Mahanine induces apoptosis, cell cycle arrest, inhibition of cell migration, invasion and PI3K/AKT/mTOR signalling pathway in glioma cells and inhibits tumor growth in vivo

Gliomas are among the most frequent types of primary malignancies in the central nervous system. The main treatment for glioma includes surgical resection followed by a combination of radiotherapy and chemotherapy. Despite the availability of several treatments, the average survival for patients with glioma at advanced stages still remains 16 months only. Therefore, there is an urgent need to look for novel and more efficient drug candidates for the treatment of glioma. In the current study the anticancer activity of Mahanine was evaluated against a panel of glioma cells. The results revealed that Mahanine exerted significant anticancer effects on the glioma HS 683 cells with an IC50 of 7.5 mu M. However, the cytotoxic effects were less pronounced on the normal human astrocytes. Further the results showed that the anticancer effects were mainly due to induction of apoptosis and G2/M cell cycle arrest. Western blotting showed that Mahanine caused upregulation of Bax, cytochrome c, cleaved caspase 3 and 9 and cleaved PARP. However, the expression of cell cycle related proteins pCdc25c, Cdc25c, pCdc2, Cdc2 and cyclin B1 was significantly downregulated. The effect of Mahanine on the migration and invasion of HS 683 cells was also determined and results indicated that Mahanine inhibited the cell migration and invasion at IC50 . Additionally, Mahanine-inhibited cell growth was simultaneous with suppression of p-PI3K, p-AKT and p-mTOR. Taken together these results indicate that Mahanine may prove to be an important lead molecule for the treatment of glioma and warrants further investigation.