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(+)-Episesamin exerts anti-neoplastic effects in human hepatocellular carcinoma cell lines via suppression of nuclear factor-kappa B and inhibition of MMP-9

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Summary

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Treatment options, especially in advanced tumor stages, are still limited. Inhibition of signaling cascades involved in the pathogenesis of HCC - such as NF-ĸB - offer a promising therapeutic approach. Aim of this study was to examine anti-neoplastic effects of (+)-episesamin which has been isolated from an anti-fibrotic extract of Lindera obtusiloba on human HCC cells with particular interest in activation of NF-κB. The human HCC cell lines HepG2, Huh-7 and SK-Hep1 were treated with (+)-episesamin. Beside measurement of proliferation, invasion and apoptosis, effects of (+)-episesamin on NF-κB-activity, VEGF secretion and enzymatic MMP-9 activity were determined. Anti-inflammatory effects were assessed by IL-6 ELISA using HCC cells and RAW264.7 macrophages. 10 μM (+)-episesamin reduced the proliferation of HCC cells by ~50%, suppressed invasion and induced apoptosis. DNA-binding ELISA experiments revealed that (+)-episesamin treated HCC cells showed a suppressed basal and TNFα-induced activation of NF-κB and a subsequent suppression of TNFα- and LPS-induced IL-6 production. Further, (+)-episesamin exhibited inhibitory effects on the enzymatic activity of recombinant MMP-9 and the secretion of MMP-9 and VEGF by HCC cells into their supernatants. Our findings show that anti-neoplastic effects of (+)-episesamin are mediated via suppressed activation of NF-κB which entails a decreased release of pro-inflammatory IL-6. In addition, (+)-episesamin inhibits MMP-9, which is strongly expressed in invasive HCC, and the production of proangiogenic VEGF. We conclude that (+)-episesamin has the potential to be further explored as a complementary treatment for HCC.

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Acknowledgements

This work was supported by the Collaborative Research Centers (SFB366 C5/C10) and (SFB633 Z1) from the Deutsche Forschungsgemeinschaft and the Berliner Sparkassenstiftung Medizin.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Gastroenterology, Infectiology and Rheumatology, Charité - Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany

    Christian Freise, Martin Ruehl, Ulrike Erben, Martin Zeitz & Rajan Somasundaram

  2. Department of Chemical and Pharmaceutical Engineering, Beuth Hochschule für Technik Berlin, Berlin, Germany

    Wolfram Trowitzsch-Kienast

  3. Department of General, Visceral and Transplantation Surgery, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany

    Daniel Seehofer

  4. Faculty of Beauty Design, Human Environmental Science College, Wonkwang University, Iksan City, South Korea

    Ki Young Kim

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  1. Christian Freise
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  2. Wolfram Trowitzsch-Kienast
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Correspondence to Rajan Somasundaram.

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Freise, C., Trowitzsch-Kienast, W., Ruehl, M. et al. (+)-Episesamin exerts anti-neoplastic effects in human hepatocellular carcinoma cell lines via suppression of nuclear factor-kappa B and inhibition of MMP-9. Invest New Drugs 30, 2087–2095 (2012). https://doi.org/10.1007/s10637-011-9762-x

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