Empagliflozin and Doxorubicin Synergistically Inhibit the Survival of Triple-Negative Breast Cancer Cells via Interfering with the mTOR Pathway and Inhibition of Calmodulin: In Vitro and Molecular Docking Studies

Abstract

Triple-negative breast cancers (TNBCs) comprise 10−15% of all breast cancers but with more resistance affinity against chemotherapeutics. Although doxorubicin (DOX) is the recommended first choice, it has observed cardiotoxicity together with apparent drug resistance. The anti-hyperglycemic drug, empagliflozin (EMP), was recently indicated to have in vitro anticancer potential together with its previously reported cardioprotective properties related to calmodulin inhibition. In this study, we carried out molecular docking studies which revealed the potential blocking of the calmodulin receptor by EMP through its binding with similar crucial amino acids compared to its cocrystallized inhibitor (AAA) as a proposed mechanism of action. Moreover, combination of DOX with EMP showed a slightly lower cytotoxic activity against the MDA-MB-231 cell line (IC 50 = 1.700 ± 0.121) compared to DOX alone (IC 50 = 1.230 ± 0.131), but it achieved a more characteristic arrest in the growth of cells by 4.67-fold more than DOX alone (with only 3.27-fold) in comparison to the control as determined by cell cycle analysis, and at the same time reached an increase in the total apoptosis percentage from 27.05-to 29.22-fold, compared to DOX alone as indicated by Annexin V-FITC apoptosis assay. Briefly, the aforementioned in vitro studies in addition to PCR of pro-and antiapoptotic genes (mTOR, p21, JNK, Bcl2, and MDR1) suggest the chemosensitization effect of EMP combination with DOX which can reduce the required therapeutic dose of DOX in TNBC and eventually will decrease its toxic side effects (especially cardiotoxicity), along with decreasing the chemoresistance of TNBC cells to DOX treatment.

The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin

“…The same results were obtained under pro-in ammatory conditions in LPS-and LPS/EMPA-treated cells ( Figure 1C). As control, we evaluated the effects of EMPA on the anticancer e cacy of DOXO in human estrogen-responsive (Figure 1, D) and triple negative breast cancer cells (Figure 1, E); in line with literature [31], EMPA did not affects the anticancer effects of DOXO in breast cancer cells, indeed, at some concentrations it seems to increase slightly the cytotoxicity of DOXO. These preliminary results, although already con rmed by recent research [31], are of great interest and will be the performed by our group in further in-depth studies.…”

Molecular Docking and Dynamics Simulation Revealed the Potential Inhibitory Activity of ACEIs Against SARS-CoV-2 Targeting the hACE2 Receptor

“…After completion of docking processes, the obtained poses were studied and the best ones showing the best acceptable rmsd_refine values with the same binding mode of the native ligand were selected. Also, a program validation process was performed at first and confirmed by a low RMSD value (<1Å) as described before (Eliaa et al, 2020 ).…”

Strong Inhibitory Activity and Action Modes of Synthetic Maslinic Acid Derivative on Highly Pathogenic Coronaviruses: COVID-19 Drug Candidate

“…The previously discussed database was selected and inserted at the site of ligand at the beginning of the general docking process and the default methodology was performed as described before [ 57 ]. Finally, we selected the best poses according to their binding scores, RMSD values, and binding modes for further considerations.…”