Bcl-2 inhibition sensitizes triple-negative human breast cancer cells to doxorubicin

// Touko Inao 1, 2 , Yuichi Iida 1 , Tamami Moritani 1 , Tamio Okimoto 3 , Ryosuke Tanino 3 , Hitoshi Kotani 1 and Mamoru Harada 1 1 Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan 2 Department of Breast Surgery, Takasago City Hospital, Hyogo, Japan 3 Division of Medical Oncology & Respiratory Medicine, Department of Internal Medicine, Shimane University Faculty of Medicine, Shimane, Japan Correspondence to: Mamoru Harada, email: haramamo@med.shimane-u.ac.jp Keywords: breast cancer; triple-negative; Bcl-2; ABT-199; doxorubicin Received: March 20, 2018     Accepted: April 24, 2018     Published: May 22, 2018 ABSTRACT Breast cancers can be divided into several types. Because triple-negative breast cancer (TNBC) is the most refractory to current anti-cancer therapies, efficient treatment has been urgently required. Members of the Bcl-2 family play pro- and anti-apoptotic roles in mitochondria-mediated apoptosis. Some Bcl-2 family members are expressed in breast cancer and influence the response to anti-cancer therapies. In this study, we investigated whether Bcl-2 inhibition could sensitize TNBC cells to the genotoxic drug doxorubicin (DR). Treatment with a combination of the Bcl-2 inhibitor ABT-199 and DR synergistically decreased the viability of the TNBC cell lines MDA-MB-231 and BT-549. In an apoptosis assay, the combination treatment resulted in only a marginal effect in BT-549 cells, whereas drastic apoptosis was induced in MDA-MB-231 cells treated with both ABT-199 and DR. Both caspase-8 and -9 were involved in the combination treatment-induced apoptosis. Short interfering RNA-mediated knockdown of Bcl-2 increased the sensitivity of both cell lines to DR. The combination treatment also significantly decreased the colony-forming ability of the TNBC cell lines. In a xenograft mouse model, oral administration of ABT-199 augmented the DR-induced antitumor effect on subcutaneously established MDA-MB-231 cells. These results indicate that the combination of DR with Bcl-2 inhibitors, including ABT-199, may be a promising treatment modality for TNBC patients.