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Digoxin up-regulates MDR1 in human colon carcinoma Caco-2 cells
Kohji Takara1, Masayuki Tsujimoto, Noriaki Ohnishi
1Department of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan. takara@mb.kyoto-phu.ac.jp
Abstract:
Because MDR1 (P-glycoprotein) plays an important role in pharmacokinetics such as absorption and excretion of xenobiotics and multidrug resistance, an understanding of the factors regulating its function and expression is important. Here, the effects of digoxin on cell sensitivity to an anticancer drug, MDR1 function, and expression were examined by assessing the growth inhibition by paclitaxel, the transport characteristics of the MDR1 substrate Rhodamine123, and the level of MDR1 mRNA, respectively, using human colon carcinoma Caco-2 cells, which are widely used as a model of intestinal epithelial cells. The sensitivity to paclitaxel, an MDR1 substrate, in Caco-2 cells pretreated with digoxin was lower than that in non-treated cells. The accumulation of Rhodamine123 was reduced by pretreatment with digoxin and its efflux was enhanced. The level of MDR1 mRNA in Caco-2 cells was increased in a digoxin concentration-dependent manner. These results taken together suggested that digoxin up-regulates MDR1 in Caco-2 cells.
Insights
Digoxin reduces sensitivity to anticancer drugs by increasing MDR1 (P-glycoprotein) expression in Caco-2 cells. This suggests digoxin up-regulates MDR1, impacting drug transport and resistance.
Area of Science:
- Pharmacology
- Cell Biology
- Biochemistry
Background:
- Multidrug resistance protein 1 (MDR1), also known as P-glycoprotein, is crucial for xenobiotic pharmacokinetics and multidrug resistance.
- Understanding factors that regulate MDR1 function and expression is vital for drug development and treatment efficacy.
Purpose of the Study:
- To investigate the effects of digoxin on cancer cell sensitivity to paclitaxel.
- To assess digoxin's impact on MDR1 function, specifically Rhodamine123 transport.
- To determine if digoxin influences MDR1 gene (mRNA) expression in human colon carcinoma Caco-2 cells.
Main Methods:
- Caco-2 cells were pretreated with varying concentrations of digoxin.
- Cell sensitivity to paclitaxel was measured by growth inhibition assays.
- MDR1 substrate Rhodamine123 accumulation and efflux were analyzed.
- MDR1 mRNA levels were quantified using molecular biology techniques.
Main Results:
- Digoxin pretreatment decreased Caco-2 cell sensitivity to paclitaxel.
- Digoxin reduced Rhodamine123 accumulation within cells and enhanced its efflux.
- MDR1 mRNA levels in Caco-2 cells increased in a digoxin concentration-dependent manner.
Conclusions:
- Digoxin up-regulates MDR1 expression in Caco-2 cells.
- This up-regulation of MDR1 by digoxin affects drug transport and sensitivity.
- The findings highlight digoxin's role in modulating P-glycoprotein activity.