Study On Anti-tumor Activity Of New Camptothecin Derivatives

This study aimed to examine the effects of new camptothecin derivatives on proliferation and apoptosis in cancer cells, and to explore its potential mechanism.Three kinds of new camptothecin derivatives, Prolinol-10-Hydroxy Camptothecin (PR-HCPT), Hydroxyethyl-piperazine-10-Hydroxy Camptothecin (HP-HCPT), Piperidinol-10-Hydroxy Camptothecin (PI-HCPT) were evaluated by utilizing molecular docking technology and MTT method. They were synthesized by State Key Laboratory of Fine Chemicals Dalian University of Technology. We investigated how PR-HCPT induce MCF-7cell apoptosis, and researched the expression level of the protein in cell apoptosis pathway, to figure out the fine mechanism of its promotion of MCF-7cell apoptosis.Results from MTT assay proved that camptothecin derivatives could inhibit the growth of five human tumor cells (human breast cancer cell line MCF-7, human cervical carcinoma cell line SMMC-7721, human gastric cancer BGC-823cell lines, human small cell lung cancer NCI-H1688and NCI-H446cell line) in a time and dose-dependent manner. Among the cancer cell lines tested, MCF-7cells were the most vulnerable to PR-HCPT with an IC50value of11.59μM in48h. Molecular docking results proved that the camptothecin derivatives’ binding sites located in same area, and the binding may be related to hydrogen bond.Results from Hoechst33258staining and flow cytometry analysis showed PR-HCPT could induce apoptosis in MCF-7cells. Cell shrinkage, nuclear condensation, formation of apoptotic bodies could be observed after being exposed to PR-HCPT; the apoptotic rate of MCF-7was increased from0.4%to72.2%and76.2%after being dealt with10μM and25μM PR-HCPT. Using transient transfection technique establishing cell system of protein overexpression, and results from western blot showed that the expression level of NF-κB reduced obviously and the expression level of IκB increased, but the levels of PTEN and AKT did not have obvious change. All these three kinds of camptothecin derivatives had anti-tumor biological activity, and the PR-HCPT could induce apoptosis, this effect may be matter with NF-κB cell signaling pathway.These results suggest that the new camptothecin derivatives possess biological activity that could promote tumor cell’s apoptosis. The specific mechanism is that camptothecin derivatives regulated expression of IκB and downstream target genes, and then induced cell apoptosis.