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

Ying Dong; Erik A Bey; Long-Shan Li; Wareef Kabbani; Jingsheng Yan; Xian-Jin Xie; Jer-Tsong Hsieh; Jinming Gao; David A Boothman

doi:10.1158/0008-5472.CAN-10-1418

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

Journal article

Open access

Peer reviewed

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

Ying Dong, Erik A Bey, Long-Shan Li, Wareef Kabbani, Jingsheng Yan, Xian-Jin Xie, Jer-Tsong Hsieh, Jinming Gao and David A Boothman

Cancer research (Chicago, Ill.), Vol.70(20), pp.8088-8096

10/15/2010

DOI: 10.1158/0008-5472.CAN-10-1418

PMCID: PMC2955807

PMID: 20940411

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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.

Glutathione - metabolism

Humans

Male

Radiation-Sensitizing Agents - therapeutic use

Prostatic Neoplasms - genetics

Cell Death

Dicumarol - pharmacology

Colony-Forming Units Assay

Prostatic Neoplasms - drug therapy

In Situ Nick-End Labeling

Prostatic Neoplasms - pathology

Enzyme Inhibitors - pharmacology

Naphthoquinones - therapeutic use

Comet Assay

Regression Analysis

Poly(ADP-ribose) Polymerases - metabolism

Animals

Poly(ADP-ribose) Polymerases - genetics

Mice, Nude

Prostatic Neoplasms - enzymology

Poly(ADP-ribose) Polymerases - radiation effects

Mice

DNA Damage

DNA, Neoplasm - genetics

Enzyme Activation

Poly (ADP-Ribose) Polymerase-1

Apoptosis

Details

Title: Subtitle: Prostate cancer radiosensitization through poly(ADP-Ribose) polymerase-1 hyperactivation
Creators: Ying Dong - Departments of Pharmacology, Radiation Oncology, Pathology, Biostatistics and Clinical Sciences, and Urology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-8807, USA
Erik A Bey
Long-Shan Li
Wareef Kabbani
Jingsheng Yan
Xian-Jin Xie
Jer-Tsong Hsieh
Jinming Gao
David A Boothman
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.70(20), pp.8088-8096
DOI: 10.1158/0008-5472.CAN-10-1418
PMID: 20940411
PMCID: PMC2955807
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Publisher: United States
Grant note: P30 CA142543 / NCI NIH HHS R01 CA102792 / NCI NIH HHS 2 R01 CA102792-08 / NCI NIH HHS
Language: English
Date published: 10/15/2010
Academic Unit: Preventive and Community Dentistry; Biostatistics; Dental Research
Record Identifier: 9983917788802771

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