Tirapazamine sensitizes hepatocellular carcinoma cells to topoisomerase I inhibitors via cooperative modulation of hypoxia-inducible factor-1α

Molecular Cancer Therapeutics
Tian-Yu CaiBo Yang

Abstract

Topoisomerase I inhibitors are a class of anticancer drugs with a broad spectrum of clinical activity. However, they have limited efficacy in hepatocellular cancer. Here, we present in vitro and in vivo evidence that the extremely high level of hypoxia-inducible factor-1α (HIF-1α) in hepatocellular carcinoma is intimately correlated with resistance to topoisomerase I inhibitors. In a previous study conducted by our group, we found that tirapazamine could downregulate HIF-1α expression by decreasing HIF-1α protein synthesis. Therefore, we hypothesized that combining tirapazamine with topoisomerase I inhibitors may overcome the chemoresistance. In this study, we investigated that in combination with tirapazamine, topoisomerase I inhibitors exhibited synergistic cytotoxicity and induced significant apoptosis in several hepatocellular carcinoma cell lines. The enhanced apoptosis induced by tirapazamine plus SN-38 (the active metabolite of irinotecan) was accompanied by increased mitochondrial depolarization and caspase pathway activation. The combination treatment dramatically inhibited the accumulation of HIF-1α protein, decreased the HIF-1α transcriptional activation, and impaired the phosphorylation of proteins involved in the h...Continue Reading

References

Mar 14, 1995·Proceedings of the National Academy of Sciences of the United States of America·T HaafD C Ward
Feb 1, 1997·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·C A JohnsonP J O'Dwyer
Jan 20, 1998·Journal of Immunological Methods·K T PapazisisA H Kortsaris
Nov 12, 2002·Proceedings of the National Academy of Sciences of the United States of America·Bart L StakerLance Stewart
Jan 24, 2006·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Valérie BoigeMichel Ducreux
Sep 23, 2006·Nature Reviews. Cancer·Yves Pommier
Feb 9, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Min HuangJian Ding
Jan 12, 2008·Cell Death and Differentiation·L E Huang
Oct 16, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Samantha M YeligarVijay K Kalra
Jun 11, 2010·Chemistry & Biology·Yves PommierChristophe Marchand
Jul 8, 2010·International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society·Danny RischinAnthony Fyles
Jul 29, 2010·Seminars in Liver Disease·Olivier Rosmorduc, Chantal Housset
Jul 13, 2011·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Yeonghwan KimSung-Soo Kim
Dec 24, 2011·PloS One·Phyllis Fung Yi CheungSiu Tim Cheung
Jan 10, 2013·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Yingjian LiangLianxin Liu
Feb 21, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Dong M ShinZhuo Georgia Chen

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Citations

Apr 6, 2016·Frontiers in Pharmacology·Guyue ChengZonghui Yuan
Jul 29, 2017·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Michał SzewczukKatarzyna Błaszczak-Świątkiewicz
Mar 24, 2018·Cancer Cell International·K LohiteshSudeshna Mukherjee
Apr 25, 2020·Biotechnology Journal·Johannes W M Osterrieth, David Fairen-Jimenez
Nov 9, 2019·International Journal of Molecular Sciences·Tünde SzatmáriKatalin Lumniczky

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