Zbh-1205: a Novel Camptothecin Derivate Revealed Potent Antitumor Activities Mainly Through Cell Apoptosis Pathway

ABSTRACT Aim: The aim of this study is to characterize the antitumor activity of a novel camptothecin derivate ZBH-1205 and compare with other Topo I inhibitors CTP-11 and SN38. Methods: MTT assay was employed to assess cell growth inhibition with treatment of ZBH-1025, CPT-11 or SN38. A panel of 11 human tumor cell lines was used in the assay and normal human diploid 293 cell line was also included. DNA relaxation assays were used to detected the formation of single-strand breaks induced by Topo-1 in the presence of ZBH-1205. Induction of cell apoptosis by ZBH-1205, CPT-11 and SN38 was analyzed by flow cytometer using FITC Annexin V/PI double staining method. DNA content assay was used to detect cell cycle profile. The levels of pro- and active-Caspase 3 and PARP was examined by Western blot and flowcytometry. The in vivo tumor growth inhibition of Topo I drugs was evaluated in human colon cancer xenografts. Results: ZBH-1205 retains Topo-I poisoning activities in DNA relaxation assays, as compared with CPT-11 and SN38. IC50 values for ZBH-1205 were consistently lower in cell growth assays for 11 tumor cell lines(IC50 values of ZBH-1205: 0.0009mM–2.5671mM). ZBH-1205 induced apoptosis in SW1116 and K562 cells in a dose and time dependent manner. Such abilities were greater than that of CPT-11 and SN38 especially at lower concentrations. Annexin-V+/PI- cells became detectable starting from ∼18h (or before) of drugs exposure. The induction of cell cycle arrest remains the same among three Topo I drugs. Consistent with this, there was a time and dose dependent decrease in pro-caspase-3 and PARP expression, and a significant increase in active-caspase-3. In tumor xenografts, a stronger tumor growth inhibition was observed with ZBH-1205 treatment than those of other two Topo I drugs. Conclusions: The results of current study clearly shows that ZBH-1205 is more active than SN38 and CPT-11. Also, different from CPT-11 and SN38, its antitumor mechanisms were more involved in apoptosis-related signaling pathway. Notably, ZBH-1205 can significantly induce tumor cell apoptosis at lower concentrations, which enables the drug to be more efficient and overcome the toxic effects of CPT-11 in vivo. These findings open a new route for improving the pharmacological properties of CPT-11 derivatives and support the development of novel series of CPT-11 as anticancer agents in the clinic. Disclosure: All authors have declared no conflicts of interest.