Cytotoxicity and Application on Drug Resistant Cells of Halide Derivatives of Rutaecarpine

The drug resistance emerging in both prokaryotic and eukaryotic organisms gives rise to lowered susceptibility to antimicrobial or anticancer therapy and results in enhanced survival ability or virulence. Topoisomerases are involved in DNA replication and transcription; thus, the topoisomerase inhibitors are able to be used for anti-tumor, anti-virus, anti-bacterial agents. To impede the activity of topoisomerase is often utilized in clinic for therapeutical strategy. Among the disclosed mechanisms conferring to drug resistance, elicitation of AMPK-associated autophagy was recently reported to cause cancer cell escaping from anticancer drug poisoning. A DNA damage agent causes the genetic instability and often results in becoming cancer stem cells, which are more resistant to chemotherapy. Development on side population cell poisoning or AMPK signaling blockade may ameliorate the plight of cancer chemotherapy. We first disclosed topoisomerase I (Top1)-inhibitory activity of evodiamine (EVO) that could be used for cancer cell-killing. We used EVO analog rutaecarpine as a lead compound to design and synthesize novel halide derivatives as resistant cancer cell poisons. In this proposal, Top1 poison camptothecin resistant ovarian cancer cells (A2780R2000) are screened and characterized. Halide derivatives of rutaecarpine are evaluated for TopI inhibition in vitro and in vivo that can be applied for A2780R2000-killing. We further develop the therapeutic medication comprising the rutaecarpine derivatives against antibiotic resistant Klebsiella pneumonia isolated from Taipei Medical University Hospital. We successfully establish a high throughput platform of Top1 inhibitor screening both in the in vitro and in vivo. Besides, the mechanisms associated with the resistant cell-killing effect by the rutaecarpine derivatives will be explored. The rutaecarpine derivatives are potent medication against resistant tumor cells and bacteria.