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Dietary supplementation of silymarin is associated with decreased cell proliferation, increased apoptosis, and activation of detoxification system in hepatocellular carcinoma

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Abstract

Hepatocellular carcinoma (HCC) incidence rates are increasing in many parts of the world. HCC’s limited treatment remedies and the poor prognosis emphasize the importance in developing an effective chemoprevention for this disease. Here, we investigated the molecular mechanisms involved in the chemoprevention of silymarin in N-nitrosodiethylamine (NDEA)-induced rat model of HCC. Liver of the rats treated with NDEA showed higher proliferation index and glycoconjugates. NDEA treatment also increased the level of anti-apoptotic proteins with simultaneous decrease in the level of pro-apoptotic proteins along with increased accumulation of Cytochrome c in mitochondria. The carcinogenic insult also increased microsomal phase I metabolizing enzymes with a simultaneous decrease in the Phase II detoxifying enzyme glutathione-S-transferase (GST). Whereas dietary silymarin administration along with NDEA treatment significantly decreased the proliferation and down regulated the expression of anti-apoptotic proteins with simultaneously increased expression of pro-apoptotic proteins along with the release of Cytochrome c to cytosol there by activating the intrinsic apoptotic pathway. Silymarin administration also decreased the level of glycoproteins and activated the phase II detoxifying enzyme GST. These results demonstrate that suppression of HCC by silymarin in vivo involves inhibition of proliferation, activation of apoptosis, and efficient detoxification.

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Acknowledgments

The authors wish to thank Prof. Lorenzo Lo Muzio, University of Foggia, Italy for his kind gift of antibodies to β-catenin and Survivin, Prof. Carmen Martha Elinos-baez, UNAM, Mexico for his kind gift of antibodies to Bcl-2 and Bax, Prof. Nalini Rajamannan, Northwestern Universitry, USA for the kind gift of antibody to PCNA, Prof. Ron Jemmerson, University of Minnesota, USA for his kind gift of antibody to Cyt c, Prof. Hyder Raza, uaeu, UAE for his kind gift of antibody to Caspase-3, Dr. C Lazzari, Regina Elena cancer institute, Italy for his kind gift of antibody to p53. The funding by Indian Council of Medical Research is gratefully acknowledged.

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  1. Department of Biochemistry, University of Madras, Guindy campus, Chennai, 600025, Tamil Nadu, India

    Ramakrishnan Gopalakrishnan, Jagan Sundaram, Kamaraj Sattu, Anandakumar Pandi & Devaki Thiruvengadam

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  1. Ramakrishnan Gopalakrishnan
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Correspondence to Devaki Thiruvengadam.

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Gopalakrishnan, R., Sundaram, J., Sattu, K. et al. Dietary supplementation of silymarin is associated with decreased cell proliferation, increased apoptosis, and activation of detoxification system in hepatocellular carcinoma. Mol Cell Biochem 377, 163–176 (2013). https://doi.org/10.1007/s11010-013-1582-1

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