Abstract
The efficacy of anti-cancer drugs in patients can be attenuated by the development of multi-drug resistance (MDR) due to ATP-binding cassette (ABC) transporters overexpression. In this in vitro study, we determined the reversal efficacy of the epidermal growth factor receptor (EFGR) inhibitor, saptinib, in SW620 and SW720/Ad300 colon cancer cells and HEK293/ABCB1 cells which overexpress the ABCB1 transporter. Sapitinib significantly increased the efficacy of paclitaxel and doxorubicin in ABCB1 overexpressing cells without altering the expression or the subcellular location of the ABCB1 transporter. Sapitinib significantly increased the accumulation of [3H]-paclitaxel in SW620/AD300 cells probably by stimulating ATPase activity which could competitively inhibit the uptake of [3H]-paclitaxel. Furthermore, sapitinib inhibited the growth of resistant multicellular tumor spheroids (MCTS). The docking study indicated that sapitinib interacted with the efflux site of ABCB1 transporter by π-π interaction and two hydrogen bonds. In conclusion, our study suggests that sapitinib surmounts MDR mediated by ABCB1 transporter in cancer cells.
Highlights
The efficacy of anticancer drugs, whether in patients 1) who are drug-naïve, 2) have advanced cancer, or 3) that experience treatment relapse, can be attenuated or abrogated by inherent or acquired resistance [1, 2]
SW620/Ad300 cells, which were used in this study, are a doxorubicin-selected cell line that was incubated with various concentrations of doxorubicin over a period of six months
The expression of the ABCB1 transporter has been reported to vary in colon cancer patients depending upon the chemotherapeutic regimen [44,45,46]
Summary
The efficacy of anticancer drugs, whether in patients 1) who are drug-naïve, 2) have advanced cancer, or 3) that experience treatment relapse, can be attenuated or abrogated by inherent or acquired resistance [1, 2]. Numerous studies indicate that the ABCB1 transporter protein is overexpressed in a number of different MDR cancers, producing a significant decrease in the intracellular levels, and the efficacy of many different anti-cancer drugs, such as paclitaxel, doxorubicin [14, 15], and targeted therapies such as crizotinib and ceritinib [16]. It has been shown that MDR in cancer cells due to the overexpression of the ABCB1 transporter can be surmounted by 1) the blockade of the efflux function of the ABCB1 transporter by compounds such as verapamil, dacomitinib, selonsertib, and other tyrosine kinase inhibitors [17, 18]; 2) a decrease in the expression level of the ABCB1 protein or 3) a decrease in the localization of ABCB1 transporter in the cellular membrane [19,20,21]. The ABCB1 transporter represents a potential therapeutic target for the treatment of MDR in cancers
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
