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

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Summary

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.

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Abbreviations

NPC:

Nasopharyngeal carcinoma

EBV:

Epstein-Barr virus

LMP1:

Latent membrane protein 1

TPZ:

Tirapazamine

CA IX:

Carbonic anhydrase IX

HIF-1α:

Hypoxia inducible factor 1α

VEGF:

Vascular endothelial growth factor

OPN:

Osteopontin

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Acknowledgements

Financial support: Research Grant Council, Hong Kong Government (CUHK4442/06M, to ATC Chan and EP Hui). Result of this study was presented in parts at AACR annual meeting in San Diego, USA, 2008.

Conflict of Interest

Authors have no financial/commercial conflicts of interest regarding the study.

Author information

Authors and Affiliations

  1. Cancer Signaling Laboratory, Department of Clinical Oncology, The Chinese University of Hong Kong, New Territories, Hong Kong

    Bo Hong & Vivian W. Y. Lui

  2. Cancer Drug Testing Unit, State Key Laboratory of Oncology in South China, Department of Clinical Oncology, The Chinese University of Hong Kong, New Territories, Hong Kong

    Vivian W. Y. Lui

  3. Department of Clinical Oncology, Sir YK Pao Center for Cancer, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, New Territories, Hong Kong

    Edwin P. Hui, Fion L. Sung & Anthony Tak-Cheung Chan

  4. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, New Territories, Hong Kong

    Margaret H. L. Ng & Suk-Hang Cheng

  5. Department of Anatomy, University of Hong Kong, Pokfulam, Hong Kong

    Chi-Man Tsang & Sai-Wah Tsao

  6. Department of Clinical Oncology, Prince of Wales Hospital, Shatin, Hong Kong

    Anthony Tak-Cheung Chan

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  1. Bo Hong
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  2. Vivian W. Y. Lui
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  9. Anthony Tak-Cheung Chan
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Correspondence to Anthony Tak-Cheung Chan.

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Bo Hong and Vivian WY Lui are co-first author.

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Supplementary Figure 1

LMP-1 or EBV positive HONE-1 cells showed an increased expression of HIF-1α. Protein lysates of HONE-1, HONE-1-LMP1 and HONE-1-EBV cells were analysed for basal expression of HIF-1α protein, as determined by western blotting. Actin is shown as loading control. Similar results were obtained in three independent experiments. (GIF 106 kb)

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Hong, B., Lui, V.W.Y., Hui, E.P. et al. Hypoxia-targeting by tirapazamine (TPZ) induces preferential growth inhibition of nasopharyngeal carcinoma cells with Chk1/2 activation. Invest New Drugs 29, 401–410 (2011). https://doi.org/10.1007/s10637-009-9356-z

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