Phytomedicine Plus (May 2022)
Swietephragmin D, a limonoid from Swietenia mahagoni, reverses multidrug resistance by inhibiting P-glycoprotein dependent efflux
Abstract
Background: : P-glycoprotein mediated efflux leads to multidrug resistance of tumor cells, which is an important reason for chemotherapy failure. Thus inhibiting P-gp is an effective approach to reverse multidrug resistance. Purpose: : Swietephragmin D is a limonoid compound isolated from the fruits and leaves of Swietenia mahagoni (L.) Jacq.. The reversal efficiency of swietephragmin D was examined in this study. Methods: : Rhodamine 123 efflux assays were used to measure inhibition efficiency of swietephragmin D. Cytotoxicity assays were used to measure the reversal effect of swietephragmin D. Real-time PCR and ATPase assays were performed to explore the mechanisms of reversion. Results: : Swietephragmin D inhibited P-glycoprotein-induced efflux in a dose and time dependent manner. This compound inhibited P-glycoprotein more effectively than verapamil. The IC50 values of the multidrug resistant cells were reduces by swietephragmin D significantly. The transcription levels of ABCB1 (encoded P-glycoprotein) were not affected by swietephragmin D. However, the ATPase activity of P-glycoprotein was stimulated by swietephragmin D. Conclusion: : Swietephragmin D was a substrate of P-glycoprotein and inhibited P-gp mediated efflux. It did not interfere with expression of ABCB1. Thus swietephragmin D reversed multidrug resistance as a competitive inhibitor of P-glycoprotein.
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