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Gambogenic acid-induced time- and dose-dependent growth inhibition and apoptosis involving Akt pathway inactivation in U251 glioblastoma cells

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Abstract

Glioblastoma multiforme is the most common and aggressive type of primary brain tumor. Uncontrolled activation of the PI3K/Akt signaling pathway resulting from genetic alterations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and epidermal growth factor receptor (EGFR) correlates with poor prognosis and resistance to chemotherapy and radiotherapy of glioblastomas. In this study, we found that gambogenic acid (GNA), a polyprenylated xanthone isolated from the traditional medicine gamboge, efficiently arrested the cell cycle at the G0/G1 phase by specifically repressing the expression of cyclin D1 and cyclin E, suppressed cell proliferation, colony formation and cell migration, and induced caspase-dependent apoptosis in U251 glioblastoma cells in a time- and dose-dependent manner. The pro-apoptotic effect of GNA on U251 cells was shown to be mediated through inactivation of the Akt pathway, because GNA efficiently suppressed the expression level of EGFR and reduced the phosphorylation of Akt (T308) and GSK3β (S9). Furthermore, the combined treatment with LY294002, a specific inhibitor of the PI3K/Akt kinase pathway, and GNA showed a synergistic or additive effect on the growth of U251 cells. Our results showed that GNA is a promising therapeutic agent for glioblastomas.

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Acknowledgments

We are grateful for the funding (to L.H.) from the Shenzhen Municipal Government and the Bureau of Science Technology and Information through the programs of the Shenzhen National Key Laboratory of Health Science and Technology and the Key Laboratory of Gene and Antibody Therapy; and partly from key projects in the National Science and Technology Pillar Program during the 11th 5-year plan period 2009ZX09103-399 (Q. Li, co-PI).

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Authors and Affiliations

  1. School of Life Sciences, Tsinghua University, 100084, Beijing, China

    Hong-Bo Chen, Lin Mei, Xiao-Jun Shi & Laiqiang Huang

  2. The Shenzhen Key Laboratory of Gene and Antibody Therapy, Division of Life & Health Sciences, Graduate School at Shenzhen, Tsinghua University, 518055, Shenzhen, China

    Hong-Bo Chen, Lin Mei, Xiao-Jun Shi & Laiqiang Huang

  3. Anhui Province Key Laboratory of R&D of Chinese Medicine, Anhui Key Laboratory of Modernized Chinese Material, Anhui University of Traditional Chinese Medicine, 230038, Hefei, China

    Lan-Zhen Zhou, Xiao-Shan Wang & Qing-Lin Li

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  1. Hong-Bo Chen
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  2. Lan-Zhen Zhou
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Correspondence to Qing-Lin Li or Laiqiang Huang.

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H.-B. Chen and L.-Z. Zhou contributed equally to this work.

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Chen, HB., Zhou, LZ., Mei, L. et al. Gambogenic acid-induced time- and dose-dependent growth inhibition and apoptosis involving Akt pathway inactivation in U251 glioblastoma cells. J Nat Med 66, 62–69 (2012). https://doi.org/10.1007/s11418-011-0553-7

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  • DOI: https://doi.org/10.1007/s11418-011-0553-7

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