Sempervirine Mediates Autophagy and Apoptosis via the Akt/mTOR Signaling Pathways in Glioma Cells

Abstract

The potential antitumor effects of sempervirine (SPV), an alkaloid compound derived from the traditional Chinese medicine Gelsemium elegans Benth., on different malignant tumors were described in detail. The impact of SPV on glioma cells and the basic atomic components remain uncertain. This study aimed to investigate the activity of SPV in vitro and in vivo. The effect of SPV on the growth of human glioma cells was determined to explore three aspects, namely, cell cycle, cell apoptosis, and autophagy. In this study, glioma cells, U251 and U87 cells, and one animal model were used. Cells were treated with SPV (0, 1, 4, and 8 μM) for 48 h. The cell viability, cell cycle, apoptosis rate and autophagic flux were examined. Cell cycle, apoptotic, autophagy, and Akt/mTOR signal pathway-related proteins, such as CDK1, Cyclin B1, Beclin-1, p62, LC3, AKT, and mTOR were investigated by Western blot approach. As a result, cells induced by SPV led to G2/M phase arrest and apoptosis. SPV also promoted the effect of autophagic flux and accumulation of LC3B. SPV reduced the expression of p62 protein and induced the autophagic death of glioma cells. Furthermore, SPV downregulated the expressions of AKT and mTOR phosphorylated proteins in the mTOR signaling pathway, thereby affecting the onset of apoptosis and autophagy in U251 cells. In conclusion, SPV induced cellular G2/M phase arrest and blockade of the Akt/mTOR signaling pathway, thereby triggering apoptosis and cellular autophagy. The in vivo and in vitro studies confirmed that SPV inhibits the growth of glioma cancer.

Recent progress in chemistry and bioactivity of monoterpenoid indole alkaloids from the genus gelsemium : a comprehensive review

“…An in vivo experimental result showed that sempervirine (4.0 and 8.0 mg/kg, i.p. , for 28 days) significantly decreased the growth of glioma cancer by 44.76% and 61.26%, respectively 50 . In human hepatocellular carcinoma, sempervirine (0.1, 0.5, and 1.0 μM) induced HepG2 cells apoptosis and blocked the cell cycle in the G1 phase, accompanied by the upregulation of p53 and the downregulation of cyclin D1, cyclin B1, and CDK2.…”

Bufotalin enhances apoptosis and TMZ chemosensitivity of glioblastoma cells by promoting mitochondrial dysfunction via AKT signaling pathway

“…Therefore, inhibiting the activity of AKT is of significant importance for the treatment of GBM. For instance, Sempervirine induces G2/M phase cell cycle arrest and promotes cell apoptosis by inhibiting the AKT/mTOR signaling pathway [ 38 ]. Besides, inhibiting the AKT signaling pathway can enhance the sensitivity of GBM to TMZ [ 39 , 40 ].…”

Hirudin inhibits glioma growth through mTOR‐regulated autophagy

“…Consequently, autophagy is taken as a potential therapeutic target into consideration for both glioma prevention and therapy, whereas its role and mechanisms require further clarification. Recently, a number of studies have shown that downregulation of the pro‐survival mTOR pathway can prevent autophagosome fusion to lysosomes at later time points to induce the autophagic death of glioblastoma cells 19–21 . In addition, transcriptome‐based network analysis and follow‐up experimental research have shown that the expression of autophagy‐related pathway proteins, such as mTOR, was significantly reduced by hirudin treatment in rats with unilateral ureteral obstruction 22 .…”

“…Recently, a number of studies have shown that downregulation of the pro‐survival mTOR pathway can prevent autophagosome fusion to lysosomes at later time points to induce the autophagic death of glioblastoma cells. 19 , 20 , 21 In addition, transcriptome‐based network analysis and follow‐up experimental research have shown that the expression of autophagy‐related pathway proteins, such as mTOR, was significantly reduced by hirudin treatment in rats with unilateral ureteral obstruction. 22 However, whether the inhibitory effect of hirudin on human glioma involves autophagy has not been demonstrated.…”