Silibinin Efficacy against Human Hepatocellular Carcinoma

• Published in: Clinical cancer research Vol. 11; no. 23; pp. 8441 - 8448
• Main Authors: VARGHESE, Leyon, AGARWAL, Chapla, TYAGI, Alpana, SINGH, Rana P, AGARWAL, Rajesh
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-12-2005
• Subjects: Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; CDK inhibitor; CDKs; Cell Cycle - drug effects; Cell Proliferation - drug effects; Cyclin D1 - metabolism; Cyclin D3; Cyclin E - metabolism; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-Dependent Kinase 4 - metabolism; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; cyclins; Cyclins - metabolism; Flow Cytometry; Gastroenterology. Liver. Pancreas. Abdomen; Hepatitis B virus; Hepatocellular carcinoma; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Pharmacology. Drug treatments; silibinin; Silybin; Silybum marianum; Silymarin - therapeutic use; Tumor Cells, Cultured; Tumors; Human; Polyphenol; Efficiency; Silibinin; Phenols; Digestive diseases; Hepatic disease; Hepatocellular carcinoma; Malignant tumor; Flavonoid
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-1646

Purpose: Hepatocellular carcinoma (HCC) is one of the most common recurrent malignancies, for which, currently, there is no effective
therapy. Considering the antihepatotoxic activity of silibinin, a widely used drug and supplement for various liver disorders,
together with its strong preventive and anticancer efficacy against various epithelial cancers, we investigated the efficacy
of silibin against human HCC cells.
Experimental Design: Silibinin effects were examined on growth, cytotoxicity, apoptosis, and cell cycle progression in two different HCC cell
lines, HepG2 (hepatitis B virus negative; p53 intact) and Hep3B (hepatitis B virus positive; p53 mutated). At molecular level, cell cycle effects of silibinin were assessed by immunoblotting and in-bead kinase assays.
Results: Silibinin strongly inhibited growth of both HepG2 and Hep3B cells with a relatively stronger cytotoxicity in Hep3B cells,
which was associated with apoptosis induction. Silibinin also caused G 1 arrest in HepG2 and both G 1 and G 2 -M arrests in Hep3B cells. Mechanistic studies revealed that silibinin induces Kip1/p27 but decreases cyclin D1, cyclin D3,
cyclin E, cyclin-dependent kinase (CDK)-2, and CDK4 levels in both cell lines. In Hep3B cells, silibinin also reduced the
protein levels of G 2 -M regulators. Furthermore, silibinin strongly inhibited CDK2, CDK4, and CDC2 kinase activity in these HCC cells.
Conclusion: Together, these results for the first time identify the biological efficacy of silibinin against HCC cells, suggesting the
importance of conducting further investigations in preclinical HCC models, especially on in vivo efficacy, to support the clinical usefulness of silibinin against hepatocellular carcinoma in addition to its known clinical
efficacy as an antihepatotoxic agent.