Targeting Base Excision Repair in Cancer: NQO1-Bioactivatable Drugs Improve Tumor Selectivity and Reduce Treatment Toxicity Through Radiosensitization of Human Cancer

This is the authors' abstract. We don't add key points for this paper.

Ionizing radiation creates lethal DNA damage and effectively kills tumor cells; however, the high dose required for a therapeutic outcome also damages healthy tissue. A method for reducing the dose without losing efficacy is highly desirable. NAD(P)H quinone oxidoreductase 1 (NQO1) is over-expressed in the majority of solid tumors in comparison with normal tissue. The ortho-naphthoquinone β-lapachone is bioactivated by NQO1, which mediates a futile redox cycle leading to DNA damage, poly (ADP-ribose) polymerase 1 (PARP1) hyperactivation, and catastrophic ATP loss, culminating in cellular lethality via NAD+-Keresis. At high in vivo doses, however, NQO1-bioactivatable drugs may induce methemoglobinemia and hemolytic anemia. Conveniently, NQO1-bioactivatable drugs synergize with PARP1 inhibitors, pyrimidine radiosensitizers, and ionizing radiation at a sub-lethal dose, allowing for a reduction in the dose of both therapeutic agents, reducing potential side effects, all the while increasing tumor specificity. Base excision repair is induced by ionizing radiation and inhibited by NQO1-bioactivatable drugs, leading to the persistence of lethal double-strand DNA breaks. In this review, we discuss the mechanisms of synergy between NQO1-bioactivatable drugs and ionizing radiation with a focus on the involvement of base excision repair. β-Lapachone and ionizing radiation combination therapy presents a unique tumor-specific, minimally toxic strategy for targeting solid tumors expressing NQO1.