Regulation of CP-25 on P-glycoprotein in synoviocytes of rats with adjuvant arthritis

• Main Authors: Hao Tang, Yi-jin Wu, Feng Xiao, Bin Wang, James Asenso, Yong Wang, Wei Sun, Chun Wang, Wei Wei
• Format: Article
• Language: English
• Published: Elsevier 2019-11-01
• Series: Biomedicine & Pharmacotherapy
• Subjects: Methotrexate; P-glycoprotein; Paeoniflorin-6′-O-benzene sulfonate; Adjuvant arthritis; Resistance
• Online Access: http://www.sciencedirect.com/science/article/pii/S0753332219334845

Objective: Methotrexate (MTX) is a commonly used drug for the treatment of rheumatoid arthritis (RA) and it has been studied in RA resistance recently. P-glycoprotein (P-gp) is one of the important transporters that mediate MTX resistance. This study investigated the effect of Paeoniflorin-6′-O-benzene sulfonate (code: CP-25) in the resistance of P-gp-mediated MTX to RA. Methods: Adjuvant arthritis (AA) was induced in rats via complete Freund’s adjuvant. The experimental groups were divided into normal group; AA model group; monotherapy groups, including CP-25, MTX and dexamethasone; and CP-25 combined with MTX group. The expression of P-gp in synovial tissue was measured by western blot and histochemistry. Besides, P-gp high expression of human hepatoma cell line Bel7402/5-FU and Bel7402 were chose to study in MTX resistance and the function of P-gp was detected by Flow cytometry. Results: CP-25 had a good therapeutic effect on AA rats, significantly improved manifestations and reduced the expression of P-gp in synovial tissue, spleen medulla and small intestinal epithelial cells in the apical tissues of AA rats. In addition, CP-25 significantly inhibited the up-regulation of P-gp induced by TNF-α stimulation in synoviocytes. Furthermore, according to the accumulation and efflux of rhodamine 123 in Bel7402/5-FU resistant cells and Bel7402 sensitive cells, CP-25 could reverse the resistance of MTX in Bel7402/5-FU cells compared with Bel7402 cells, which was reflected by the reduced IC50 values of MTX. Further study indicated that CP-25 could decrease P-gp expression and inhibit P-gp function in Bel7402/5-FU cells. Conclusion: CP-25 regulates the expression of P-gp and inhibits the function of P-gp, thereby improving the resistance of MTX.