OGG1 co-inhibition antagonizes the tumor-inhibitory effects of targeting MTH1

Zhang, Ling; Misiara, Laura; Samaranayake, Govindi J.; Sharma, Nisha; Nguyen, Dao M.; Tahara, Yu Ki; Kool, Eric T.; Rai, Priyamvada

doi:10.1016/j.redox.2020.101848

Cited by 10 publications

(4 citation statements)

References 52 publications

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“…As corroborative evidence, other research found that the CDK4/6 inhibitor sensitized G1-arrested cells to anticancer drugs by downregulating the expression of PARP1, on which OGG1 depends to conduct its DNA damage repair function [107]. Additionally, the anticancer effects of MTH1 inhibition also require the existence of OGG1, transforming the mismatch caused by 8-oxoG to the DNA strand break to injure oncocyte [108].…”

Section: The Roles Of Ogg1 In Lung Cancermentioning

confidence: 67%

OGG1 in Lung—More than Base Excision Repair

Xiang

2022

Antioxidants

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As the organ executing gas exchange and directly facing the external environment, the lungs are challenged continuously by various stimuli, causing the disequilibration of redox homeostasis and leading to pulmonary diseases. The breakdown of oxidants/antioxidants system happens when the overproduction of free radicals results in an excess over the limitation of cleaning capability, which could lead to the oxidative modification of macromolecules including nucleic acids. The most common type of oxidative base, 8-oxoG, is considered the marker of DNA oxidative damage. The appearance of 8-oxoG could lead to base mismatch and its accumulation might end up as tumorigenesis. The base 8-oxoG was corrected by base excision repair initiated by 8-oxoguanine DNA glycosylase-1 (OGG1), which recognizes 8-oxoG from the genome and excises it from the DNA double strand, generating an AP site for further processing. Aside from its function in DNA damage repairment, it has been reported that OGG1 takes part in the regulation of gene expression, derived from its DNA binding characteristic, and showed impacts on inflammation. Researchers believe that OGG1 could be the potential therapy target for relative disease. This review intends to make an overall summary of the mechanism through which OGG1 regulates gene expression and the role of OGG1 in pulmonary diseases.

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Section: The Roles Of Ogg1 In Lung Cancermentioning

confidence: 67%

OGG1 in Lung—More than Base Excision Repair

Xiang

2022

Antioxidants

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“…[ 8 ] Interestingly, Warpman Berglund U et al [ 34 ] later refuted the previously reported microtubule-targeting mechanism of TH588, demonstrating that TH588 has a distinct mode of action from microtubule-targeting drugs, such as paclitaxel and nocodazole, and emphasized the high selectivity of MTH1 inhibitors for MTH1 binding and inhibition. Subsequent studies once again affirm that MTH1 inhibition may provide a survival advantage to treated tumors by blocking DNA nicks caused by base excision repair and inducing p53 [ 35 ]. Warpman Berglund U further demonstrated that the MTH1 inhibitor TH1579 is an anticancer agent for acute myeloid leukemia via inducing oxidative DNA damage and mitotic arrest [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting MutT Homolog 1 (MTH1) for Breast Cancer Suppression by Using a Novel MTH1 Inhibitor MA−24 with Tumor-Selective Toxicity

Kang,

Ma,

et al. 2024

Pharmaceuticals

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Background: Breast cancer is a commonly diagnosed cancer worldwide. Human MutT homolog 1 (MTH1) is found to be elevated in breast tumors and cancer cells need MTH1 for survival. Pharmacological inhibition of MTH1 may be potentially beneficial in the treatment of breast cancer. Methods: MA−24 was screened by malachite green colorimetric assay for MTH1 inhibitors and the kinetic characteristics of MA−24 were assessed. The features of MA−24’s binding with MTH1 were ascertained through molecular docking, and the cytotoxic activity of MA−24 was validated in vitro and in vivo. Target engagement assays, comet assay, and Western blot confirmed the intracellular target and mechanism of MA−24. Results: MA−24 shows potent antitumor bioactivity both in vitro and in vivo. MA−24 competitively inhibited the MTH1 and further induced DNA strand breaks, leading to increased apoptosis of cancer cells depending on the upregulation of the cleaved-caspase 3–cleaved-PARP axis. In particular, MA−24 exhibited a powerful efficacy and safety in vivo (tumor growth inhibition rate: 61.8%). Conclusions: MA−24 possesses a broad spectrum of breast cancer cytotoxicity and offered valuable insights for overcoming the challenges of chemotherapy-related toxicity, which holds great potential for the further development MA−24 as an anti-cancer drug.

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“…Subsequent studies once again affirm that MTH1 inhibition may provide a survival advantage to treated tumors by blocking DNA nicks caused by base excision repair and inducing p53. [34] Warpman Berglund U further demonstrated that the MTH1 inhibitor TH1579 is an anticancer agent for acute myeloid leukemia via inducing oxidative DNA damage and mitotic arrest. [35] This study aimed to report the therapeutic effect of novel MTH1 inhibitors MA-24 in breast cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Targeting MutT homolog 1 (MTH1) for breast cancer suppression by a novel MTH1 inhibitor MA-24 with tumor-selective toxicity

Kang,

Ma,

et al. 2023

Preprint

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Background: Breast cancer is a commonly diagnosed cancer worldwide. Human MutT homolog 1 (MTH1) is found to be elevated in breast tumors and cancer cells are addicted to MTH1 for sur-vival. Pharmacological inhibition of MTH1 may be potentially beneficial in the treatment of breast cancer. Methods: MA-24 was screened by malachite green colorimetric assay from MTH1 inhibitors and the kinetic characteristics of MA-24 was assessed. Binding features of MA-24 with MTH1 was as-certained through molecular docking, and cytotoxic activity of MA-24 was validated in vitro and in vivo. Target engagement assays, comet assay and western blot confirmed that the intracellular target and mechanism of MA-24. Results: MA-24 with potent antitumor bioactivity both in vitro and in vivo. MA-24 competitively inhibited the MTH1 and further induce DNA strand breaks, leading to increased apoptosis of cancer cells depending on upregulation of cleaved-caspase 3 – cleaved-PARP axis. Especially, MA-24 exhibited a powerful efficacy and safety in vivo (tumor growth inhibition rate: 61.8%). Conclusions: MA-24 possesses a broad spectrum of breast cancer cytotoxicity and offered valuable insights for overcoming the challenges of chemotherapy-related toxicity, which holds great po-tential for further development MA-24 as an anti-cancer drug.

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OGG1 co-inhibition antagonizes the tumor-inhibitory effects of targeting MTH1

Cited by 10 publications

References 52 publications

OGG1 in Lung—More than Base Excision Repair

OGG1 in Lung—More than Base Excision Repair

Targeting MutT Homolog 1 (MTH1) for Breast Cancer Suppression by Using a Novel MTH1 Inhibitor MA−24 with Tumor-Selective Toxicity

Targeting MutT homolog 1 (MTH1) for breast cancer suppression by a novel MTH1 inhibitor MA-24 with tumor-selective toxicity

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