Abstract
BackgroundGlioblastoma 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Glioblastoma multiforme (GBM) is the most lethal primary brain tumors which remains difficult to cure despite advances in surgery, radiotherapy and chemotherapy
The studies of α-carboline derivatives were limited [13, 14]. α-carboline derivatives were usually isolated from marine animals such as Britannia marine tunicate Dendrodoa grossularia 14 and Indonesian ascidian Polycarpa
We found that TJY-16induced cell death was associated with G2/M cell cycle arrest followed by induction of sub-G1 phase
Summary
Glioblastoma multiforme (GBM) is the most lethal primary brain tumors which remains difficult to cure despite advances in surgery, radiotherapy and chemotherapy. 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. We have synthesized several α-carboline compounds and examined their anti-glioma activities. Glioblastoma multiforme (GBM), an astrocytic origin of glioma, is among the most common and malignant subtype [1]. Recurrence of GBM after standard therapies is almost inevitable [6, 7] highlighting an imperative need to develop novel strategies for the treatment of GBM. Α-carboline derivatives were usually isolated from marine animals such as Britannia marine tunicate Dendrodoa grossularia 14 and Indonesian ascidian Polycarpa The studies of α-carboline derivatives were limited [13, 14]. α-carboline derivatives were usually isolated from marine animals such as Britannia marine tunicate Dendrodoa grossularia 14 and Indonesian ascidian Polycarpa
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