Synergistic Effect Of Exemestane And Aspirin On MCF-7Human Breast Cancer Cells And Its Mechanism

Backgroud:Breast cancer is the leading cause of cancer death in females worldwide, accounting for23%of the total new cancer cases and14%of the total cancer deaths. Approximately75%of all patients with breast cancer have a tumor expressing the estrogen receptor (ER) and/or the progesterone receptor. The third generation AIs(letrozole,anastrozole and exemestane) are now widely recommended for adjuvant therapy in postmenopausal breast cancer patients with hormone-sensitive disease. Currently, AIs have been used as the standard first-line treatment for patients with advanced estrogen dependent breast cancer. Cyclooxygenases (COX)-1and COX-2have been found to be over-expressed in breast cancer tissue when compared to normal tissue. NSAIDs are thought to interfere with breast carcinogenesis mainly via inhibiting the cyclooxygenase1and2enzymes (COX-1and COX-2). Strategies using combination drugs to enhance the efficacy of cancer treatment have been proved in recent years. They may react together to give synergistic action to inhibit tumors through regulation of different signaling pathways or compensation for the opposite properties in cancer cell proliferation or apoptosis. Therefore, in this study, we investigated the effects of combined exemestane and aspirin on breast cancer cells, including cell survival, cell cycle, and alterations in signaling pathway.Objectives:The purpose of this study is to investigate the combined effects of exemestane and aspirin on MCF-7human breast cancer cells.Methods:Antiproliferative effects of exemestane and aspirin, alone and in combination, on growth of MCF-7human breast cancer cells were assessed using MTT assay. The synergistic interaction between the two drugs was evaluated in vitro using the combination index (CI) method. Cell cycle distribution was analyzed by flow cytometry. Western blot analysis was used to investigate the expression of cyclooxygenase-1, cyclooxygenase-2and Bcl-2in MCF-7cells treated with various regimens.Results:MTT assay indicated that combination treatment obviously decreased the viability of MCF-7human breast cancer cells compared to individual drug treatment (CI<1). In addition, combination of exemestane and aspirin exhibited a synergistic inhibition of cell proliferation,significantly arrested the cell cycle at G0/G1phase and produced a stronger inhibitory effect on COX-1and Bcl-2expression than control or individual drug treatment.Conclusion:The combination of exemestane with aspirin for72h resulted in a synergistic effect (CI<1) on the inhibition of the growth of MCF-7cells. It could be inferred that synergistic effect by exemestane combined with aspirin might be attributed to cell cycle arrest at G0/G1phase and down-regulation of the COX-1and Bcl-2expression. These results indicate that combination of exemestane and aspirin might become a useful method to the treatment of hormone-dependent breast cancer.