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Updated: Sep 16, 2025
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Isorhamnetin Modulates Drug-Resistance-Related Biomarkers in Colon Cancer Cells
Nikola Radenković1, Dejan Milenković2, Danijela Nikodijević1
1Department of Biology and Ecology, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000 Kragujevac, Serbia.
Abstract:
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.
Insights
Isorhamnetin, a natural compound, shows potent anticancer effects against colon cancer cells by reducing drug resistance markers. This suggests its potential as a novel therapeutic agent to overcome resistance to standard chemotherapy.
Area of Science:
- Pharmacology
- Molecular Biology
- Natural Products Chemistry
Background:
- Drug resistance to standard chemotherapy, like 5-fluorouracil (5-FU), is a major challenge in colon cancer treatment.
- Natural compounds are being explored as alternative anticancer agents to overcome this resistance.
- ATP-binding cassette (ABC) transporters play a key role in multidrug resistance.
Purpose of the Study:
- To evaluate the anticancer effects of isorhamnetin, a plant-derived flavonol, on colon cancer cells.
- To investigate isorhamnetin's ability to modulate drug-resistance-related biomarkers, including ABC transporters.
- To assess the potential of isorhamnetin as a modulator of drug resistance in colon cancer.
Main Methods:
- Cytotoxicity and apoptosis assays were performed on SW-480 and HT-29 colon cancer cells and HaCaT normal cells.
- mRNA expression levels of drug-metabolizing enzymes (CYP1A1, CYP1B1) and drug transporters (MRP1, MRP5, P-gp) were analyzed.
- Molecular docking simulations were used to predict the binding affinity of isorhamnetin to target proteins.
Main Results:
- Isorhamnetin exhibited significant cytotoxic and proapoptotic activity in colon cancer cells with lower toxicity in normal cells.
- Isorhamnetin suppressed the mRNA expression of CYP1A1, CYP1B1, MRP1, MRP5, and P-gp in colon cancer cells.
- Molecular docking indicated high binding affinity of isorhamnetin to CYP1A1, CYP1B1, P-gp, MRP1, MRP5, and GST, with stronger interactions than 5-FU.
Conclusions:
- Isorhamnetin demonstrates promising anticancer properties and the ability to reduce key drug resistance markers in colon cancer.
- The findings suggest isorhamnetin's potential to interfere with the function of drug-metabolizing enzymes and ABC transporters.
- Isorhamnetin warrants further investigation as a therapeutic agent to overcome drug resistance in colon cancer therapy.
