Volume 35, Issue 6 (September 2024)
Studies in Medical Sciences 2024, 35(6): 467-478 |
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Research code: 2174
Ethics code: IR.UMSU.REC.1396.146
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Yousefi B, Valizadeh A, Molavand M, Majidinia M. Reversal effect of fenofibrate on P-glycoprotein-mediated multidrug resistance through PPARγ-dependent upregulation of PTEN expression in SW-480 colorectal cancer cells. Studies in Medical Sciences 2024; 35 (6) :467-478
URL: http://umj.umsu.ac.ir/article-1-6306-en.html
URL: http://umj.umsu.ac.ir/article-1-6306-en.html
Assistant Professor of Clinical Biochemistry, Urmia University of Medical Sciences, Urmia, Iran (Corresponding Author) , majidinia25@gmail.com
Abstract: (314 Views)
Background & Aims: Multidrug resistance is a major challenge in cancer treatment. This study investigated the role and potential mechanisms of peroxisome proliferator-activated receptors gamma (PPARγ) in 5-FU-resistant colon cancer cells (SW480/5-FU).
Materials & Methods: SW480 and SW480/5-FU cells (2x10⁴ cells/well) were treated with different concentrations of 5-FU (0.01-100 μM) and fenofibrate (1-25 μM) for 24, 48, and 72 hours. Cell viability was evaluated by the MTT test. The accumulation of Rh123 (5 μM) was measured during 120-30 minutes to investigate the activity of P-gp and MRP-1. Gene expression and protein expression were evaluated by RT-PCR and western blot.
Results: Fenofibrate (10 μM) increased the cytotoxicity of 5-FU significantly (P<0.05) and decreased the IC50 from 30 μM to 10 μM. Fenofibrate decreased the expression and activity of P-gp in SW480/5-FU cells by 40% (P<0.01) and increased the intracellular accumulation of 5-FU by 2.5 times. PTEN expression increased 3-fold after fenofibrate treatment in a PPARγ-dependent manner (P<0.001).
Conclusion: Fenofibrate reverses multidrug resistance in colorectal cancer cells by increasing PTEN expression and inhibiting PI3K/Akt pathway. This study suggests targeting PPARγ as an effective approach to overcome multidrug resistance in cancer chemotherapy.
Materials & Methods: SW480 and SW480/5-FU cells (2x10⁴ cells/well) were treated with different concentrations of 5-FU (0.01-100 μM) and fenofibrate (1-25 μM) for 24, 48, and 72 hours. Cell viability was evaluated by the MTT test. The accumulation of Rh123 (5 μM) was measured during 120-30 minutes to investigate the activity of P-gp and MRP-1. Gene expression and protein expression were evaluated by RT-PCR and western blot.
Results: Fenofibrate (10 μM) increased the cytotoxicity of 5-FU significantly (P<0.05) and decreased the IC50 from 30 μM to 10 μM. Fenofibrate decreased the expression and activity of P-gp in SW480/5-FU cells by 40% (P<0.01) and increased the intracellular accumulation of 5-FU by 2.5 times. PTEN expression increased 3-fold after fenofibrate treatment in a PPARγ-dependent manner (P<0.001).
Conclusion: Fenofibrate reverses multidrug resistance in colorectal cancer cells by increasing PTEN expression and inhibiting PI3K/Akt pathway. This study suggests targeting PPARγ as an effective approach to overcome multidrug resistance in cancer chemotherapy.
Keywords: Drug resistance, Colorectal cancer, Fenofibrate, PPARγ, PTEN, P-glycoprotein, Apoptosis, PI3K/Akt
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