Abstract
P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) remains a significant impediment to the success of cancer chemotherapy. The natural flavonoid Quercetin (Que) has been reported to be able to inhibit P-gp-mediated MDR in various cancer cells. However, the MDR reversal effect of Que on human colon cancer cells and its mechanism at the metabolic level requires further clarification. This study was designed to provide a better understanding of the MDR reversal effect of Que. Our present results showed that 33 μM of Que significantly improved the cytotoxicity of doxorubicin (Dox) to P-gp-overexpressed SW620/Ad300 cells by proliferation and apoptpsis assay. Further mechanism studies demonstrated that Que inhibited the ATP-driven transport activity of P-gp, which in turn increased the intracellular accumulation of Dox. The metabolomics studies based on UPLC-MS/MS analysis revealed that Que could reverse the MDR by significantly blocking D-glutamine and D-glutamate metabolism, and the underlying mechanism is that Que down-regulated the expression of the glutamine transporter solute sarrier family 1, member 5 (SLC1A5) in SW620/Ad300 cells. This is the first time to report that Que was a SLC1A5 inhibitor, which could be served as a template compound to potentially develop novel P-gp-mediated MDR reversal modulators in cancer chemotherapy.
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