Apigenin Modulates Expression Pattern of Cancer Multidrug Resistance Proteins in Non-Small Lung Cancer Cell Line

Abstract

Multidrug resistance (MDR), the most common cause of waning in cancer chemotherapy, hampers the effectiveness of available different anticancer drugs in treating this disease. This MDR is triggered by a class of membrane transporter proteins called ATP-binding cassette (ABC) transporters via drug efflux mechanism which is ATP-dependent. P-glycoprotein (P-gp), an ABC transporter is encoded by the MDR1/ABCB1 gene, is normally involved in the expulsion of toxins from normal cells and also confers resistance to certain chemotherapeutic agents. Inhibition of these membrane bound ABC transporters in drug resistant cells to reverse this MDR mechanism is a well-known approach to enhance the safety and efficacy of cancer chemotherapy. The molecular docking studies between apigenin & P-glycoprotein (P-gp)/ABCB1/MDR1 revealed that apigenin possesses greater binding affinity with transmembrane domain (TMD) region of P-gp/ABCB1/MDR1. In this study, pretreatment with apigenin significantly enhanced antiproliferative effect of PTX in NCI-H460 cells. Comparing Rhodamine-123 (Rh-123) drug efflux mechanism studies among the treatment groups, revealed that apigenin significantly and PTX moderately inhibit transport function when compared to control. Additionally, in comparison to control cells, apigenin treatment drastically decreased the mRNA expression levels of ABCB1/MDR1. Furthermore, expression of ABCB1/MDR1 was found to be downregulated during apigenin treatment. In this study, apigenin enhanced cytotoxicity of PTX in NCI-H460 cells. This might be due to enhanced PTX availability as apigenin inhibits membrane transport function. Thus, the present findings illustrate the modulatory role of apigenin on PTX sensitization in relatively resistant NCI-H460 cells.