NQO1-mediated tumor-selective lethality and radiosensitization for head and neck cancer.

NQO1-mediated tumor-selective lethality and radiosensitization for head and neck cancer.

Mol Cancer Ther. 2016 Apr 12;

Authors: Li LS, Reddy S, Lin ZH, Liu S, Park H, Chun SG, Bornmann WG, Thibodeaux J, Yan J, Chakrabarti G, Xie XJ, Sumer BD, Boothman DA, Yordy JS

Abstract
Ionizing radiation (IR) is a key therapeutic regimen for many head and neck cancers (HNCs). However, the 5-year overall survival rate for locally-advanced HNCs is ~50% and better therapeutic efficacy is needed. NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in many cancers, and β-lapachone (β-lap), an unique NQO1 bioactivatable drug, exploits this enzyme to release massive reactive oxygen species (ROS) levels that synergizes with IR to kill by programmed necrosis. β-Lap represents a novel therapeutic opportunity in HNC leading to tumor-selective lethality that will enhance the efficacy of ionizing radiation. Immunohistochemical staining and western blot assays were used to assess the expression levels of NQO1 in HNC cells and tumors. Forty-five percent of endogenous HNCs express elevated NQO1 levels. In addition, multiple HNC cell lines and tumors demonstrated elevated levels of NQO1 expression and activity and were tested for anticancer lethality and radiosensitization by β-lap using long-term survival assays. The combination of nontoxic β-lap doses and IR significantly enhanced NQO1-dependent tumor cell lethality, increased ROS, TUNEL positive cells, DNA damage, NAD+ and adenosine triphosphate (ATP) consumption, and resulted in significant antitumor efficacy and prolonged survival in two xenograft murine HNC models, demonstrating β-Lap radiosensitization of HNCs through a NQO1-dependent mechanism. This translational study offers a potential biomarker-driven strategy using NQO1 expression to select tumors susceptible to β-lap-induced radiosensitization.

PMID: 27196777 [PubMed - as supplied by publisher]

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