Abstract
Multidrug resistance (MDR), mainly mediated by ABCB1 transporter, is a major cause for chemotherapy failure. Bufalin (BU), an active component of the traditional Chinese medicine chan’su, has been reported to have antitumor effects on various types of cancer cells. The purpose of this present study was to investigate the reversal effect of BU on ABCB1-mediated multidrug resistance in colorectal cancer. BU at safe concentration (5, 10, 20 nM) could reverse chemosensitivity of ABCB1-overexpression HCT8/ADR, LoVo/ADR and HCT8/ABCB1 nearly back to their parental cells level. In addition, results from the drug accumulation studies revealed that BU was able to enhance intracellular accumulation of doxorubicin (DOX) and Rhodamine 123 (Rho-123) in a dose-dependent manner. Furthermore, Western blot assays showed that BU significantly inhibited the expression level of ABCB1 protein. Meanwhile, BU stimulated the ATPase activity of ABCB1, which suggested that BU might be a substrate of ABCB1. More interestingly, docking analysis predicted that BU could be docked into the large hydrophobic drug-binding cavity of human ABCB1. Importantly, BU remarkable increased the effect of DOX against the ABCB1 resistant HCT8/ADR colorectal cell xenografts in nude mice, without inducing any obvious toxicity. Overall, we concluded that BU efficiently reversed ABCB1-mediated MDR through not only inhibited the efflux function of ABCB1, but also down-regulate its protein expression, which might represent a potential and superior ABCB1 modulator in colorectal cancer.
Highlights
Multidrug resistance (MDR) is the main reason for the failure of cancer chemotherapy[1]
We examined the effect of BU in ABCB1transfected HCT8/ABC transporter-subfamily B member 1 (ABCB1) cells
Our results indicated that BU could reverse ABCB1-mediated MDR in colorectal cancer cells
Summary
Multidrug resistance (MDR) is the main reason for the failure of cancer chemotherapy[1]. The mechanisms of MDR are complex, including overexpression of ATP-binding cassette (ABC) transporter, apoptosis inducing, autophagy inducing, DNA damage and repair, and epigenetic regulation and so on[3]. The export of chemotherapy drugs from cancer cells by adenosine triphosphate (ATP)-binding cassette (ABC) transporters is the most important mechanism of MDR[4]. The ABC transporters mainly include ABCB1 (P-glycoprotein/P-gp), ABCC1 (Multidrug resistance-associated protein/MRP1) and ABCG2 (Breast cancer resistance protein/BCRP)[5]. Among these transporters, ABCB1 is the most important resistance-inducing protein[6]. ABCB1 binds to chemotherapy drugs that enter tumour cells and expels them from the cell. The substrates of ABCB1 include chemotherapy drugs such as vinca alkaloids, taxanes, epipodophyllotoxins and so on[8]
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