The Pharmacological Mechanism Of S1on Drug-resistant Breast Cancer Cells

Resistance to cytototoxic chemotherapy is the major problem to treatments of many malignant tumor. Similarly, it is also the important reason for the failure to chemotherapy in the breast cancer. MCF-7/ADR cells were established to develop adriamycin (ADR) resistance from parental drug-sensitive MCF-7cells, and exhibited the phenotype of multidrug resistance (MDR), such as high levels of P-glycoprotein (P-gp) expression. MCF-7/ADR cells have been widely used as a multidrug-resistant breast cancer cell model in searching for effective therapeutic agents. BH3mimetics which induce apoptosis via releasing and activating Bax/Bak in cancer cells through binding into BH3grooves are newly promising anti-tumor strategy. S1(3-thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9carbonitrile) has been verified as a low-toxic, high potency Bcl-2/Mcl-1dual inhibitor and exhibiting the broad-spectrum anti-tumor effect via targeting BH3binding groove of anti-apoptotic proteins to induce Bax/Bak-dependent mitochondrial apoptosis. Recently, BH3mimetics were reported could maintain effectiveness in drug-resistant cancer cells due to the bypass of some roadblocks for drug-induced cell death. BH3mimetic could provide a new solution for treatments of many drug-resistant tumor.In this paper, we aimed to study the The pharmacological mechanism of a pan-BH3mimetic S1on drug-resistant MCF-7/ADR cells.This study takes MCF-7cells and their multidrug-resistant counterparts,MCF-7/ADR as the research object. By means of MTT and Western blot experiments, S1was found to exhibit greater and faster Bak-dependent apoptosis in MCF-7/ADR cells than in MCF-7cells. The study revealed that S1can induce phosphor S70of Bcl-2in MCF-7cells. Results of FP and western blot suggested that S1could antagonize Mcl-1Bcl-2but not unphosphorylated Bcl-2(pBcl-2). Futher, By Bax/Bak releasing and activation experiments suggested that pBcl-2induced by S1accounted for relative MCF-7resistance, but it was not induced in MCF-7/ADR cells leading to the cell line more sensitivity to S1.Under this study, we examined the effect of S1on ER stress proteins. Western blotting analysis showed that the different Bcl-2phosphorylation in the two lines resulted from the specific induction of ER stress by S1in MCF-7cells rather than MCF-7/ADR cells. Then we suggested that ER stress played a protective role in MCF-7cells, delay and reduce S1-induced apoptosis by Bcl-2phosphorylation via combining the effect of ERK inhibitor PD98059and S1.Therefore, BH3mimetic could develop a broader prospect for treatments of many drug-resistant tumor by directly targeting BH3-binding grooves of the antiapoptotic Bcl-2proteins.