Int. J. Mol. Sci. 2013, 14(2), 3773-3785; doi:10.3390/ijms14023773
Article

Inhibition of Poly(ADP-Ribose) Polymerase Enhances Radiochemosensitivity in Cancers Proficient in DNA Double-Strand Break Repair

Lauren Shunkwiler † email, Gina Ferris † email and Charles Kunos †,* email
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
(This article belongs to the Special Issue Radiation Toxicity in Cells)
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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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MDPI and ACS Style

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.

AMA Style

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.

Chicago/Turabian Style

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.

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