期刊
CELL COMMUNICATION AND SIGNALING
卷 16, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12964-018-0263-9
关键词
Breast cancer; Topoisomerasell; DNA damage; p53; Mdm2
类别
资金
- Municipal Twelfth Five-year Major projects of the People's Republic of China [2013HXW-13]
- China National Natural Sciences Foundation [81202556]
Background: Targeting Topoisomerasell (Topoll) and generate enzyme mediated DNA damage is an effective strategy for treatment of breast cancer. Topoll is known as a validated target for drug discovery and cancer chemotherapy. Methods: XWL-1-48, a new orally podophyllotoxin derivative, was designed and synthesized. The effect of XWL-1-48 on Topoll binding and activity was determined by molecular docking software and kDNA-decatenation assay, respectively. In vitro and in vivo breast cancer models were used to document the antitumor activity of XWL-1-48. Cellular apoptosis, cell cycle and ROS were analyzed by flow cytometry. Alteration of XWL-1-48-mediated downstream pathways was determined by western blot analysis. Results: The cytotoxicity of XWL-1-48 is more potent than that of its congener GL331. Molecular docking demonstrated that XWL-1-48 could bind to Topoll through forming two strong hydrogen bonds and potential pi-pi interactions. Noticeably, XWL-1-48 exerts potent antitumor activity in in vitro and in vivo breast cancer model. Treatment with XWL-1-48 caused ROS generation and triggered DNA damage through induction of gamma-H2AX and activation of ATM/p53/p21 pathway. Further studies showed that XWL-1-48 led to S-phase arrest and mitochondrial apoptosis. Meanwhile, XWL-1-48 significantly blocked PI3K/Akt/Mdm2 pathway and enhanced Mdm2 degradation. Conclusion: XWL-1-48 may be a promising orally topoll inhibitor, its mechanisms are associated with suppression of Topoll, induction of DNA damage and apoptosis, blockage of PI3K/AKT/Mdm2 pathway.
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