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Silibinin Inhibits Glioma Cell Proliferation via Ca2+/ROS/MAPK-Dependent Mechanism In Vitro and Glioma Tumor Growth In Vivo

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Abstract

Anticancer activity of silibinin, a flavonoid, has been demonstrated in various cancer cell types. However, the underlying mechanism and in vivo efficacy in glioma were not elucidated. The present study was undertaken to determine the effect of silibinin on glioma cell proliferation in vitro and to examine whether silibinin inhibits tumor growth in vivo. Silibinin resulted in inhibition of proliferation in a dose- and time-dependent manner, which was largely attributed to cell death. Silibinin induced a transient increase in intracellular Ca2+ followed by an increase in reactive oxygen species (ROS) generation. The silibinin-induced cell death was prevented by EGTA, calpain inhibitor and antioxidants (N-acetylcysteine and Trolox). Western blot analysis showed that silibinin also induced ROS-dependent activation of extracellular signal-regulated kinase, p38 kinase, and c-Jun N-terminal kinase. Inhibitors of these kinases prevented the silibinin-induced cell death. Silibinin caused caspase activation and the silibinin-induced cell death was prevented by caspase inhibitors. Glioma cell migration was also decreased by silibinin treatment. Oral administration of silibinin in animals with subcutaneous U87MG glioma cells reduced tumor volume. Subsequent tumor tissue analysis showed a decrease in Ki-67 positive cells, an increase in TUNEL-positive cells, and caspase activation. These results indicate that silibinin induces a caspase-dependent cell death via Ca2+/ROS/MAPK-mediated pathway in vitro and inhibits glioma growth in vivo. These data suggest that silibinin may serve as a potential therapeutic agent for malignant human gliomas.

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Acknowledgments

This work was supported by the MRC program of MOST/KOSEF (R13-2005-009) in Korea.

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Authors and Affiliations

  1. Department of Neurosurgery, College of Medicine, Pusan National University, Pusan, 602-739, Korea

    Kwang Won Kim & Chang Hwa Choi

  2. Department of Physiology, College of Medicine, Pusan National University, Pusan, 602-739, Korea

    Thae Hyun Kim, Chae Hwa Kwon, Jae Suk Woo & Yong Keun Kim

  3. Department of MRC for ischemic tissue regeneration, College of Medicine, Pusan National University, Pusan, 602-739, Korea

    Yong Keun Kim

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  1. Kwang Won Kim
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Kim, K.W., Choi, C.H., Kim, T.H. et al. Silibinin Inhibits Glioma Cell Proliferation via Ca2+/ROS/MAPK-Dependent Mechanism In Vitro and Glioma Tumor Growth In Vivo. Neurochem Res 34, 1479–1490 (2009). https://doi.org/10.1007/s11064-009-9935-6

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