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Inhibition of Poly(ADP-Ribose) Polymerase Enhances Radiochemosensitivity in Cancers Proficient in DNA Double-Strand Break Repair
Department of Radiation Oncology, CASE Comprehensive Cancer Center, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH 44106, USA
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 9 January 2013; in revised form: 29 January 2013 / Accepted: 6 February 2013 / Published: 8 February 2013
Abstract: Pharmacologic inhibitors of poly(ADP-ribose) polymerase (PARP) putatively enhance radiation toxicity in cancer cells. Although there is considerable information on the molecular interactions of PARP and BRCA1- and BRCA2-deficient cancers, very little is known of the PARP inhibition effect upon cancers proficient in DNA double-strand break repair after ionizing radiation or after stalled replication forks. In this work, we investigate whether PARP inhibition by ABT-888 (veliparib) augments death-provoking effects of ionizing radiation, or of the topoisomerase I poison topotecan, within uterine cervix cancers cells harboring an unfettered, overactive ribonucleotide reductase facilitating DNA double-strand break repair and contrast these findings with ovarian cancer cells whose regulation of ribonucleotide reductase is relatively intact. Cell lethality of a radiation-ABT-888 combination is radiation and drug dose dependent. Data particularly highlight an enhanced topotecan-ABT-888 cytotoxicity, and corresponds to an increased number of unrepaired DNA double-strand breaks. Overall, our findings support enhanced radiochemotherapy toxicity in cancers proficient in DNA double-strand break repair when PARP is inhibited by ABT-888.
Keywords: poly(ADP-ribose) polymerase; veliparib; cervical cancer; radiation; topotecan
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Shunkwiler, L.; Ferris, G.; Kunos, C. Inhibition of Poly(ADP-Ribose) Polymerase Enhances Radiochemosensitivity in Cancers Proficient in DNA Double-Strand Break Repair. Int. J. Mol. Sci. 2013, 14, 3773-3785.
Shunkwiler L, Ferris G, Kunos C. Inhibition of Poly(ADP-Ribose) Polymerase Enhances Radiochemosensitivity in Cancers Proficient in DNA Double-Strand Break Repair. International Journal of Molecular Sciences. 2013; 14(2):3773-3785.
Shunkwiler, Lauren; Ferris, Gina; Kunos, Charles. 2013. "Inhibition of Poly(ADP-Ribose) Polymerase Enhances Radiochemosensitivity in Cancers Proficient in DNA Double-Strand Break Repair." Int. J. Mol. Sci. 14, no. 2: 3773-3785.