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Nonhomologous End Joining Is Essential for Cellular Resistance to the Novel Antitumor Agent, ß-Lapachone

Departments of ¹ Pharmacology and ² Biochemistry, Case Western Reserve University, Cleveland, Ohio; and ³ Department of Pharmacology, Laboratory of Molecular Stress Responses, and the Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas

Requests for reprints: David A. Boothman, Departments of Pharmacology, Oncology and Radiation Oncology, Laboratory of Molecular Stress Responses Program in Cell Stress and Nanomedicine, and the Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, ND2.210K 5323 Harry Hines Boulevard, Dallas, TX 75390. Phone: 214-645-6371; Fax: 214-645-6437; E-mail: David.Boothman{at}UTSouthwestern.edu.

Commonly used antitumor agents, such as DNA topoisomerase I/II poisons, kill cancer cells by creating nonrepairable DNA double-strand breaks (DSBs). To repair DSBs, error-free homologous recombination (HR), and/or error-prone nonhomologous end joining (NHEJ) are activated. These processes involve the phosphatidylinositol 3'-kinase–related kinase family of serine/threonine enzymes: ataxia telangiectasia mutated (ATM), ATM- and Rad3-related for HR, and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) for NHEJ. Alterations in these repair processes can cause drug/radiation resistance and increased genomic instability. ß-Lapachone (ß-lap; also known as ARQ 501), currently in phase II clinical trials for the treatment of pancreatic cancer, causes a novel caspase- and p53-independent cell death in cancer cells overexpressing NAD(P)H:quinone oxidoreductase-1 (NQO1). NQO1 catalyzes a futile oxidoreduction of ß-lap leading to reactive oxygen species generation, DNA breaks, -H2AX foci formation, and hyperactivation of poly(ADP-ribose) polymerase-1, which is required for cell death. Here, we report that ß-lap exposure results in NQO1-dependent activation of the MRE11-Rad50-Nbs-1 complex. In addition, ATM serine 1981, DNA-PKcs threonine 2609, and Chk1 serine 345 phosphorylation were noted; indicative of simultaneous HR and NHEJ activation. However, inhibition of NHEJ, but not HR, by genetic or chemical means potentiated ß-lap lethality. These studies give insight into the mechanism by which ß-lap radiosensitizes cancer cells and suggest that NHEJ is a potent target for enhancing the therapeutic efficacy of ß-lap alone or in combination with other agents in cancer cells that express elevated NQO1 levels. [Cancer Res 2007;67(14):6936–45]

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