A novel irinotecan derivative ZBH-1207 with different anti-tumor mechanism from CPT-11 against colon cancer cells.

ABSTRACT

PURPOSE: Irinotecan (CPT-11) is a camptothecin derivative whose potent anti-tumor activity depends on the rapid formation of an in vivo active metabolite, SN38 (7-ethyl-10-hydroxycamptothecin). CPT-11 combine with other agents are often the treatment of choice for patients with advanced or metastatic colorectal cancer (CRC). This study evaluates the cytotoxic mechanism of a novel CPT-11 derivative, ZBH-1207 in CRC cells in vitro. METHODS: The anti-proliferation effect of ZBH-1207 on tumor cells was assessed by MTT assay. The inhibition of TOP1, the alteration of cell cycle and apoptosis, and the expression of caspase-3 and PARP in CRC cells induced by ZBH-1207 were detected by DNA relaxation assay, flow cytometry, and Western blot, respectively. RESULTS: ZBH-1207 significantly inhibits the proliferation of seven tumor cell lines and retains the activity of TOP1 as compared with CPT-11. Treatment with ZBH-1207 results in more apparent cell cycle arrests and apoptosis of CRC cells than that of CPT-11 and SN38. Accordingly, up-regulation of active caspase-3 and PARP expression were relatively higher in ZBH-1207 group than that in CPT-11 and SN38 group. CONCLUSION: ZBH-1207 has higher cytotoxicity than CPT-11/SN38 in CRC cells. Its molecular mechanism involves apoptosis signaling pathway.