Prostate Cancer Radiosensitization through Poly(ADP-Ribose) Polymerase-1 Hyperactivation

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-10, Vol.70 (20), p.8088-8096
• Main Authors: YING DONG, BEY, Erik A, LI, Long-Shan, KABBANI, Wareef, JINGSHENG YAN, XIE, Xian-Jin, HSIEH, Jer-Tsong, JINMING GAO, BOOTHMAN, David A
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Apoptosis; Biological and medical sciences; Cell Death; Colony-Forming Units Assay; Comet Assay; Dicumarol - pharmacology; DNA Damage; DNA, Neoplasm - genetics; Enzyme Activation; Enzyme Inhibitors - pharmacology; Glutathione - metabolism; Gynecology. Andrology. Obstetrics; Humans; In Situ Nick-End Labeling; Male; Male genital diseases; Medical sciences; Mice; Mice, Nude; Naphthoquinones - therapeutic use; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Poly(ADP-ribose) Polymerases - radiation effects; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Radiation-Sensitizing Agents - therapeutic use; Regression Analysis; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-1418

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.