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- W2565327596 abstract "B89 Extracts of milk thistle (Silybum marianum), termed silymarin or used worldwide as non-prescription dietary supplements for hepatoprotective properties are now being investigated in cancer chemoprevention and treatment, alone and in combination with conventional cytotoxic chemotherapy. We demonstrated recently that one of the eight primary compounds identified in milk thistle extracts, isosilybin B, exhibits the greatest potency in suppressing prostate carcinoma cell proliferation in vitro. In the current study, isosilybin B is also shown to be the most potent compound in killing HCT-116 colorectal adenocarcinoma cells. Using isogenic HCT-116 cell line pairs with homozygous-null p53 or p21 phenotypes (kind gift of Dr. B. Vogelstein), the cytotoxic or growth-suppressive activity of all milk thistle compounds is shown to be unaltered by loss of either gene product. To the contrary, several milk thistle flavonolignans exhibit enhanced growth-suppressive cytotoxic action against p53-/- and p21-/- HCT-116 cells relative to their respective controls. The most commonly used milk thistle extract, silibinin, is composed of a roughly 1:1 mixture of silybin A and silybin B. Inhibition of HCT-116 cell growth by silibinin was also independent of p53 or p21 status and was characterized by G2/M arrest in all cases. Studies of these compounds and mixtures in human prostate adenocarcinoma cells (DU145 and MDA PCa 2b) also revealed that silibinin dose-dependently suppresses expression and cellular levels of DNA topoisomerase IIα (topo IIα), a known marker required for cellular proliferation and whose DNA decatenation activity is essential to faithful chromosomal segregation. Among the pure compounds, silybin A, isosilybin A, and isosilybin B are most efficacious as topo IIα suppressors. While wild-type p53 is a known repressor of topo IIα gene expression, treatment of DU145 cells pure compounds reveal a striking loss of the mutant p53 of these cells upon isosilybin B exposure. Other known mediators of prostate carcinoma tumorigenesis and proliferation are also affected by exposure to milk thistle extracts and compounds. Milk thistle extract activate the IGFBP-3 gene promoter in DU145 cells and nearly all of the flavonolignans are capable of inducing IGFBP-3 protein in these cells. In contrast, only some milk thistle compounds and extracts suppress the expression of the fatty acid racemase, AMACR, a protein identified from differential gene expression profiling of normal and tumorigenic prostate carcinoma cells. In this case, only isosilybin B and a isosilibinin mixture are capable of suppressing AMACR expression. The NCI Developmental Therapeutics Program panel of isogenic yeast strains (developed in S. cerevisiae by Dr. J.A. Simon et al.) were investigated for synthetic lethality with milk thistle compounds to provide hints toward their proximal mechanism of action. Several of the compounds exhibit synthetic lethality with the sgs1 mgt1(homologue of the Blooms and Werner syndrome genes and O6-alkylguaninetransferase), bub3 (mitotic checkpoint), and CLN2oe rad14 (overexpression of yeast G1 cyclin and nucleotide excision repair) phenotypes. In yeast, however, isosilybin A and other compounds were consistently more potent than isosilybin B, the most potent compound against human tumor cells. Therefore, it appears that milk thistle compounds have a broad spectrum of chemopreventive and antitumor effects and the potency of isosilybin B may be selective to human cells. Moreover, milk thistle compounds are cytotoxic and/or growth-suppressive in tumor cells lacking functional p53 or p21." @default.
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- W2565327596 date "2006-12-01" @default.
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- W2565327596 title "Flavonolignans from extracts of milk thistle (Silybum marianum) suppress biomarkers of prostate oncogenesis and colon carcinoma cell proliferation independently of p53 or p21." @default.
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