dorsman, Josephine C.; Rockx, Davy; Pinedo, H.M.; Boven, Epie

doi:10.1016/j.bcp.2007.04.003

Cited by 62 publications

(56 citation statements)

References 36 publications

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“…A previous study reported that the anthracycline aclacinomycin B inhibited expression of a HIF-1-dependent reporter gene in Chinese hamster ovary cells, but, in contrast to our results, this study reported that neither DXR nor DNR had an inhibitory effect (20). DXR was shown to inhibit hypoxia-induced VEGF mRNA expression in cultured ovarian cancer cells, but the mechanism of action was not established (21). Anthracyclines have been reported to inhibit AP1, GATA4, and SP1 (22)(23)(24), indicating that they have multiple effects on transcription.…”

Section: Discussioncontrasting

confidence: 99%

Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells

Lee¹,

Qian²,

Rey³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

272

206

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Using a cell-based reporter gene assay, we screened a library of drugs in clinical use and identified the anthracycline chemotherapeutic agents doxorubicin and daunorubicin as potent inhibitors of hypoxia-inducible factor 1 (HIF-1)-mediated gene transcription. These drugs inhibited HIF-1 by blocking its binding to DNA. Daily administration of doxorubicin or daunorubicin potently inhibited the transcription of a HIF-1-dependent reporter gene as well as endogenous HIF-1 target genes encoding vascular endothelial growth factor, stromal-derived factor 1, and stem cell factor in tumor xenografts. CXCR4 ؉ /sca1 ؉ , VEGFR2 ؉ /CD34 ؉ , and VEGFR2 ؉ / CD117 ؉ bone-marrow derived cells were increased in the peripheral blood of SCID mice bearing prostate cancer xenografts but not in tumor-bearing mice treated for 5 days with doxorubicin or daunorubicin, which dramatically reduced tumor vascularization. These results provide a molecular basis for the antiangiogenic effect of anthracycline therapy and have important implications for refining the use of these drugs to treat human cancer more effectively.hypoxia ͉ xenograft ͉ adriamycin ͉ endothelial progenitor cells ͉ hepatocellular carcinoma

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Section: Discussioncontrasting

confidence: 99%

Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells

Lee¹,

Qian²,

Rey³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

272

206

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“…20 These results further support the antiangiogenic and anticancer effects of chaetocin against hepatoma, and suggest that chaetocin does not potentiate the effects of cytotoxic anticancer agents. The potential combinatorial use of chaetocin needs to be reevaluated with other drugs using different treatment schedules.…”

Section: Resultsmentioning

confidence: 54%

Antihepatoma activity of chaetocin due to deregulated splicing of hypoxia-inducible factor 1α pre-mRNA in mice and in vitro

et al. 2010

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Chaetocin, an antibiotic produced by Chaetomium species fungi, was recently found to have antimyeloma activity. Here we examined whether chaetocin has anticancer activities against solid tumors. Chaetocin inhibited the growth of mouse and human hepatoma grafts in nude mice. Immunohistochemical analyses revealed that chaetocin inhibits hypoxia-inducible factor-1a (HIF-1a) expression and vessel formation in the tumors. Chaetocin also showed antiangiogenic anticancer activities in HIF-1a(1/1) fibrosarcoma grafted in mice, but not in HIF-1a(2/2) fibrosarcoma. Biochemical analyses showed that chaetocin down-regulated HIF-1a and the transcripts of HIF-1 target genes including vascular endothelial growth factor in hepatoma tissues and in various hepatoma cell lines. Based on the reported literature, unsuccessful efforts were made to determine the mechanism underlying the action of chaetocin. Unexpectedly, chaetocin was found to cause the accumulation of HIF-1a premessenger RNA (pre-mRNA) but to reduce mature mRNA levels in hepatoma cells and tissues. Such an effect of chaetocin was not observed in cell lines derived from normal cells, and was cell type-dependent even among cancer cell lines. Conclusions: Our results suggest that chaetocin could be developed as an anticancer agent to target HIF-1 in some cancers including hepatoma. It is also suggested that the HIF-1a premRNA splicing is a novel therapeutic target for controlling HIF-1-mediated pathological processes. (HEPATOLOGY 2011;53:171-180) H epatocellular carcinoma (also called malignant hepatoma) is one of the most common malignant tumors and the third leading cause of cancer mortality worldwide.1 Despite many efforts to develop various classes of agents, systemic chemotherapy and hormone therapy have failed to significantly increase the survival of patients with advanced hepatoma. However, recent advances in the understanding of hepatoma progression have led to the development of novel molecularly targeted therapies.2 Because angiogenesis is pivotal for the development and progression of hepatoma, key molecules regulating angiogenesis are regarded as promising targets for treating hepatoma. Hypoxia inevitably develops in rapidly growing tumors and is an important microenvironment that forces changes in tumor behavior. In particular, hypoxia activates hypoxia-inducible factor-1a (HIF-1a), which promotes the progression of malignancy by stimulating angiogenesis and by augmenting the ability of tumors to survive. 4,5 The roles of HIF-1a have been extensively investigated in cancer patients and in tumor-bearing mice. 6,7 Consequently, HIF-1a is believed to be a valid target for the treatment of aggressive tumors, and many efforts have been made to identify suitable HIF-1a inhibitors. 8 Chaetocin, which is produced by Chaetomium sp., is an antibiotic having the thiodioxopiperazine structure (a disulfide-bridged piperazine).9 Other thiodioxopiperazines are known to have antimicrobial, antiviral, Abbreviations: ATP, adenosine triphosphate; CA9, carbonic anhydrase 9...

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“…3) as previously reported. 28 The inhibitory effect was stronger in cisplatin-sensitive A2780 cells. Cisplatin-induced downregulation of HIF-1a expression was enhanced by combination with fasudil or Y-27632 in both cell lines.…”

Section: Resultsmentioning

confidence: 96%

Inhibition of the Rho/ROCK pathway enhances the efficacy of cisplatin through the blockage of hypoxia-inducible factor-1α in human ovarian cancer cells

Ohta

Takahashi²,

Shibuya³

et al. 2012

Cancer Biology & Therapy

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Cisplatin and doxorubicin repress Vascular Endothelial Growth Factor expression and differentially down-regulate Hypoxia-inducible Factor I activity in human ovarian cancer cells

Cited by 62 publications

References 36 publications

Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells

Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells

Antihepatoma activity of chaetocin due to deregulated splicing of hypoxia-inducible factor 1α pre-mRNA in mice and in vitro

Inhibition of the Rho/ROCK pathway enhances the efficacy of cisplatin through the blockage of hypoxia-inducible factor-1α in human ovarian cancer cells

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