Novel virosecurinine bivalent mimetics as potent reversal agents against P-glycoprotein-mediated multidrug resistance.

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ID: 61338
2019
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Abstract
Multidrug resistance (MDR) is a main cause of chemotherapy failure and patient death. This situation usually involves a glycoprotein (P-gp) mediated drug efflux, resulting in a low cellular drug concentration and insensitivity. Here we report the design, synthesis and evaluation of novel (+/-)-securinine bivalents as P-gp inhibitors in vitro and in vivo. MTT assays reflected that bivalent mimetics of securinine particularly the virosecurinine bivalent mimetic 8C showed promissing MDR reversal potential in both P-gp highly expressed cell line HepG2/DOX and MCF-7/ADM. At a 10 μM concentration, 8C can entirely reverse the resistance of HepG2/DOX to doxorubicin (DOX), and is more effective than the positive control verapamil (VRP). Fluorescence, flow cytometry, and DOX efflux assays demonstrated that 8C can facilitate the accumulation and diminish the efflux of intracellular DOX. Molecular docking analysis and western blot assays indicated that 8C accomplished this by competitively inhibiting the activity of P-gp rather than by affecting its expression. Compound 8C was also observed to reverse drug resistance effectively in xenograft models when combined with DOX. This study lays a foundation for the discovery of (+/-)-securinine ramifications as P-gp inhibitors and provides a promising lead compound 8C as a P-gp mediated MDR reversal agent.
Reference Key
hou2019noveleuropean Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Hou, Wen;Meng, Ying;Xu, Xiao-Fang;Huang, Zhi-Xing;Liu, Jun;Wang, Zhen-Ya;Lin, Jing;Chen, Wei-Min;
Journal European journal of medicinal chemistry
Year 2019
DOI
S0223-5234(19)30878-5
URL
Keywords
multidrug resistance tumor bivalent p-gp securinine virosecurinine

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