Dihydroartemisinin exhibits anti-glioma stem cell activity through inhibiting p-AKT and activating caspase-3

• Published in: Pharmazie Vol. 69; no. 10; pp. 752 - 758
• Main Authors: Cao, Liu, Duanmu, Wangsheng, Yin, Yi, Zhou, Zhihang, Ge, Hongfei, Chen, Tunan, Tan, Liang, Yu, Anyong, Hu, Rong, Li, Fei, Feng, Hua
• Format: Journal Article
• Language: English
• Published: Germany Govi-Verlag 01.10.2014
• Subjects: Animals; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Artemisinins - pharmacology; Brain Neoplasms - drug therapy; Caspase 3 - metabolism; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Enzyme Activators - pharmacology; G1 Phase - drug effects; Glioma - drug therapy; Mice; Neoplastic Stem Cells - drug effects; Phosphorylation; Proto-Oncogene Proteins c-akt - antagonists & inhibitors
• ISSN: 0031-7144
• DOI: 10.1691/ph.2014.4600

Glioma stem cells (GSCs) have been proven to play key roles in tumorigenesis, metastasis and recurrence. Although dihydroartemisinin (DHA), a derivative of the antimalaria drug artemisinin, has been shown to have anti-cancer activity, it is still unclear whether DHA affects GSCs. This study investigated the effects of DHA on the growth and apoptosis of GSCs, as well as the possible molecular mechanism involved in these processes. GSCs were enriched using a non-adhesive culture system with serum-free neural stem cell medium. Their stemness characteristics were identified by assessment of tumor sphere formation, mRNA expression analysis, and immunofluorescence staining of stem cell markers (CD133, SOX2, and nestin). We found that DHA not only inhibited proliferation, which was determined with the cell counting kit-8 (CCK8) assay, but also induced apoptosis of GSCs, as evaluated with the annexin-V/PI flowcytometric assay. Interestingly, DHA treatment also induced a concentration-dependent cell cycle arrest in the G1 phase according to the cell cycle assay. To reveal the underlying mechanisms, we detected the expression levels of p-Akt and Cleaved Caspase-3. The data showed that Cleaved Caspase-3 increased significantly in a dose-dependent manner (p < 0.05) after the GSCs sphere cells were treated with 20, 40, and 80 μM of DHA for 24 h, which correlated with significantly decreased expression levels of p-Akt (p < 0.05). These data indicate that DHA selectively inhibits proliferation and induces apoptosis of GSCs through the down-regulation of Akt phosphorylation, which is followed by Caspase-3 activation, and these findings offer a new approach for treating gliomas.