Subburayan Karthikeyan, Sugeerappa Laxmanappa Hoti and Nagarajan Rajendra Prasad
Multidrug resistance is one of the most common causes of relapse in cancer chemotherapy. Inhibition of ABC transporters to reverse MDR is a prominent approach to enhance the efficacy of cancer chemotherapy. We investigated the effect of resveratrol (RSV) on the membrane transport function and the expression of proteins involved in the multidrug resistance in NCI-H460 cells. The molecular interactions of RSV with P-gp were analyzed by Schrodinger software. The membrane transport function and cell cycle distribution were measured using flow cytometry. The mRNA expression level of MDR1, LRP, MRP2, ABCC1, ABCC2 and ABCC3 genes were detected by qRT-PCR and BCRP expression was detected by western blot analysis. In silico docking studies revealed that RSV possesses greater binding affinity with TMD region of P-gp. In this study, RSV pretreatment significantly enhanced Paclitaxel (PTX) antiproliferative effect in NCI-H460 cells. The rhodamine 123 drug efflux studies revealed that there was a significant transport function inhibition by RSV treatment and moderate transport function inhibition by PTX. Further, RSV treatment significantly decreased the mRNA expression levels of various ABC transporters genes. Furthermore, expression of BCRP was found to be down-regulated during RSV treatment. It was also found that this enhanced anticancer efficacy of RSV was associated with PTX-induced cell arrest in the G2/M phase of cell cycle. Interestingly, we observed significantly enhanced antiproliferative effect, transport function inhibition and downregulation of ABC transporters in RSV-PTX combination group. This might be due to additive or synergistic effect of RSV with PTX in NCI-H460 cells. Thus, the present findings illustrate the modulatory role of RSV on PTX sensitization in relatively resistant NCI-H460 cells.
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