Milk Thistle and Prostate Cancer: Differential Effects of Pure Flavonolignans from Silybum marianum on Antiproliferative End Points in Human Prostate Carcinoma Cells

Abstract

Extracts from the seeds of milk thistle, Silybum marianum, are known commonly as silibinin and silymarin and possess anticancer actions on human prostate carcinoma in vitro and in vivo. Seven distinct flavonolignan compounds and a flavonoid have been isolated from commercial silymarin extracts. Most notably, two pairs of diastereomers, silybin A and silybin B and isosilybin A and isosilybin B, are among these compounds. In contrast, silibinin is composed only of a 1:1 mixture of silybin A and silybin B. With these isomers now isolated in quantities sufficient for biological studies, each pure compound was assessed for antiproliferative activities against LNCaP, DU145, and PC3 human prostate carcinoma cell lines. Isosilybin B was the most consistently potent suppressor of cell growth relative to either the other pure constituents or the commercial extracts. Isosilybin A and isosilybin B were also the most effective suppressors of prostate-specific antigen secretion by androgen-dependent LNCaP cells. Silymarin and silibinin were shown for the first time to suppress the activity of the DNA topoisomerase IIa gene promoter in DU145 cells and, among the pure compounds, isosilybin B was again the most effective. These findings are significant in that isosilybin B composes no more than 5% of silymarin and is absent from silibinin. Whereas several other more abundant flavonolignans do ultimately influence the same end points at higher exposure concentrations, these findings are suggestive that extracts enriched for isosilybin B, or isosilybin B alone, might possess improved potency in prostate cancer prevention and treatment. (Cancer Res 2005; 65(10): 4448-57)

Isosilybin B causes androgen receptor degradation in human prostate carcinoma cells via PI3K-Akt-Mdm2-mediated pathway

“…Recently we showed the effect of isosilybin B and its other isomers namely silybin A, silybin B and isosilybin A (Figure 1a) on secreted PSA levels in LNCaP cells after 72 h treatment (Davis-Searles et al, 2005). Here, first we examined a comparative effect of these diastereoisomers, following 24 h of their treatment, on both secreted and intracellular PSA levels in PCA LNCaP, 22Rv1 and LAPC4 cells.…”

“…seeds, and is widely known for its hepatoprotective and cancer chemopreventive action (Wellington and Jarvis, 2001;Agarwal, 2002, 2006;Deep et al, 2006). Recently, we have isolated and purified from silymarin seven distinct flavonolignans namely silybin A, silybin B, isosilybin A, isosilybin B, silydianin, silychristin, isosilychristin and one flavonoid taxifolin ; and assessed their biological effects on many antiproliferative end points in human PCA cell lines (Davis-Searles et al, 2005). Isosilybin B ranked the most potent flavonolignan for nearly all end points including inhibition of prostate-specific antigen (PSA) secretion (Davis-Searles et al, 2005), which is used as a clinical tool in screening, diagnosis and treatment decisions for human PCA (Nelson et al, 2003).…”

“…Recently, we have isolated and purified from silymarin seven distinct flavonolignans namely silybin A, silybin B, isosilybin A, isosilybin B, silydianin, silychristin, isosilychristin and one flavonoid taxifolin ; and assessed their biological effects on many antiproliferative end points in human PCA cell lines (Davis-Searles et al, 2005). Isosilybin B ranked the most potent flavonolignan for nearly all end points including inhibition of prostate-specific antigen (PSA) secretion (Davis-Searles et al, 2005), which is used as a clinical tool in screening, diagnosis and treatment decisions for human PCA (Nelson et al, 2003). Here we conducted detailed mechanistic studies with isosilybin B focusing on AR by employing androgen-dependent LNCaP cells with single AR mutation (T877A), LAPC4 cells with wild-type AR and androgen-independent 22Rv1 cells with mutated AR (H874Y), though all the three cell lines have functional AR (Nagabhushan et al, 1996;Klein et al, 1997;Mendoza et al, 2002;Bernard et al, 2003).…”

Chemopreventive effects of silymarin and silibinin on N-butyl-N-(4-hydroxybutyl) nitrosamine–induced urinary bladder carcinogenesis in male ICR mice

“…One such naturally occurring agent is silibinin (Fig. 1B), a major flavonolignan component in silymarin, which is a mixture of flavonoids present in milk thistle; the chemical structures of these isomers were recently reported by us (8). Several studies by us and others have shown the cancer-preventive and therapeutic efficacy of silymarin and silibinin in different animal tumor models and cancer cells in culture (9).…”

First detailed quantification of silymarin components in the leaves ofSilybum marianumcultivated in egypt during different growth stages

“…Several studies on sily-marin declared its valuable effects in treatment of type II diabetic patients which was attributed to its antioxidant effect [5]. Moreover, inhibition of cancer cell growth in human prostate, skin, breast, and cervical cells was reported [6]. A number of methods utilizing HPLC and capillary electrophoresis were used for partial separation of the six components of silymarin [7,8], but the majority of these methods suffered from incomplete separation of silychristin, silydianin, and the two diastereoisomers of silybin and isosilybin.…”