The clinical experimental agent, β-
lapachone (β-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 β-lap may warrant clinical evaluation as a radiosensitizer. β-Lap killed
prostate cancer cells by
NAD(P)H:
quinone oxidoreductase 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 μ-
calpain-induced programmed
necrosis. In combination with ionizing radiation (IR), β-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, γ-H2AX foci formation, and poly(ADP-ribosylation) of PARP-1, which were associated with
ATP loss and induction of μ-
calpain-induced programmed cell death. Radiosensitization by β-lap was blocked by the NQO1 inhibitor
dicoumarol or the PARP-1 inhibitor DPQ. In a mouse xenograft model of
prostate cancer, β-lap synergized with IR to promote antitumor efficacy. NQO1 levels were elevated in ∼60% of human prostate
tumors evaluated relative to adjacent normal tissue, where β-lap might be efficacious alone or in combination with radiation. Our findings offer a rationale for the clinical utilization of β-lap (
Arq 501) as a radiosensitizer in
prostate cancers that overexpress NQO1, offering a potentially synergistic targeting strategy to exploit PARP-1 hyperactivation.