Enhancement of the Anticancer Activity of Imatinib Coupled with Naringin through Inhibition of P-Glycoprotein: An In-Silico and In-Vitro Study

Abstract

Imatinib is widely used in chronic myeloid leukemia as signal transduction inhibitor. Multidrug resistance is one of the limiting factors of the imatinib due to overexpression of the P-glycoprotein gene.Naringin, flavanone glycoside, has anti-inflammatory, antioxidant, antiviral, and antitumor properties. Moreover, it modulates and interacts with varieties of signaling pathways.Naringin has been demonstrated to inhibit many malignancies through the control of multiple cellular signaling cascades, including malignant cell growth inhibition, angiogenesis, and alteration in oxidative stress processes.A molecular docking study of Imatinib and Naringin was carried out on human P-glycoprotein (PDB ID: 6C0V) using the Autodock Vina programme. P-gp expression study was carried out in K562 cell lines with the addition of 10μL of P-gp antibody (E-10) FITC antibody while test samples were characterizedusing flow cytometry technique. In comparison to Naringin (-5.6 kcal/mol), Imatinib's strong hydrogen bonding, non-covalent, and hydrophobic interactions with human P-glycoprotein demonstrated better stability with a binding energy of -7.3 kcal/mol. Through docking study, it has been clarified that Naringin had an excellent affinity towards human p glycoprotein. Imatinib alone at a concentration of 5μM had shown 73.6% of P-gp expression but when combined with increased concentration of Naringin (25μM to 200μM), P-gp expression was drastically reduced to 9.7%. In our study, pure Naringin (alone) had also displayed excellent inhibition in P-gp expression.The combinatorial approach consisting of Imatinib with Naringindisplayed an excellent reduction in P-gp expression in K562 cell line by enhancing anticancer activity and delaying drug resistance.