The Selective Effect Of Glycyrrhizin And Glycyrrhetinic Acid In Combination With Etoposide On Triple Negative Breast Cancer MDA-MB-231 Cells

Background&Objective:Triple negative breast cancer(TNBC)is triple negative of PR,ER and HER-2.It has generated growing interests due to its aggressive biologic behavior and absence of targeted therapy approach.Glycyrrhizin(GL)from licorice root and its metabolite,glycyrrhetinic acid(GA)have shown extensive bioactivities in clinic.Reports show both GL and GA can inhibit cancer.However,other reports also reveal the contradictory of anti-cancer and anti-oxidant actions between GL and GA.To our best knowledge,there are no evaluation of phamacological effect between GL and GA on TNBC.Here,we explore the anti-cancer effect and the related mechanism of GL and GA on TNBC MDA-MB-231 cells.Content&Results:Through the MTT assay,we found that GL and GA exhibited different effect on TNBC MDA-MB-231 cells.Beside its inhibition of cell proliferation,GA at non-cytotoxic concentration(below 20?M)showed synergistic effect in combination with anti-cancer drug,etoposide(VP-16).Specifically,according to the RT-PCR and Western blot,GA enhanced cytotoxicity through regulating topoisomerase ?a(TOPO 2A)targeted by etoposide.GA sensitized the cells to etoposide through elevating TOPO 2A with a 2.4 fold rate at 12 hour.However,from 12 to 48 hours,GA halved the expression of TOPO 2A.Furthermore,GA depleted the GSH in cells and stimulated apoptosis,which strengthened its antineoplastic effect.On the other side,GL show minimum regulation of TOPO 2A or apoptosis.From 0-80 ?M,GL showed protection and detoxication by decreasing ROS generation and maintaining GSH.Our experiments revealed that the modulation of MAPK and AKT pathways by GL and GA accounted for their bioactivities.ConclusionCollectively,our results demonstrate that GA,instead of GL,is a better candidate for TNBC treatment because of its anti-cancer effect and sensitization of topoisomerase ?a inhibitor.Other specific mechanism are related to regulation of TOPO 2A expression,apoptosis and oxidative stress.