Effective Elimination of Cancer Stem Cells By a Novel Drug Combination Strategy§

Authors

  • Shuqiang Yuan,

    1. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
    2. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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  • Feng Wang,

    1. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
    2. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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  • Gang Chen,

    1. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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  • Hui Zhang,

    1. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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  • Li Feng,

    1. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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  • Lei Wang,

    1. Department of Colorectal Surgery, Sixth Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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  • Howard Colman,

    1. Department of Neuro-Oncology, University of Utah, Salt Lake City, Utah, USA
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  • Michael J. Keating,

    1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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  • Xiaonan Li,

    1. Department of Molecular and Cellular Biology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
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  • Rui-Hua Xu,

    1. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
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  • Jianping Wang,

    1. Department of Colorectal Surgery, Sixth Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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  • Peng Huang

    Corresponding author
    1. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
    2. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
    • Department of Molecular Pathology, Unit 951, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA
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    • Telephone: 713-834-6044; Fax: 713-834-6084


  • Author contributions: S.Y. and F.W.: conception and design, collection/assembly of data, data analysis/interpretation, manuscript writing, and final approval; G.C., H.Z., L.W., H.C., M.K., R.X., and J.W.: provision of study materials and final approval; L.F.: collection/assembly of data; X.L.: design of animal study and data analysis/interpretation; P.H.: conception and design, provision of study materials, data analysis/interpretation, and final approval; S.Y. and F.W. contributed equally to this article.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS November 6, 2012.

Abstract

Development of effective therapeutic strategies to eliminate cancer stem cells, which play a major role in drug resistance and disease recurrence, is critical to improve cancer treatment outcomes. Our study showed that glioblastoma stem cells (GSCs) exhibited low mitochondrial respiration and high glycolytic activity. These GSCs were highly resistant to standard drugs such as carmustine and temozolomide (TMZ), but showed high sensitivity to a glycolytic inhibitor 3-bromo-2-oxopropionate-1-propyl ester (3-BrOP), especially under hypoxic conditions. We further showed that combination of 3-BrOP with carmustine but not with TMZ achieved a striking synergistic effect and effectively killed GSCs through a rapid depletion of cellular ATP and inhibition of carmustine-induced DNA repair. This drug combination significantly impaired the sphere-forming ability of GSCs in vitro and tumor formation in vivo, leading to increase in the overall survival of mice bearing orthotopic inoculation of GSCs. Further mechanistic study showed that 3-BrOP and carmustine inhibited glyceraldehyde-3-phosphate dehydrogenase and caused a severe energy crisis in GSCs. Our study suggests that GSCs are highly glycolytic and that certain drug combination strategies can be used to effectively overcome their drug resistance based on their metabolic properties. STEM Cells2013;31:23–34

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