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

ABSTRACT: The clinical experimental agent, ?-lapachone (?-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 ?-lap may warrant clinical evaluation as a radiosensitizer. ?-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 ?-calpain-induced programmed necrosis. In combination with ionizing radiation (IR), ?-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, ?-H2AX foci formation, and poly(ADP-ribosylation) of PARP-1, which were associated with ATP loss and induction of ?-calpain-induced programmed cell death. Radiosensitization by ?-lap was blocked by the NQO1 inhibitor dicoumarol or the PARP-1 inhibitor DPQ. In a mouse xenograft model of prostate cancer, ?-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 ?-lap might be efficacious alone or in combination with radiation. Our findings offer a rationale for the clinical utilization of ?-lap (Arq 501) as a radiosensitizer in prostate cancers that overexpress NQO1, offering a potentially synergistic targeting strategy to exploit PARP-1 hyperactivation.

SUBMITTER: Dong Y

PROVIDER: S-EPMC2955807 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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

Dong Ying Y Bey Erik A EA Li Long-Shan LS Kabbani Wareef W Yan Jingsheng J Xie Xian-Jin XJ Hsieh Jer-Tsong JT Gao Jinming J Boothman David A DA

Cancer research 20101012 20

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 (PA ...[more]

PMID: 20940411

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Project description:Poly(ADP-ribose) polymerases (PARPs) are involved in many aspects of the cellular response to various forms of damage. PARP-1 and PARP-2, the most abundant PARPs, are central to the response to specific types of DNA damage, especially single-strand breaks. Inhibition of PARP activity may sensitize the cell to exogenous agents such as chemotherapy and radiation. In circumstances where rescue pathways are deficient, particularly the homologous recombination (HR)-directed DNA repair pathway, inhibition of PARP may result in "synthetic lethality." BRCA mutation-associated breast cancers are a paradigm of HR-directed repair deficient tumors. Early clinical trials have demonstrated significant activity of single-agent PARP inhibitors in BRCA-deficient breast and ovarian cancer. Because of phenotypic similarities between some "triple-negative" breast cancers (TNBC) and the most prevalent type of breast cancer seen in BRCA1 mutation carriers, some have hypothesized that TNBC might also be specifically sensitive to PARP inhibition. The activity of single-agent PARP inhibitors in TNBC has not been reported. One trial did suggest significant enhancement of the activity of platinum-based combination chemotherapy, without incremental toxicity. These studies indicate that PARP inhibition is an exciting new approach to the treatment of breast cancers in women with underlying BRCA mutations and possibly in sporadic cancers with defects in HR-directed repair. Future studies will be necessary to determine whether the effectiveness of PARP inhibitors in nonhereditary cancer requires an underlying HR defect or whether these agents may improve the activity of conventional chemotherapy by other means. In addition, studies will be required to determine whether PARP inhibitors may induce synthetic lethality in tumors with defects in pathways other than the BRCA-dependent DNA repair pathway. If either or both of these prove to be the case, then PARP inhibition may benefit a wide spectrum of cancer patients.

Dataset Information

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

Publications

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

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