Journal
NUCLEIC ACIDS RESEARCH
Volume 39, Issue 9, Pages 3607-3620Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkq1304
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Funding
- Center for Cancer Research
- National Cancer Institute
- National Institutes of Health
- National Institutes of Health, US Government
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Poly(ADP-Ribose) (PAR) polymerase (PARP) inhibitors represent a promising class of novel anticancer agents. The present study explores the molecular rationale for combining veliparib (ABT-888) with camptothecin (CPT) and its clinical derivatives, topotecan and irinotecan. ABT-888 inhibited PAR induction by CPT and increased CPT-induced cell killing and histone gamma H2AX. Increased DNA breaks by ABT-888 were not associated with a corresponding increase of topoisomerase I cleavage complexes and were further increased by inactivation of tyrosyl-DNA phosphodiesterase 1. SiRNA knockdown for the endonuclease XPF-ERCC1 reduced the ABT-888-induced gamma H2AX response in non-replicating and replicating cells but enhanced the antiproliferative effect of ABT-888 in CPT-treated cells. Our findings indicate the involvement of XPF-ERCC1 in inducing gamma H2AX response and repairing topoisomerase I-induced DNA damage as an alternative pathway from PARP and tyrosyl-DNA phosphodiesterase 1.
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