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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
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2013, 14(2), 3773-3785; https://doi.org/10.3390/ijms14023773
Received: 9 January 2013 / Revised: 29 January 2013 / Accepted: 6 February 2013 / Published: 8 February 2013
(This article belongs to the Collection 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. View Full-Text
Keywords: poly(ADP-ribose) polymerase; veliparib; cervical cancer; radiation; topotecan poly(ADP-ribose) polymerase; veliparib; cervical cancer; radiation; topotecan
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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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.

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