In Silico and In Vitro Synergistic Anticancer Effects of The Metformin-Lapatinib Combination By The Regulation of Apoptotic Biomarkers Expression In SKBR3 Cells
Abstract
Abstract We examined the effect of Metformin (MET) on Lapatinib (LAP)-induced apoptosis in SK-BR3 cells. The cell viability and cell death were measured by MTT assay and Annexin V-FITC/PIstaining, respectively. The mRNA expression of Bax, Bcl2, and P21 was determined by real-time PCR. The activity of caspase 3 and 9 was measured using an ELISA kit. The MET-LAP combination index (CI) was calculated using CompuSyn software. The molecular docking studies of LAP with Akt, AMPK, and HER2 were performed using Auto Dock 4.2.5.1. The strongest synergistic apoptotic death [combination index (CI) = 0.51] was obvious in MET 100 mM plus LAP 100 nM. The MET-LAP combination causes a more powerful apoptotic death (46%) compared to LAP 100 nM individually. The combination could significantly increase the expression of Bax and P21, as well as the activity of caspase 3 and 9, but decreased the expression of Bcl2. Moreover, the combination could significantly increase the level of AMPK in LAP 100 nM plus MET 30 mM and decreased the level of Akt in LAP 100 nM plus MET 40 mM. Molecular docking studies showed that LAP interacts with the active site amino acids of Akt, AMPK, and HER2 by hydrogen and hydrophobic interactions. MET-LAP combination induces more extensive apoptotic death than either drug alone in SKBR3 cells. MET-LAP combination may be considered as a valuable therapeutic intervention in breast cancer patients. However, further in-vivo studies are needed to assess the MET-LAP…
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