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Prostate cancer radiosensitization through poly(ADP-Ribose) polymerase-1 hyperactivation.

Abstract
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.
AuthorsYing Dong, Erik A Bey, Long-Shan Li, Wareef Kabbani, Jingsheng Yan, Xian-Jin Xie, Jer-Tsong Hsieh, Jinming Gao, David A Boothman
JournalCancer research (Cancer Res) Vol. 70 Issue 20 Pg. 8088-96 (Oct 15 2010) ISSN: 1538-7445 [Electronic] United States
PMID20940411 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Copyright©2010 AACR.
Chemical References
  • DNA, Neoplasm
  • Enzyme Inhibitors
  • Naphthoquinones
  • Radiation-Sensitizing Agents
  • beta-lapachone
  • Dicumarol
  • PARP1 protein, human
  • Poly(ADP-ribose) Polymerases
  • Glutathione
Topics
  • Animals
  • Apoptosis
  • Cell Death
  • Colony-Forming Units Assay
  • Comet Assay
  • DNA Damage
  • DNA, Neoplasm (genetics)
  • Dicumarol (pharmacology)
  • Enzyme Activation
  • Enzyme Inhibitors (pharmacology)
  • Glutathione (metabolism)
  • Humans
  • In Situ Nick-End Labeling
  • Male
  • Mice
  • Mice, Nude
  • Naphthoquinones (therapeutic use)
  • Poly(ADP-ribose) Polymerases (genetics, metabolism, radiation effects)
  • Prostatic Neoplasms (drug therapy, enzymology, genetics, pathology)
  • Radiation-Sensitizing Agents (therapeutic use)
  • Regression Analysis

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