title: Response of human prostate cancer cells and tumors to combining PARP inhibition with ionizing radiation.
abstract: Radiation therapy remains a promising modality for curative treatment of localized prostate cancer, but dose-limiting toxicities significantly limit its effectiveness. Agents that enhance efficacy at lower radiation doses might have considerable value in increasing tumor control without compromising organ function. Here, we tested the hypothesis that the PARP inhibitor ABT-888 (veliparib) can enhance the response of prostate cancer cells and tumors to ionizing radiation (IR). Following exposure of DU-145 and PC-3 prostate cancer cell lines to the combination of 10 μmol/L ABT-888 and 6 Gy, we observed similar persistence between both cell lines of DNA damage foci and in vitro radiosensitization. We have previously observed that persistent DNA damage foci formed after ABT-888 plus IR efficiently promote accelerated cell senescence, but only PC-3 cells displayed the expected senescent response of G(2)-M arrest, induction of p21 and β-galactosidase expression, and accumulation as large flat cells. In turn, combining ABT-888 with 6 Gy resulted in delayed tumor regrowth compared with either agent alone only in PC-3 xenograft tumors, whereas DU-145 tumors continued to grow. By 7 days after treatment with ABT-888 plus IR, PC-3 tumors contained abundant senescent cells displaying persistent DNA damage foci, but no evidence of senescence was noted in the DU-145 tumors. That equivalent radiosensitization by ABT-888 plus IR in vitro failed to predict comparable results with tumors in vivo suggests that the efficacy of PARP inhibitors may partially depend on a competent senescence response to accumulated DNA damage.
authors.affiliation: Ludwig Center for Metastasis Research, The University of Chicago, 5841 South Maryland Avenue, MC 9006, Chicago, IL 60637, USA.
authors.forename: Juan Camilo
authors.initials: JC
authors.lastname: Barreto-Andrade
authors.forename: Elena V
authors.initials: EV
authors.lastname: Efimova
authors.forename: Helena J
authors.initials: HJ
authors.lastname: Mauceri
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beckett
authors.forename: Harold G
authors.initials: HG
authors.lastname: Sutton
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Darga
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
authors.forename: Mitchell C
authors.initials: MC
authors.lastname: Posner
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kron
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
mesh_terms: D000375:Aging / Q000187:drug effects / Q000528:radiation effects; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D011839:Radiation, Ionizing; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib