LS-2-3j Reverses Multidrug Resistance Targeting For ABCB1 And ABCG2 In Cancer Cells

Cancer is a major public health problem that threatens human health worldwide.In recent years,new cancer cases and deaths have increased year by year.Multidrug resistance(MDR)means that cancer cells not only develop resistance to a type of anticancer drug,but also cross-resistance to other anticancer drugs with different structures and different mechanisms of action.MDR to chemotherapeutic drugs is a serious problem that,in many cases,leads to cancer treatment failure.The most prominent cause of MDR is the overexpression of the ATP-binding cassette(ABC)superfamily of transporters,which can transport intracellular anticancer drugs out of cells,leading to decreased drug accumulation in cells.Among these transporters,ABCB1 and the ABCG2 are known to play an important role in mediating multidrug resistance in cancer cells.10-oxo-5-(3-(pyrrolidin-1-yl)propyl)-5,10-dihydroindeno[1,2-b]indol-9-yl propionate(LS-2-3j)is a novel synthetic indole compound.In the preliminary work,we conducted a preliminary test on the reversal drug-resistance activities of 17 compounds of this series by MTT method.And LS-2-3j with better activity was selected as the research object of this paper.This study aimed to evaluate the multidrug resistance(MDR)reversal effects and associated mechanisms of LS-2-3j in drug-resistant cancer cells.The inhibition of cell proliferation in tested agents was evaluated by the 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide(MTT)assay.Accumulation or efflux of chemotherapy drugs was analyzed by flow cytometry.The ATPase activity was measured using an ATPase activity assay kit.The mRNA transcripts and protein expression levels were detected by real-time PCR and Western blot,respectively.In this connection,LS-2-3j significantly enhanced the activity of chemotherapeutic drugs in MDR cells and could significantly increase the intracellular accumulation of doxorubicin(DOX)and mitoxantrone(MITX)by inhibiting the function of the efflux pumps in ABCB1-or ABCG2-overexpressing cells.Furthermore,reduced ATPase activity,mRNA transcription,and protein expression levels of ABCB1 and ABCG2 were observed in a concentration dependent manner in MDR cancer cells.In conclusion,LS-2-3j,a new chemically synthesized indole compound reported for the first time,has multidrug resistant reversal effects.LS-2-3j reversed MDR via inhibiting the function and down-regulating the mRNA and protein expression levels of both ABCB1 and ABCG2.LS-2-3j might be useful as a lead compound in drug discovery and development for ABCB1-or ABCG2-mediated MDR cancer treatment.