Experimental Study Of ES2,A Jatrophane Diterpenoid Ester From Euphorbia Sororia,Reverses ABCB1-mediated Tumor Multidrug Resistance

Background:Tumor multidrug resistance is one of the main causes of the current failure of traditional chemotherapy drugs in clinical treatment.There is no good anti-tumor reversal agent applied to clinical due to low efficacy and high toxicity by now.In recent years,there are more and more development and application for natural products.And natural products due to diversity,high efficiency,low toxicity and other characteristics,have becomed the focus of multidrug resistance reversal agents.In the previous study,we had found that ES2 had a good effect to reverse multidrug resistance,and the main mechanism of its role was as a substrate of the ATPase of Pgp protein,to bind Pgp point competitivly to achieve drug resistance reversal activity.Purpose:The aim of this study is to investigate the effect of ES2 on tumor growth in vivo,and then explore the selective effect of ES2 on three ABC transporters like ABCB1 on the basis of previous studies on the reversal of drug resistance pharmacodynamics in vitro.Methods:l.To explore the bioavailability of ES2 in vivo by performing bioavailability experiments in ICR mouse.2.The tumor multidrug-resistant xenograft model was established,which was used to investigate the effect of ES2 on the antitumor effect of vinorelbine,and the toxicity of the drug in vivo.3.The expression of Pgp protein on the cell membrane and in the cell were detected by immunoblotting and flow cytometry.4.The plasmids containing ABCB1/Pgp,ABCG2 and ABCC1 were transfected into HEK293 cells to express corresponding protein.CCK8 assay was used to detect drug resistance reversal activity.Results:1.ES2 had good pharmacokinetic parameters in vivo.2.In the KBv200 tumor multidrug resistant xenograft model,ES2 whose dose was 150 mg/kg,had no significant inhibitory effect on the growth of the tumor,but could significantly enhance the inhibitory effect of vinorelbine.3.ES2 played a drug resistance reversal function,not because of changing the expression of total Pgp protein in the cell,on the contrary,increasing the expression of Pgp protein on the cell membrane.4.ES2 reserved multidrug resistance due to overexpressing ABCB1 protein and had a little reversal effect on multidrug resistance of tumor cells produced by high expression of ABCC1 protein,And ES2 did not have the effects of high expression of ABCG2-mediated multidrug resistance.Conclusion:ES2 in vitro and in vivo,has a good resistance to reverse the effect of resistance,and ES2 reserved multidrug resistance due to overexpressing ABCB1 protein had a little reversal effect on multidrug resistance of tumor cells produced by high expression of ABCC1 protein.And had no effects on high expression of ABCG2-mediated multidrug resistance.ES2 did not change the expression of intracellular Pgp protein to reserve tumor multidrug resistance,but increased the cell membrane Pgp protein expression.ES2 was different from the previous mutidrug resistance reversal agents,and this paper laid the experimental basis for the new drug resistance research and development.