Hypoxia-targeting by tirapazamine (TPZ) induces preferential growth inhibition of nasopharyngeal carcinoma cells with Chk1/2 activation
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摘要Hypoxia is commonly developed in solid tumors, which contributes to metastasis as well as radio- and chemo-resistance. Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic head and neck cancer prevalent in Southeast Asia with a high incidence rate of 15-30/100,000 persons/year (comparable to that of pancreatic cancer in the US). Previous clinical studies in NPC showed that hypoxia is detected in almost 100% of primary tumors and overexpression of hypoxia markers correlated with poor clinical outcome. Tirapazamine (TPZ) is a synthetic hypoxia-activated prodrug, which preferentially forms cytotoxic and DNA-damaging free radicals under hypoxia, thus selectively eradicate hypoxic cells. Here, we hypothesized that specific hypoxia-targeting by this clinical trial agent may be therapeutic for NPC. Our findings demonstrated that under hypoxia, TPZ was able to induce preferential growth inhibition of NPC cells, which was associated with marked cell cycle arrest at S-phase and PARP cleavage (a hallmark of apoptosis). Examination of S-phase checkpoint regulators revealed that Chk1 and Chk2 were selectively activated by TPZ in NPC cells under hypoxia. Hypoxia-selectivity of TPZ was also demonstrated by preferential downregulation of several important hypoxia-induced markers (HIF-1 alpha, CA IX and VEGF) under hypoxia. Furthermore, we demonstrated that TPZ was equally effective and hypoxia-selective even in the presence of the EBV oncoprotein, LMP1 or the EBV genome. In summary, encouraging results from this proof-of-concept study implicate the therapeutic potential of hypoxia-targeting approaches for the treatment of NPC.
著者Hong B, Lui VWY, Hui EP, Ng MHL, Cheng SH, Sung FL, Tsang CM, Tsao SW, Chan ATC
期刊名稱Investigational New Drugs
詳細描述Epub ahead of print.
出版年份2011
月份6
日期1
卷號29
期次3
出版社Springer Verlag (Germany)
頁次401 - 410
國際標準期刊號0167-6997
電子國際標準期刊號1573-0646
語言英式英語
關鍵詞Chk1/2 activation; Hypoxia-selectivity; Hypoxia-targeting; Nasopharyngeal carcinoma (NPC); Tirapazamine
Web of Science 學科類別Oncology; ONCOLOGY; Pharmacology & Pharmacy; PHARMACOLOGY & PHARMACY

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