DNA damage and apoptosis induced by a potent orally podophyllotoxin derivative in breast cancer

• Published in: Cell communication and signaling 2018-09, Vol.16 (1), p.52-52, Article 52
• Main Authors: Wang, Yajie, Sun, Hua, Xiao, Zhiyan, Zhang, Gang, Zhang, Dan, Bao, Xiuqi, Li, Fangfang, Wu, Shaoyu, Gao, Yuanchao, Wei, Ning
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Analysis; Antitumor activity; Antiviral drugs; Apoptosis; Breast cancer; Cancer therapies; Care and treatment; Cell cycle; Chemotherapy; Cytotoxicity; Deoxyribonucleic acid; Design; DNA; DNA damage; Drug discovery; Drug therapy; Enzymes; Flow cytometry; Genetic aspects; Hydrogen bonding; Hydrogen bonds; Kinases; Mdm2; MDM2 protein; Mitochondria; p53; p53 Protein; Physiological aspects; Podophyllotoxin; Proteins; Topoisomerase II; TopoisomeraseII
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-018-0263-9

Targeting TopoisomeraseII (TopoII) and generate enzyme mediated DNA damage is an effective strategy for treatment of breast cancer. TopoII is known as a validated target for drug discovery and cancer chemotherapy. XWL-1-48, a new orally podophyllotoxin derivative, was designed and synthesized. The effect of XWL-1-48 on TopoII 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. 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 TopoII 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 γ-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. XWL-1-48 may be a promising orally topoII inhibitor, its mechanisms are associated with suppression of TopoII, induction of DNA damage and apoptosis, blockage of PI3K/AKT/Mdm2 pathway.