Version 1
: Received: 21 December 2023 / Approved: 21 December 2023 / Online: 21 December 2023 (11:49:21 CET)
How to cite:
Kang, N.; Ma, J.; Hu, Y.; Di, R.; Wang, L.; Zhang, X.; Lai, Y.; Liu, Y. Targeting MutT homolog 1 (MTH1) for breast cancer suppression by a novel MTH1 inhibitor MA-24 with tumor-selective toxicity. Preprints2023, 2023121649. https://doi.org/10.20944/preprints202312.1649.v1
Kang, N.; Ma, J.; Hu, Y.; Di, R.; Wang, L.; Zhang, X.; Lai, Y.; Liu, Y. Targeting MutT homolog 1 (MTH1) for breast cancer suppression by a novel MTH1 inhibitor MA-24 with tumor-selective toxicity. Preprints 2023, 2023121649. https://doi.org/10.20944/preprints202312.1649.v1
Kang, N.; Ma, J.; Hu, Y.; Di, R.; Wang, L.; Zhang, X.; Lai, Y.; Liu, Y. Targeting MutT homolog 1 (MTH1) for breast cancer suppression by a novel MTH1 inhibitor MA-24 with tumor-selective toxicity. Preprints2023, 2023121649. https://doi.org/10.20944/preprints202312.1649.v1
APA Style
Kang, N., Ma, J., Hu, Y., Di, R., Wang, L., Zhang, X., Lai, Y., & Liu, Y. (2023). Targeting MutT homolog 1 (MTH1) for breast cancer suppression by a novel MTH1 inhibitor MA-24 with tumor-selective toxicity. Preprints. https://doi.org/10.20944/preprints202312.1649.v1
Chicago/Turabian Style
Kang, N., Yisheng Lai and Yu Liu. 2023 "Targeting MutT homolog 1 (MTH1) for breast cancer suppression by a novel MTH1 inhibitor MA-24 with tumor-selective toxicity" Preprints. https://doi.org/10.20944/preprints202312.1649.v1
Abstract
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.
Keywords
Breast cancer, MutT homolog 1(MTH1), Antitumor activity, Oxidized nucleotide, MA-24
Subject
Medicine and Pharmacology, Medicine and Pharmacology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.