Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives

Abstract

Since accelerated metabolism produces much higher levels of reactive oxygen species (ROS) in cancer cells compared to ROS levels found in normal cells, human MutT homolog 1 (MTH1), which sanitizes oxidized nucleotide pools, was recently demonstrated to be crucial for the survival of cancer cells, but not required for the proliferation of normal cells. Therefore, dozens of MTH1 inhibitors have been developed with the aim of suppressing cancer growth by accumulating oxidative damage in cancer cells. While several inhibitors were indeed confirmed to be effective, some inhibitors failed to kill cancer cells, complicating MTH1 as a viable target for cancer eradication. In this review, we summarize the current status of developing MTH1 inhibitors as drug candidates, classify the MTH1 inhibitors based on their structures, and offer our perspectives toward the therapeutic potential against cancer through the targeting of MTH1.

Fluorescence Imaging of Mitochondrial DNA Base Excision Repair Reveals Dynamics of Oxidative Stress Responses

“…In this more severe case, higher levels of direct DNA damage are expected, along with the increased incorporation of oxidized dNTP, where the role of MTH1 would play a role (Figure 4 f,g). Under these conditions, the mtDNA base excision activity was greatly elevated in the MTH1 KO cell line, consistent with expectations and also consistent with prior observations that this cell line is more vulnerable to oxidative damage than is the WT line [35] . In the case of the OGG1 KO cell line, mtDNA base excision activity appeared to be enhanced the least.…”

“… [34] In the experimental setup, two knockout (KO) HAP1 cell lines by CRISPR‐Cas9 were studied (HAP1 wild type, MTH1‐knockout, and OGG1‐knockout, Figure 4 b). Deficiency in each of these enzymes is known to increase susceptibility to oxidative damage in cellular DNA [35] . The chief difference between the MTH1 and OGG1 KO cell lines is expected to be the glycosylation capacity: the OGG1‐deficient cell line is expected to have reduced glycosylation capacity, while the MTH1‐deficient cells should have full glycosylation capacity.…”

Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

“…Another category of inhibitors targets proteins involved in DNA repair such as RAD51 and POLQ, respectively from the HR and MMEJ processes, or PARP and MTH1 [226][227][228][229]. The discovery of PARP inhibitors was a milestone for anticancer chemotherapies directed against DDR proteins.…”

Roles for the 8-Oxoguanine DNA Repair System in Protecting Telomeres From Oxidative Stress

“…Some studies suggest cancer cells may be more sensitive to MTH1 inhibitors, due to higher levels of ROS compared to non-diseased cells (Gad et al, 2014). However, despite the demonstrated effectiveness of some newly developed MTH1 inhibitor drugs, the potential efficacy in targeting MTH1 to treat cancer remains controversial and may depend on the tumor properties (Warpman Berglund et al, 2016;Yin and Chen, 2020).…”