The Mechanism Study Of A New Microtubule Inhibitor SQ On The Proliferation Of MDA-MB-231 And MCF-7 Cells

Breast cancer is the leading cause of cancer death in Asian women.Novel chemotherapeutic drugs with high activity and no drug resistance for treating breast cancer are needed urgently.Taxol,a microtubule targeted agent,has been used for breast cancer as first-line drug for a long time;however,the major problem contributing to its failure in clinical chemotherapy is drug resistance.Combretastatin A-4(CA-4)is an alkaloid isolated from the South African Willow Combretum cafrum by Pettit and his colleagues.CA-4 is an efficient microtubule-destabilizing agents and not acting as a substrate of multidrug resistance pump,shows potential anti-cancer ability.However,CA-4 is easy to be isomerized into other inactive forms.To resolve the stability problems of CA-4,Dr.Zhang’s laboratory from Shenyang Pharmaceutical University designed a series of compounds by using selenium atom to replace the olefin group between two rings.According to multiple times of trials,we found that no matter activity or stability,the compound 2-methoxy-5((3,4,5-trimethosyphenyl)seleninyl)phenol(SQ)is the best.In this study,we investigated the antitumor effect of SQ,which has a strong inhibition of cell growth in MCF-7(p53 wild type)and MDA-MB-231(p53 mutant)cells.SQ exhibited superior in vivo efficacy and low toxicity than CA-4.We demonstrated that SQ time-dependently induced cell cycle arrest at G2/M phase and subsequently progressed into apoptosis in breast cancer cells,which is associated with microtubule depolymerization.Our study demonstrated that SQ-induced apoptosis is p53-independent while caspase-dependent,and apoptosis induced by SQ is correlated with the down-regulation of the PI3K-Akt-MDM2 pathway in MCF-7 and MDA-MB-231 cells.Moreover,SQ induced MCF-7 and MDA-MB-231 cells to generate reactive oxygen species(ROS),and the SQ-induced cell death was ROS dependent.In addition,our study showed that SQ dissociated the MDM2-p53 complex and directly induced MDM2 degradation through the ubiquitin-dependent proteasome pathway in MCF-7 and MDA-MB-231 cells.Besides apoptosis,SQ also induces autophagy in MCF-7 and MDA-MB-231 cells.Here in this study,we focus on the natural role of autophagy induced by SQ.We found that SQ induced different role of autophagy in breast cancer cells,which is SQ-induced cytoprotective autophagy in MCF-7 cells,but nonprotective autophagy in MDA-MB-231 cells,while the overall extent of SQ-induced autophagy does not appear to differ in the two cell lines.In conclusion,all the data demonstrated that SQ exhibited its antitumor activity through disrupting the microtubule assembly,inducing cell cycle arrest,directly inhibiting the expression of MDM2 protein and eventually inducing apoptosis in MCF-7 and MDA-MB-231 cells.Therefore,the novel compound SQ is a promising microtubule inhibitor that has tremendous potentials for therapeutic treatment of human breast cancer.