Hesperetin reverses P-glycoprotein-mediated cisplatin resistance in DDP-resistant human lung cancer cells via modulation of the nuclear factor-κB signaling pathway

Lung cancer is the leading cause of cancer-associated mortality worldwide. Cisplatin (DDP) is a first-line chemotherapeutic drug for the treatment of lung cancer; however, the majority of patients develop resistance to DDP. P-glycoprotein (P-gp), also referred to as multidrug resistance (MDR) protein 1, is associated with an MDR phenotype, which results in failure of cancer chemotherapy; thus, identifying effective MDR pump inhibitors may improve the outcomes of patients who develop resistance to treatment. Hesperetin is a derivative of hesperidin, which is extracted from tangerine peel and exhibits multiple antitumor properties. In the present study, human lung adenocarcinoma A549 and A549/DDP cells were treated with different concentrations of hesperetin and DDP, respectively. Furthermore, rhodamine 123 efflux assays, Cell Counting Kit-8 assays, immunofluorescence, reverse transcription-quantitative PCR and western blot analysis were used to elucidate the mechanisms underlying the effects of hesperetin On A549/DDP cells. Additionally, a xenograft model of lung cancer in nude mice was established to explore the effects of hesperetin on A549/DDP cell growth in vivo. The results demonstrated that hesperetin sensitized A549/DDP cells to DDP. In vivo, hesperetin pretreatment significantly inhibited tumor growth. Mechanistically, hesperetin markedly decreased the expression of P-gp and increased the intracellular accumulation of the P-gp substrate, rhodamine 123, in A549/DDP cells. In addition, pretreatment of A549/DDP cells with hesperetin significantly inhibited nuclear factor (NF)-κB (p65) activity and its nuclear translocation. Taken together, the results of the present study suggest that hesperetin reversed P-gp-mediated MDR by decreasing P-gp expression in A549/DDP cells, which was associated with inhibition of the NF-κB signaling pathway. These findings may provide the basis for the use of hesperetin clinically to reverse MDR.