The Mechanism of Evodiamine Derivatives Induced Cytotoxicity of Ovarian Carcinoma cells

• Main Authors: Hsiang-Ping Thsai, 蔡湘萍
• Other Authors: Chun-Mao Lin
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/63643962662573105572

碩士 === 臺北醫學大學 === 醫學科學研究所 === 98 === The regulation of DNA topology by topoisomerase I (TopoI) is essential for DNA replication, transcription, and recombination events. Camptothecins (CPTs) are family of compounds that specifically target TopoI. These compounds ‘poison’ TopoI by stabilize reversible TopoI–DNA cleavage complex and prevent the religation of DNA. TopoI activity is elevated in various cancer cells, thus TopoI has been identified as an important therapeutic target in cancer chemotherapy. However drug resistance is the main problem in the successful treatment of cancer. Our previous studies have shown that evodiamine (EVO), a major constituent of Chinese herb evodiae fructus, exhibited anti-tumor activities by inhibit TopoI activity. In our present study, we demonstrated EVO and rutaecarpine (RUT) are strong topoisomerase inhibitors by using TopoI Docking Study, SPR assay and TopoI relaxation assay in vitro. EVO exhibited dose-dependent cytotoxicity of A2780 cells whereas RUT was less cytotoxicity than EVO. EVO showed decreasing cytotoxicity in siRNA-knockdown cells, but not for RUT. Both EVO and RUT induced DNA tailing in the Comet assay and elevation of γ-H2AX levels. EVO induced TopoI depletion in a dose-dependent manner while RUT increased TopoI level in the same treatment. Furthermore, we compared the cytotoxic effect of EVO and RUT in CPT resistance cell line A2780R2000. Both EVO and RUT were able to inhibit A2780R2000 cell growth. These results suggested that EVO and RUT are potential chemotherapeutic agents in the treatment of CPT resistant cancer cells.