Starcher, Colton L.Pay, S. LouiseSingh, NaveenYeh, I.-JuBhandare, Snehal B.Su, XiaolinHuang, XiumeiBey, Erik A.Motea, Edward A.Boothman, David A.2021-05-282021-05-282020-08-19Starcher, C. L., Pay, S. L., Singh, N., Yeh, I.-J., Bhandare, S. B., Su, X., Huang, X., Bey, E. A., Motea, E. A., & Boothman, D. A. (2020). Targeting Base Excision Repair in Cancer: NQO1-Bioactivatable Drugs Improve Tumor Selectivity and Reduce Treatment Toxicity Through Radiosensitization of Human Cancer. Frontiers in Oncology, 10. https://doi.org/10.3389/fonc.2020.015752234-943Xhttps://hdl.handle.net/1805/26076Ionizing radiation (IR) creates lethal DNA damage that can effectively kill tumor cells. However, the high dose required for a therapeutic outcome also damages healthy tissue. Thus, a therapeutic strategy with predictive biomarkers to enhance the beneficial effects of IR allowing a dose reduction without losing efficacy is highly desirable. NAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in the majority of recalcitrant solid tumors in comparison with normal tissue. Studies have shown that NQO1 can bioactivate certain quinone molecules (e.g., ortho-naphthoquinone and β-lapachone) to induce a futile redox cycle leading to the formation of oxidative DNA damage, hyperactivation of poly(ADP-ribose) polymerase 1 (PARP1), and catastrophic depletion of NAD+ and ATP, which culminates in cellular lethality via NAD+-Keresis. However, NQO1-bioactivatable drugs induce methemoglobinemia and hemolytic anemia at high doses. To circumvent this, NQO1-bioactivatable agents have been shown to synergize with PARP1 inhibitors, pyrimidine radiosensitizers, and IR. This therapeutic strategy allows for a reduction in the dose of the combined agents to decrease unwanted side effects by increasing tumor selectivity. In this review, we discuss the mechanisms of radiosensitization between NQO1-bioactivatable drugs and IR with a focus on the involvement of base excision repair (BER). This combination therapeutic strategy presents a unique tumor-selective and minimally toxic approach for targeting solid tumors that overexpress NQO1.en-USAttribution 4.0 InternationalNQO1PARP1 hyperactivationionizing radiationbase excision repairdouble-strand break repairsynergyβ-lapachoneabasic sitesArticle