α-Carboline derivative TJY-16 inhibits tumor growth by inducing G2/M cell cycle arrest in glioma cells

Background: glioblastoma multiforme (gbm) is the most lethal primary brain tumors which remains difficult to cure despite advances in surgery,radiotherapy and chemotherapy. therefore,the development of new drug is urgently needed. α-carboline derivatives were usually isolated from marine animals such as britannia marine tunicate dendrodoa grossularia and indonesian ascidian polycarpa aurata. in this study,we have synthesized several α-carboline compounds and examined their anti-glioma activities. results: we report that among α-carboline derivatives tjy-16 (6-acetyl-9-(3,4,5-trimethoxybenzyl)-9h-pyrido[2,3-b] indole) is the most potent α-carboline analog to induce glioma cell death with ic50 value of around 50 nm. tjy-16 decreased cell viability of glioma cells in a concentration- and time-dependent manner. trypan blue exclusion assay showed that the reduction of cell viability was due to both cell growth inhibition and cell death. flow cytometric analysis showed that tjy-16 induced g2/m cell cycle arrest followed by induction of sub-g1 phase. hoechst staining detected the apoptotic features such as nuclear shrinkage and dna condensation. western blot analysis showed the increased level of cleaved caspase-3. the activation of caspase-8 and depolarization of mitochondrial membrane potential (δψm) indicated that both extrinsic and intrinsic apoptotic pathways were involved in tjy-16-induced apoptosis. tjy-16 effectively inhibited tumor growth and induced caspase-3 activation in the xenograft tumor model of u87 glioma cells. conclusions: our results suggest that tjy-16 may kill glioma cells by inducing g2/m cell cycle arrest followed by apoptosis. thus,tjy-16 is a promising agent for the treatment of malignant gliomas. © 2016 huang et al.