Evodiamine And Its Derivative Induce Apoptosis In Small Cell Lung Cancer Cells Via Inhibition Of PI3K/AKT Pathway

Background and objectiveSmall cell lung cancer(SCLC)is one of the major causes of cancer-related mortality in the world.Evodiamine(EVO)is a promising drug candidate for cancer therapy,and some of its derivatives may show a stronger antitumor effect than EVO.PI3K/AKT pathway deregulation plays a crucial role in SCLC.This study was designed to investigate the effects of EVO and its derivative on SCLC cells,and wether PI3K/AKT pathway was involed in the antitumor effect.MethodsH1688 and H446 SCLC cells were treated with various doses of EVO for the indicated times,and the cell viability was subsequently quantified using MTT assay.Next,p-AKT and its downstream proteins and upstream regulator were detected using WB analyses.Trypan blue exclusion assay and flow cytometry were adopted to examine cell death and apoptosis.Fluoresence staining was used to observe cell apoptosis.PI3K/AKT pathway activator IGF-1 and inhibitor LY294002 were used to explore the underlying mechanism by which EVO induced apoptosis in SCLC cells.Additionally,EVO-NH2(C10-amino EVO derivative)was investigated in the same way.ResultsWe found that EVO markedly inhibited cell growth and induced apoptosis in H1688 and H446 cells.Futhermore,data suggested that p-AKT,a key component of PI3K/AKT pathway was regulated by EVO,and so were its downstream effectors and upstream regulator PTEN.However,when PI3K/AKT pathway was reactivated by IGF-1,the apoptosis induced by EVO was abrogated.In addition,we found that the novel EVO derivative(EVO-NH2)demonstrated a stronger antitumor effect than EVO by the similar mechanism.Conclusions1.EVO inhibits cell growth and induces apoptosis in H1688 and H446 cells.2.Inhibiton of PI3K/AKT pathway is one of the underlying mechanisms by which EVO induces apoptosis in SCLC cells.3.EVO derivative EVO-NH2 demonstrates a stronger antitumor effect than EVO by the similar mechanism.