Carcinogenesis Advance Access originally published online on March 26, 2007
Carcinogenesis 2007 28(7):1533-1542; doi:10.1093/carcin/bgm069
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Isosilybin B and isosilybin A inhibit growth, induce G1 arrest and cause apoptosis in human prostate cancer LNCaP and 22Rv1 cells
1 Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO, USA
2 Natural Products Laboratory, Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC, USA
3 University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, CO, USA
* To whom correspondence should be addressed. Tel: +303 315 1381; Fax: +303 315 6281; Email: rajesh.agarwal{at}uchsc.edu
Silymarin and, one of its constituents, silibinin exert strong efficacy against prostate cancer (PCA); however, anticancer efficacy and associated mechanisms of other components of silymarin, which is a mixture of flavonolignans, are largely unknown. Here we have assessed the anticancer efficacy of two pure compounds isosilybin B and isosilybin A, isolated from silymarin, in human prostate carcinoma LNCaP and 22Rv1 cells. Isosilybin B and isosilybin A treatment resulted in growth inhibition and cell death together with a strong G1 arrest and apoptosis in both the cell lines. In the studies examining changes in cell cycle and apoptosis regulators, isosilybin B and isosilybin A resulted in a decrease in the levels of both cyclins (D1, D3, E and A) and cyclin-dependent kinases (Cdk2, Cdk4 and cell division cycle 25A), but caused an increase in p21, p27 and p53 levels, except in 22Rv1 cells where isosilybin B caused a decrease in p21 protein level. Isosilybin B- and isosilybin A-induced apoptosis was accompanied with an increase in the cleavage of poly (ADP-ribose) polymerase, caspase-9 and caspase-3 and a decrease in survivin levels. Compared with LNCaP and 22Rv1 cells, the antiproliferative and cytotoxic potentials of isosilybin B and isosilybin A were of much lesser magnitude in non-neoplastic human prostate epithelial PWR-1E cells suggesting the transformation-selective effect of these compounds. Together, this study for the first time identified that isosilybin B and isosilybin A, two diastereoisomers isolated from silymarin, have anti-PCA activity that is mediated via cell cycle arrest and apoptosis induction.
Abbreviations: PCA, prostate cancer; PI, propidium iodide; CDK, cyclin-dependent kinase; CDKI, cyclin-dependent kinase inhibitor; Cdc25A, cell division cycle 25A; PARP, poly (ADP-ribose) polymerase
Received December 11, 2006; revised March 12, 2007; accepted March 19, 2007.
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