Medicinal plants are a promising source for identification of lead molecules for cancer therapy. In our continuous search to discover bioactive compounds from natural products, we isolated (5R, 10R)-4R, 8R-dihydroxy-2S, 3R:15, 16-diepoxycleroda-13(16), 17, 12S:18,1S-dilactone (ECD), a diterpenoid from Tinospora cordifolia and studied its chemopreventive potential in diethylnitrosamine (DEN) induced hepatocellular carcinoma (HCC) rats. Fifty male Wistar rats were divided into five groups. Group I served as normal control. Group II–IV were given DEN (0.01% in drinking water) for twenty weeks. In addition, Group III (preventive treatment) received ECD (10 mg/kg body weight) throughout the study. Group IV (curative treatment) received ECD (10 mg/kg body weight) for the last 8 weeks. Group V received ECD alone (10 mg/kg body weight) throughout the experimental period. At the end of the experimental period all the animals were sacrificed and analyzed for biochemical end points to assess the effect of ECD treatment in DEN induced HCC. The animals treated with DEN showed a decrease in the activities of antioxidant (SOD, CAT) and detoxification enzymes (GSH, GPx) with increase in the activities of the hepatic markers (SGOT, SGPT, LDH). Treatment of ECD in both preventive and curative DEN induced animals increased the level of antioxidants and detoxification enzymes, and decreased serum transaminase level and hepatic marker enzymes to near normal. Histopathological and nodular incidence also confirmed that ECD remarkably reduced tumor incidence and reversed damaged hepatocytes to normal. Our findings confirm that ECD exhibits preventive effect against chemically induced HCC in rats. ECD can be a potent chemopreventive drug for HCC.
This is a preview of subscription content, log in to check access.
We are grateful to Dr. C. S. Vijayalakshmi, Professor, Kilpauk Medical College, Chennai for helping in histopathological assay.
Feo FM, Miglio RD, Simile MM, Muroni MR, Calvisi DF, Frau M, Pascale RM (2006) Hepatocellular carcinoma as a complex polygenic disease. Interpretive analysis of recent developments on genetic predisposition. Biochim Biophys Acta 1765:126–147PubMedGoogle Scholar
Di Stefano G, Fiume L, Bolondi L, Lanza M, Pariali M, Chieco P (2005) Enhanced uptake of lactosaminated human albumin by rat hepatocarcinomas: implications for an improved chemotherapy of primary liver tumours. Liver Int 25:854–860, doi:10.1111/j.1478-3231.2005.1118.xPubMedCrossRefGoogle Scholar
Cheng YL, Change WL, Lee SC, Liu YG, Chen CJ, Harn HJ (2004) Acetone extract of Angelica sinensis inhibits proliferation of human cancer cells via including cell cycle arrest and apoptosis. Life Sci 75:1579–1594, doi:10.1016/j.lfs.2004.03.009PubMedCrossRefGoogle Scholar
Mukherjee AK, Basu S, Sarkar N, Ghosh AC (2001) Advances in cancer therapy with plant based natural products. Curr Med Chem 8:1467–1486PubMedGoogle Scholar
Oberlies NM, Burgess JP, Navarro HA, Pinos RE, Fairchild CR, Peterson RW, Soejatto DD, Famaworth NR, Kingdom AD, Wani MC, Wall ME (2002) Novel bioactive clerodane diterpenoids from the leaves and twings of Casearia sylvestris. J Nat Prod 65:95–99, doi:10.1021/np010459mPubMedCrossRefGoogle Scholar
Prakash SCV, Hoch JM, Kingston DG (2002) Structure and stereochemistry of new cytotoxic clerodane diterpenoids from the bark of Casearia lucida from the Madagascar rainforest. J Nat Prod 65:100–107, doi:10.1021/np010405cCrossRefGoogle Scholar
Morita H (1991) Structures and cytotoxic activity relationship of Casearins, New Clerodane Diterpenes from Casearia sylvestris Sw. Chem Pharm Bull (Tokyo) 39(2):693–697Google Scholar
Huang DM, Shen YC, Kung LF, Teng CM, Guh JH (2004) Investigation of extrinsic and intrinsic apoptosis pathways of new clerodane diterpenoids in human prostate cancer PC-3 cells. Eur J Pharm 503:17–24, doi:10.1016/j.ejphar.2004.09.040CrossRefGoogle Scholar
Moron MS, Depierre JW, Mannervik B (1979) Levels of glutathione, glutathione reductase and glutathione-S-transferase activities in rat lung and liver. Biochim Biophys Acta 582(1):67–78PubMedGoogle Scholar
Chung FL, Schwartz J, Herzog CR, Yang YM (2003) Tea and cancer prevention: studies in animals and humans. J Nutr 133:3268S–3274SPubMedGoogle Scholar
Prince PS, Menon VP (2001) Antioxidant action of Tinospora cordifolia root extract in alloxan diabetic rats. Phytother Res 5(3):213–218, doi:10.1002/ptr.707Google Scholar
Seifried HE, McDonald SS, Anderson DE, Greenwald P, Milner JA (2003) The antioxidant conundrum in cancer. Cancer Res 63:4295–4298PubMedGoogle Scholar
Masella R, Vari R, D’Archivio M, Benedetto R, Matarrese P, Malorni W, Scazzocchio B, Giovannini C (2004) Extra virgin olive oil biophenols inhibit cell-mediated oxidation of LDL by increasing the mRNA transcription of glutathione-related enzymes. J Nutr 134:785–791PubMedGoogle Scholar