An In-Silico and In-Vitro Study of Imatinib and Naringin Combination for Inhibiting P-Glycoprotein and Delaying Drug Resistance in Chronic Myeloid Leukemia

Abstract

Introduction: The present study describes the potential use of naringin (NAR), a flavanone glycoside, in combination
with imatinib (IMT), a signal transduction inhibitor used in chronic myeloid leukemia (CML). The study aimed to
investigate whether NAR could help overcome the multidrug resistance of IMT by inhibiting the overexpression
of the P-glycoprotein gene. Materials and Methods: Molecular docking approach is used to investigate the
binding affinity of IMT and NAR to human P-glycoprotein. The results showed that IMT had stronger interactions
with P-glycoprotein than NAR, indicating better stability with a binding energy of −7.3 kcal/mol compared
to −5.6 kcol/mol for NAR. However, NAR demonstrated an excellent affinity toward human P-glycoprotein.
Results: To investigate the effect of NAR and IMT combination on P-glycoprotein expression, flow cytometry
technique on K562 cell lines is used. The results displayed that IMT alone at a concentration of 1 μM had a P-gp
expression of 73.6%. Nevertheless, P-gp expression was substantially decreased to 9.7% when coupled with NAR
at higher doses (5–30 µM). Moreover, pure NAR alone also showed suppression of P-gp expression. In summary,
the study suggests that the combinatorial approach of IMT with NAR could enhance anticancer activity and delay
drug resistance by reducing P-gp expression in K562 cell lines. Conclusion: These results support the potential
use of NAR as an adjuvant therapy to IMT in the management of CML. However, further studies are needed to
confirm the efficacy and safety of this approach in clinical settings.