Journal
CANCER RESEARCH
Volume 70, Issue 20, Pages 8088-8096Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-10-1418
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Funding
- Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center
- National Cancer Institute/NIH [2 R01 CA102792-08]
- DoD [W81XWH-06-1-0198, W81XWH-08-1-0]
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The clinical experimental agent, beta-lapachone (beta-lap; Arq 501), can act as a potent radiosensitizer in vitro through an unknown mechanism. In this study, we analyzed the mechanism to determine whether beta-lap may warrant clinical evaluation as a radiosensitizer. beta-Lap killed prostate cancer cells by NAD(P)H:quinone oxido-reductase 1 (NQO1) metabolic bioactivation, triggering a massive induction of reactive oxygen species, irreversible DNA single-strand breaks (SSB), poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation, NAD(+)/ATP depletion, and mu-calpain-induced programmed necrosis. In combination with ionizing radiation (IR), beta-lap radiosensitized NQO1(+) prostate cancer cells under conditions where nontoxic doses of either agent alone achieved threshold levels of SSBs required for hyperactivation of PARP-1. Combination therapy significantly elevated SSB level, gamma-H2AX foci formation, and poly(ADP-ribosylation) of PARP-1, which were associated with ATP loss and induction of mu-calpain-induced programmed cell death. Radiosensitization by beta-lap was blocked by the NQO1 inhibitor dicoumarol or the PARP-1 inhibitor DPQ. In a mouse xenograft model of prostate cancer, beta-lap synergized with IR to promote antitumor efficacy. NQO1 levels were elevated in similar to 60% of human prostate tumors evaluated relative to adjacent normal tissue, where beta-lap might be efficacious alone or in combination with radiation. Our findings offer a rationale for the clinical utilization of beta-lap (Arq 501) as a radiosensitizer in prostate cancers that overexpress NQO1, offering a potentially synergistic targeting strategy to exploit PARP-1 hyperactivation. Cancer Res; 70(20); 8088-96. (C) 2010 AACR.
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