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Identification of thioridazine, an antipsychotic drug, as an antiglioblastoma and anticancer stem cell agent using public gene expression data.

Al's Comment:

 This is only in the test tube, so it is too early to get excited about it, but I love the methodology of this research and it can be used to identify other approved drugs which can be repurposed to fight brain tumors!  Thioridazine used to be used in the USA mental disorders but was stopped because it had a bad side effect of causing heart problems.


Posted on: 05/13/2015

. Cell Death Dis. 2015 May 7;6:e1753. doi: 10.1038/cddis.2015.77.
Identification of thioridazine, an antipsychotic drug, as an antiglioblastoma and anticancer stem cell agent using public gene expression data.
Cheng HW1, Liang YH2, Kuo YL3, Chuu CP4, Lin CY5, Lee MH1, Wu AT6, Yeh CT7, Chen EI2, Whang-Peng J8, Su CL9, Huang CY10.
 
Author information:
1Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
2Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
3Department of Computer Science and Information Engineering, National Taiwan University, Taipei, Taiwan.
4Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
51] Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan [2] Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
6Department of Radiation, School of Medicine, Taipei Medical University, Taipei, Taiwan.
7Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
8Municipal Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
9Program of Nutritional Science and Education, Department of Human Development and Family Studies, National Taiwan Normal University, Taipei, Taiwan.
101] Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan [2] Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
 
Abstract
 
Glioblastoma (GBM) is a common and malignant tumor with a poor prognosis. Glioblastoma stem cells (GSCs) have been reported to be involved in tumorigenesis, tumor maintenance and therapeutic resistance. Thus, to discover novel candidate therapeutic drugs for anti-GBM and anti-GSCs is an urgent need. We hypothesized that if treatment with a drug could reverse, at least in part, the gene expression signature of GBM and GSCs, this drug may have the potential to inhibit pathways essential in the formation of GBM and thereby treat GBM. Here, we collected 356 GBM gene signatures from public databases and queried the Connectivity Map. We systematically evaluated the in vitro antitumor effects of 79 drugs in GBM cell lines. Of the drugs screened, thioridazine was selected for further characterization because it has potent anti-GBM and anti-GSCs properties. When investigating the mechanisms underlying the cytocidal effects of thioridazine, we found that thioridazine induces autophagy in GBM cell lines, and upregulates AMPK activity. Moreover, LC3-II was upregulated in U87MG sphere cells treated with thioridazine. In addition, thioridazine suppressed GBM tumorigenesis and induced autophagy in vivo. We not only repurposed the antipsychotic drug thioridazine as a potent anti-GBM and anti-GSCs agent, but also provided a new strategy to search for drugs with anticancer and anticancer stem cell properties.

 


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