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

Abstract

Ionizing 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.

The diverse functionality of NQO1 and its roles in redox control

“…It would be interesting to determine the selectivity profile of other NQO1-activated antitumor compounds in tumors with active Nrf2. β-Lapachone would be an interesting prospect given the innovative combination therapies developed by Boothman and colleagues with PARP inhibitors and with ionizing radiation [ [144] , [145] , [146] ]. However, additional molecules such as the aurora kinase inhibitor AT9283 have also been identified in these screens for selective killing of tumor cells with elevated Nrf2 levels [ 147 ] which do not have obvious links to NQO1-mediated bioreductive activation, although NQO1 has been reported to bind directly to aurora A [ 148 ].…”

“…The addition of PARP inhibitors restored NAD + levels indicating that PARP was responsible for the consumption of NAD + which was consistent with oxidative DNA damage induced by β-lapachone followed by PARP-mediated DNA repair [ 144 , 176 , 177 ]. NQO1-mediated futile redox cycling of β-lapachone leads to oxidative DNA damage, hyperactivation of PARP, depletion of NAD + and ATP and a specific type of programmed necrosis termed NAD + -keresis [ 146 , [178] , [179] , [180] ]. These experiments exposed opposing roles for NQO1 in β-lapachone induced cytotoxicity where the enzyme is responsible for the generation of reactive metabolites, but at the same time produces NAD + to aid in DNA repair.…”

Understanding the Radiobiology of Vestibular Schwannomas to Overcome Radiation Resistance

“…Overall, SSBs are seldom lethal, as cells have evolved mechanisms to repair these DNA lesions [ 46 , 49 ]. Base excision repair (BER) is the most common method of repairing oxidized bases and SSBs [ 50 ]. However, in certain situations, SSBs can result in cell death through various mechanisms [ 51 ].…”

NRF2 and the Ambiguous Consequences of Its Activation during Initiation and the Subsequent Stages of Tumourigenesis

“…Some of these compounds are now being investigated in clinical trials [304,305] but more development is necessary for them to be used in the clinic. It should be mentioned that a potentially valuable use of NQO1-bioactivatable agents is their ability to synergise with PARP1 inhibitors and radiotherapy, thereby allowing a reduction in dose of agents administered and minimisation of unwanted toxic side effects [306].…”