期刊
CANCER CELL
卷 30, 期 6, 页码 940-952出版社
CELL PRESS
DOI: 10.1016/j.ccell.2016.11.006
关键词
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资金
- UTSW SCCC [5P30CA142543]
- Institute for Innovations in Medical Technology (IIMT)
- CPRIT [RP110708-C3]
- NCI [CA102792]
- UTSW-MD Anderson SPORE in lung cancer [P50CA70907]
- AACR/PanCan grants [12-60-25-BOOT, 15-65-25-BOOT]
- ArQule, Inc. [SCCC-10Y11 ARQ-761, SCCC-15Y11]
Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and beta-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1(+) cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with beta-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and beta-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.
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