Telmisartan Enhances the Accumulation of Doxorubicin as a Combination Therapy for the Management of Triple Negative Breast Cancer

Abstract

Background: Triple-negative breast cancer (TNBC) is one of the most aggressive tumours with dismal survival and a high death rate. Chemotherapeutic resistance due to P-gp overexpression was shown in MDA-MB-231 human breast cancer cells. The aim of this study was to re-sensitize of MDA-MB-231 human breast cancer cells to Doxorubicin by suggested P-gp inhibitors. Methods:Screening of around 100 in-house prepared compounds against the crystal structure of the P-glycoprotein was performed using molecular docking tool. The top ranked hits obtained were Verapamil, Benazepril, and Telmisartan.Accordingly, the anticancer activity of Doxorubicin and in combination with suggested P-gp inhibitors were examined on MDA-MB-231 breast cancer cell line, using the [3-(4,5-dimetiltiazol-2-il)-2,5-diphenyl tetrazolium bromide] MTT assay. Accumulation of Doxorubicin was analyzed by flow cytometry. Results:Telmisartan showed the lowest binding energy (-9.7 Kcal/mol) followed by Benazepril and Verapamil, with -9.2, -7.3 and -6.4 Kcal/mol, respectively. These compounds were chosen for the next phase of studies to evaluate their in vitro biological effects against TNBC cell line (MDA-231). Doxorubicin in combination with Telmisartan significantly inhibited cell proliferation in the MDA-MB-231 breast cancer cell line (IC50=0.08261 μM for MDA-MB-231) more than Doxorubicin alone (IC50=0.2847μM for MDA-MB-231). Flow cytometry examined the accumulation of Doxorubicin inside the MDA-MB-231 breast cancer cell line after 24 hours of treating them with Telmisartan. Conclusion: current findings suggest that Telmisartan re-sensitize MDA-MB-231 breast cancer cells to Doxorubicin by increasing Doxorubicin accumulation.