Enhancing Repair of Oxidative DNA Damage with Small-Molecule Activators of MTH1

Abstract

Impaired DNA repair activity has been shown to greatly increase rates of cancer clinically. It has been hypothesized that upregulating repair activity in susceptible individuals may be a useful strategy for inhibiting tumorigenesis. Here, we report that selected tyrosine kinase (TK) inhibitors including nilotinib, employed clinically in the treatment of chronic myeloid leukemia, are activators of the repair enzyme Human MutT Homolog 1 (MTH1). MTH1 cleanses the oxidatively damaged cellular nucleotide pool by hydrolyzing the oxidized nucleotide 8-oxo-2'-deoxyguanosine (8-oxo-dG)TP, which is a highly mutagenic lesion when incorporated into DNA. Structural optimization of analogues of TK inhibitors resulted in compounds such as SU0448, which induces 1000 ± 100% activation of MTH1 at 10 μM and 410 ± 60% at 5 μM. The compounds are found to increase the activity of the endogenous enzyme, and at least one (SU0448) decreases levels of 8-oxo-dG in cellular DNA. The results suggest the possibility of using MTH1 activators to decrease the frequency of mutagenic nucleotides entering DNA, which may be a promising strategy to suppress tumorigenesis in individuals with elevated cancer risks.

Calcium influx, oxidative stress, and apoptosis induced by TRPV1 in chronic myeloid leukemia cells: Synergistic effects with imatinib

“…BCR-ABL1 oncoprotein is involved in the production of ROS that are then responsible for promoting genomic instability, a sort of “auto-mutagenesis” process that leads to malignancy ( Pascu VÎnturiŞ and GĂman, 2020 ; Głowacki et al, 2021 ). In addition, it has surprisingly been found that TKI treatment during time favors the control of the redox cell state by activating the repair enzyme human MutT homolog 1 which removes the oxidatively damaged cellular nucleotide pool and repairs the DNA breaks, leading to a strong reduction in therapy efficacy itself and chemoresistance ( Lee et al, 2022 ). On the other hand, the drug-induced oxidative stress exaggeration in leukemic cells could intensify the genotoxic effects of conventional therapy, facilitating the activation of programmed cell death ( Yang et al, 2018 ).…”

Nanoplatform-based strategies for enhancing the lethality of current antitumor PDT

“…[127][128][129] As the vital enzyme of DNA repair, inhibiting the activation of intratumoral MTH1 enzyme is hoped to achieve enhanced PDT. 130,131 To verify this hypothesis, Shao et al co-assembled the PS (4-FM) and MTH1 inhibitor (TH588) with the azobenzene group-decorated polymer and obtained the FTPA nanoparticles, which could accurately release the cargos in the hypoxic tumor (Fig. 10(A)).…”

Chemical Tools for the Study of DNA Repair

“…(f) Immunofluorescence imaging of 8-oxo-dG foci in cellular DNA in the presence of the activator, showing suppression of oxidative damage. Reproduced with permission from ref , Copyright 2018 American Chemical Society, and ref , Copyright 2022 American Chemical Society.…”

“…26 Similarly, cellular dUTPase and dITPase enzymes cleave the triphosphate chains of dUTP and dITP. 26 Loss of some of these sanitation enzymes results in enhanced cancer rates, 59 and multiple enzymes in this class are considered targets for pharmaceutical development; for example, MTH1 has been investigated both for treatment of cancer 60 and for cancer prevention, 61 and a dUTPase inhibitor recently underwent clinical trials for cancer therapy. 62 In addition, some of these enzymes are also considered disease markers (see below).…”

“…Subsequent structural optimization resulted in the compound SU0448, which activates MTH1 activity in vitro by as much as 10-fold at 10 μM (Figure 6d−f). 61 Studies in live cells show that the compound decreases 8-oxo-guanine levels when the cells are exposed to reactive oxygen species.…”