Abstract
ATP-binding cassette (ABC) transporters, such as breast cancer resistance protein (BCRP), are key players in resistance to multiple anti-cancer drugs, leading to cancer treatment failure and cancer-related death. Currently, there are no clinically approved drugs for reversal of cancer drug resistance caused by ABC transporters. This study investigated if a novel drug candidate, SCO-201, could inhibit BCRP and reverse BCRP-mediated drug resistance. We applied in vitro cell viability assays in SN-38 (7-Ethyl-10-hydroxycamptothecin)-resistant colon cancer cells and in non-cancer cells with ectopic expression of BCRP. SCO-201 reversed resistance to SN-38 (active metabolite of irinotecan) in both model systems. Dye efflux assays, bidirectional transport assays, and ATPase assays demonstrated that SCO-201 inhibits BCRP. In silico interaction analyses supported the ATPase assay data and suggest that SCO-201 competes with SN-38 for the BCRP drug-binding site. To analyze for inhibition of other transporters or cytochrome P450 (CYP) enzymes, we performed enzyme and transporter assays by in vitro drug metabolism and pharmacokinetics studies, which demonstrated that SCO-201 selectively inhibited BCRP and neither inhibited nor induced CYPs. We conclude that SCO-201 is a specific, potent, and potentially non-toxic drug candidate for the reversal of BCRP-mediated resistance in cancer cells.
Highlights
Chemotherapy resistance is considered the single most important obstacle to greater success with chemotherapy for cancer patients [1,2,3]
On the basis of these findings, the aim of this study was to clarify if SCO-201 re-sensitizes cancer cells to chemotherapy substrates of breast cancer resistance protein (BCRP)
Using our DEN-50R screening platform, we found that pyrazolo-pyrimidine substrate, and re-sensitizes cancer cells to chemotherapy in two different in vitro models of BCRPderivatives might serve as potential inhibitors of drug resistance in these cell lines
Summary
Chemotherapy resistance is considered the single most important obstacle to greater success with chemotherapy for cancer patients [1,2,3]. Many cancer patients initially benefit from chemotherapy treatment, a large proportion of treatments fail due to acquisition of resistance to. Cells 2020, 9, 613 multiple anti-cancer drugs. This phenomenon is known as multidrug resistance (MDR) and refers to the concurrent development of cross-resistance to many chemically diverse anti-cancer agents [4]. MDR results in poor prognosis and decreased survival rate of cancer patients, and strategies to circumvent MDR are highly needed [3,5]. Overexpression of drug expelling ATP-binding cassette (ABC) transporters seems to be an important mechanism of MDR in cancer cells [7]. The most extensively studied and characterized ABC transporters, found to be involved in cancer
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
