​

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= 0.2847 μM for MDA-MB-231). Flow cytometry examined the accumulation of Doxorubicin inside the MDAMB-231 breast cancer cell line after 24 hours of treating them with Telmisartan.

Conclusion: current findings suggest that Telmisartan re-sensitize MDA …​