Modulation of the Main Resistance-Associated ABC Transporter’s Expression by Plant Flavonol Isorhamnetin

<b>Background/Objectives</b>: Multidrug resistance is one the leading problems in cancer treatment, where the overexpression of P-gp and other drug efflux pumps is regarded as the primary cause. With the intention to develop transporter inhibitors, natural products such as phenolics have shown great potential and diverse attention recently. Among these, isorhamnetin (ISO), an O-methylated flavonol, is predominantly found in the fruits and leaves of various plants. Thus, this study aimed to investigate the effects of ISO on the mRNA expression of membrane transporters P-gp, <i>BCRP</i>, <i>MRP 1</i>, <i>2</i>, and <i>5</i>, the protein expression of P-gp, as well as the <i>GSTP1</i> and GSH content in DLD1 and HCT-116 colon cancer cells. <b>Methods</b>: The cytotoxic effect of isorhamnetin is assessed using an MTT test, while qPCR and immunocytochemistry methods were used to determine gene and protein expression levels. The concentration of reduced glutathione was determined using the colorimetric method. <b>Results</b>: Based on the results, ISO can modulate the expression of transporters responsible for the resistance development (all transporters on the transcriptional level were downregulated in DLD1 cells, while only <i>MRP1</i> on HCT-116 cells, and reduced P-gp protein expression on both investigated cell lines). Increased glutathione content in treated cells and <i>GSTP1</i> expression suggest metabolizing the ISO and potential ejection with GSH-dependent pumps. <b>Conclusions</b>: Thus, in future experiments, ISO as a natural medicinal compound could be used as a chemosensitizer to prevent or overcome membrane transporter-mediated drug resistance.