Radenković Nikola, Milenković Dejan, Nikodijević Danijela, Jovanović Stojanov Sofija, Podolski Renić Ana, Milutinović Milena
Department of Biology and Ecology, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000 Kragujevac, Serbia.
Department of Natural Sciences, Institute for Information Technologies Kragujevac, University of Kragujevac, Jovana Cvijića bb, 34000 Kragujevac, Serbia.
Int J Mol Sci. 2025 Jun 27;26(13):6208. doi: 10.3390/ijms26136208.
The development of resistance to standard cytostatics, such as 5-fluorouracil (5-FU), significantly limits the efficacy of colon cancer therapy, prompting the search for novel anticancer agents, particularly among natural compounds. This study evaluated the anticancer effects of isorhamnetin, a plant-derived flavonol, and its ability to modulate the expression of drug-resistance-related biomarkers in SW-480 and HT-29 colon cancer cells, with a focus on ATP-binding cassette (ABC) transporters. Isorhamnetin demonstrated strong cytotoxic and proapoptotic activity on both cell lines, while showing lower toxicity toward normal HaCaT cells. In addition to suppressing the mRNA expression of drug-metabolizing enzymes (CYP1A1 and CYP1B1), isorhamnetin significantly reduced the mRNA levels of multidrug resistance-associated proteins 1 and 5 (MRP1 and MRP5), as well as the P-glycoprotein (P-gp) level in SW-480 and HT-29 cells. Molecular docking analysis revealed a high binding affinity of isorhamnetin to CYP1A1, CYP1B1, P-gp, MRP1, MRP5, and glutathione S-transferase (GST) proteins, with stronger interactions than those observed for 5-FU, suggesting potential interference with their function. These results provide a solid basis for future investigations to confirm the therapeutic potential of isorhamnetin as a modulator of drug resistance in colon cancer cells.
对标准细胞抑制剂（如5-氟尿嘧啶（5-FU））产生耐药性，严重限制了结肠癌治疗的疗效，促使人们寻找新型抗癌药物，尤其是天然化合物。本研究评估了植物来源的黄酮醇异鼠李素的抗癌作用及其调节SW-480和HT-29结肠癌细胞中耐药相关生物标志物表达的能力，重点关注ATP结合盒（ABC）转运蛋白。异鼠李素对两种细胞系均表现出强烈的细胞毒性和促凋亡活性，而对正常HaCaT细胞的毒性较低。除了抑制药物代谢酶（CYP1A1和CYP1B1）的mRNA表达外，异鼠李素还显著降低了SW-480和HT-29细胞中多药耐药相关蛋白1和5（MRP1和MRP5）的mRNA水平以及P-糖蛋白（P-gp）水平。分子对接分析显示异鼠李素与CYP1A1、CYP1B1、P-gp、MRP1、MRP5和谷胱甘肽S-转移酶（GST）蛋白具有高结合亲和力，其相互作用比5-FU更强，表明可能干扰它们的功能。这些结果为未来研究证实异鼠李素作为结肠癌细胞耐药调节剂的治疗潜力提供了坚实基础。
