A novel triazolonaphthalimide induces apoptosis and inhibits tumor growth by targeting DNA and DNA-associated processes
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Liyan Ji1,2,*, Simin Yang1,*, Shasha Li1, Shan Liu1, Shunan Tang1, Zhongqiu Liu2, Xiangbao Meng1, Siwang Yu1
1Department of Chemical Biology, Peking University School of Pharmaceutical Sciences, Beijing 100191, China
2International Institute for Translational Chinese Medicine, Guangzhou Traditional Chinese Medicine University, Guangzhou 510006, China
*These authors contributed equally to this work
Siwang Yu, email: [email protected]
Xiangbao Meng, email: [email protected]
Keywords: triazolonaphthalimide, DNA binding, topoisomerase 2, DNA replication, cell cycle arrest
Received: June 29, 2016 Accepted: March 27, 2017 Published: April 08, 2017
DNA and DNA-associated processes have been classes of the most important targets of chemotherapeutic drugs. As classic DNA intercalators and topoisomerase inhibitors, naphthalimides have been extensively investigated as potential anti-cancer drugs. We recently synthesized a novel series of triazolonaphthalimides with excellent anti-cancer activities. In the present study, one of the most potent triazolonaphthalimides, LSS-11, was investigated. LSS-11 bound to DNA in vitro and in cell mainly by minor groove binding and significantly increased the stability of DNA, which could be fundamental for the biological activities of LSS-11. In addition to inhibiting DNA topoisomerase II-catalyzed decatenation of knotted circulated DNA, LSS-11 dramatically inhibited DNA replication mediated by polymerase chain reaction and isothermal helicase-dependent amplification, as well as the expression of luciferase driven by a minimal TA promoter in cell. Furthermore, LSS-11 exhibited strong cytotoxicity in selected human colon cancer cell lines by inducing cell cycle arrest and apoptosis, which was accompanied by DNA damage response. Finally, LSS-11 potently inhibited the growth of S180 murine sarcoma and SW480 human colorectal cancer xenografts in vivo without significant major toxicities. These results suggest that LSS-11 deserves further research and development as a novel anti-cancer agent, and provided new understandings of mechanisms by which LSS-11 inhibited multiple DNA-associated processes and tumor growth.
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