Thioridazine, an antipsychotic agent, inhibits cancer stem cell growth and induces autophagy of Glioblastoma Multiforme

• Main Authors: Hui-Wen Cheng, 鄭惠文
• Other Authors: Chi-Ying F. Huang
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/03732371190588805985

碩士 === 國立陽明大學 === 生物藥學研究所 === 102 === Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by increased proliferation and resistance to chemotherapy and radiotherapy. Glioblastoma stem cells (GSCs) have been proposed to be involved in tumorigenesis, tumor maintenance and therapeutic resistance. Currently, temozolomide is the only FDA-approved treatment for GBM. Therefore, there is an urgent need to discover novel candidate therapeutic drugs for GBM. Here, we identified thioridazine, an anti-psychotic drug, as a potential treatment for GBM via the Connectivity Map database. Thioridazine can cross the blood-brain barrier (BBB), providing a significant advantage over current drug delivery limitations. We demonstrate that thioridazine inhibits the cell viability of both GBM cells and GSCs. Thioridazine induces autophagy in GBM cells and GSCs, as evident by the up-regulation of LC3II, and up-regulates AMPK activity. Moreover, thioridazine induces ER stress in GBM cells. Finally, thioridazine suppresses GBM tumorigenesis and induces autophagy in vivo. The data suggest that thioridazine-induced autophagy has an anti-cancer effect in GBM through activation of AMPK. In summary, we repurpose the anti-psychotic drug, thioridazine, as a potent anti-GBM and anti-GBM cancer stem cell agent for potential clinical trial in the future.