| Autor: |
Nannan Kang, Jun Ma, Yuling Hu, Rongrong Di, Lei Wang, Xuanling Zhang, Yisheng Lai, Yu Liu |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Pharmaceuticals, Vol 17, Iss 3, p 291 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
1424-8247 |
| DOI: |
10.3390/ph17030291 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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