title: Hypoxia-targeting by tirapazamine (TPZ) induces preferential growth inhibition of nasopharyngeal carcinoma cells with Chk1/2 activation.
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.
authors.affiliation: Cancer Signaling Laboratory, Department of Clinical Oncology, The Chinese University of Hong Kong, New Territories, Hong Kong.
authors.forename: Bo
authors.initials: B
authors.lastname: Hong
authors.forename: Vivian W Y
authors.initials: VW
authors.lastname: Lui
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Hui
authors.forename: Margaret H L
authors.initials: MH
authors.lastname: Ng
authors.forename: Suk-Hang
authors.initials: SH
authors.lastname: Cheng
authors.forename: Fion L
authors.initials: FL
authors.lastname: Sung
authors.forename: Chi-Man
authors.initials: CM
authors.lastname: Tsang
authors.forename: Sai-Wah
authors.initials: SW
authors.lastname: Tsao
authors.forename: Anthony Tak-Cheung
authors.initials: AT
authors.lastname: Chan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016679:Genome, Viral / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000821:virology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D014763:Viral Matrix Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014227:Triazines; D014763:Viral Matrix Proteins; D000077704:Tirapazamine; D011065:Poly(ADP-ribose) Polymerases; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases