Hypoxia-targeting by tirapazamine (TPZ) induces preferential growth inhibition of nasopharyngeal carcinoma cells with Chk1/2 activation

Bo Hong, Vivian W.Y. Lui, Edwin P. Hui, Margaret H.L. Ng, Suk Hang Cheng, Fion L. Sung, Chi Man Tsang, Sai Wah Tsao, Anthony Tak Cheung Chan

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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-1α, 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.

Original languageEnglish (US)
Pages (from-to)401-410
Number of pages10
JournalInvestigational New Drugs
Volume29
Issue number3
DOIs
StatePublished - Jun 2011
Externally publishedYes

Keywords

  • Chk1/2 activation
  • Hypoxia-selectivity
  • Hypoxia-targeting
  • Nasopharyngeal carcinoma (NPC)
  • Tirapazamine

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Fingerprint

Dive into the research topics of 'Hypoxia-targeting by tirapazamine (TPZ) induces preferential growth inhibition of nasopharyngeal carcinoma cells with Chk1/2 activation'. Together they form a unique fingerprint.

Cite this