Isosilybin B and isosilybin A inhibit growth, induce G1 arrest and cause apoptosis in human prostate cancer LNCaP and 22Rv1 cells.
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 G(1) 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.
Deep
Gagan
G
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO, USA.
Oberlies
Nicholas H
NH
Kroll
David J
DJ
Agarwal
Rajesh
R
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms; D012838:Silymarin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D013237:Stereoisomerism; D000077022:Survivin
D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D018797:Cell Cycle Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D012838:Silymarin; D000077022:Survivin; D018844:Cyclin-Dependent Kinases; D020169:Caspases; C523198:isosilybin A