Title: Leveraging NQO1 bioactivatable drugs for tumor-selective use of poly (ADP-ribose) polymerase inhibitors
Abstract:Therapeutic drugs that block DNA repair, including poly (ADP-ribose) polymerase (PARP) inhibitors fail because of a lack of tumor-selectivity. When PARP inhibitors and NQO1 bioactivatable drugs (s-lap...Therapeutic drugs that block DNA repair, including poly (ADP-ribose) polymerase (PARP) inhibitors fail because of a lack of tumor-selectivity. When PARP inhibitors and NQO1 bioactivatable drugs (s-lapachone or isobutyldeoxynyboquinone (IB-DNQ)) 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 (NSCLC), pancreatic or breast cancers, the cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with NQO1 bioactivatable monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and NQO1 bioactivatable drugs. 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. Poly(ADP-ribose) polymerase-1 (PARP1) is crucial to multiple DNA repair pathways, including DNA base excision (BER), single strand (SSB) and double strand break (DSB) repair.Read More
Publication Year: 2021
Publication Date: 2021-01-01
Language: en
Type: article
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