Silymarin - Molecular Targets for Anti-cancer Efficacy

Silymarin - Molecular Targets for Anti-cancer Efficacy

Both silymarin and silibinin are particularly effective in inhibiting epidermal growth factor receptor (EGFR) signaling with suppression of cyclin-dependent kinase (CDK) expression and up-regulation of the CDK-inhibitors p21^CIP1 and p27^KIP1, with concomitant increase in their binding to CDKs. Silymarin induces growth arrest at the G1 and G2 checkpoints. Silymarin, in lower doses induces the growth arrest through extracellular signal-regulated kinases (ERK1/2) inhibition and in higher doses leads to apoptosis through mitogen activated protein kinase (MAPK)/ c-Jun N-terminal kinase (JNK) pathway [14-16]. Our studies have shown that silymarin inhibits both constitutively active and transforming growth factor (TGF)-α mediated tyrosine phosphorylation of EGFR in advanced human prostate cancer DU145 cells [17]. Studies have shown that silymarin and silibinin down-regulate EGFR signaling via the inhibition in the expression and secretion of growth factors, and by inhibiting growth factor binding to and activation of EGFR and subsequent impairment of downstream mitogenic events causing anticancer efficacy in tumor cell lines [18].

Anti-inflammatory effects of silymarin

Anti-inflammatory effects of silymarin are related to inhibition of the transcription factor nuclear factor-κB (NF-κB), which regulates and coordinates the expression of various genes involved in inflammation, cell survival, differentiation and growth. In particular, NF-κB contributes to the production of interleukin (IL)-1 and -6, tumor necrosis factor (TNF)-α, lymphotoxin, granulocyte macrophage colony-stimulating factor (GM-CSF) and interferon (IFN)-γ. In most of the resting cells, NF-κB is sequestered in the cytoplasm by binding to the inhibitory-κB (IκB)-proteins which block the nuclear localization sequences of NF-κB. Studies have demonstrated that silymarin is a potent inhibitor of NF-κB activation in response to TNFα. This effect was mediated through the inhibition of phosphorylation and degradation of IκB [18]. It also decreases the p65 subunit nuclear translocation and NF-κB dependent reporter gene transcription. Silymarin also blocked NF-κB activation induced by phorbol ester, lipopolysaccharide, okadaic acid and ceramide, whereas H₂O₂-induced NF-κB activation was not significantly affected. Manna et al [19] studied the effect of silymarin on NF-κB activation induced by various inflammatory agents. Silymarin also inhibited TNF-α induced activation of MAPK and JNK, TNF-induced cytotoxicity and caspase activation. Silymarin in combination with tetrandrine attenuates NF-κB activated pathways and the induction of metallothionein gene transcription in the liver of dimethylnitrosamine (DMN) administered rats [20]. In human mesangial cells, silymarin showed dose dependent inhibition of TNF-α- and IL-1β-induced NF-κB activation, and TNF-α-induced intracellular calcium and MCP-1 expression [21]. Silymarin has a protective effect against endotoxin-induced sepsis and also have the inhibitory effect on the production of IL-1β and prostaglandin (PG)-E2 [22]. Silymarin dose-dependently inhibits both cytokine-induced nitric oxide (NO) production and cell death in RINm5F cells, and prevents IL-1β and IFN-γ-induced NO production and β-cell dysfunction in human pancreatic islets. [23].

Modulation of cell cycle progression by silymarin

Disruption of the normal regulation of cell cycle progression and division is an important event in malignant transformation. The regulation of the cell cycle is controlled by a family of cyclins, CDKs and CDK inhibitors (CDKIs). Silymarin has been reported to suppress the proliferation of tumor cells in various cancers including prostate [15-17], ovarian [25], breast [26], lung [27], skin [18] and bladder [28,29]. Numerous reports indicate that silymarin inhibits proliferation of cells by inhibiting cell cycle progression at different stages of the cell cycle. Studies from our laboratory have demonstrated that silymarin induces G1 arrest and/or G2-M arrest in human prostate cancer LNCaP, PC3 and DU145 cells. Silymarin caused an induction of the CDK inhibitors Cip1/p21 and Kip1/p27, and a decrease in CDK2 and CDK4 and associated kinase activities that led to G1 arrest [18]. Silibinin treatment showed dose- and time-dependent growth inhibition together with a G1 arrest in bladder transitional cell carcinoma (TCC) cells, T-24 (high-grade tumor) and TCC-SUP (high-grade invasive tumor). Furthermore, silibinin at high concentration induced G2/M arrest in TCC-SUP cells that was associated with a decrease in pCdc25c (Ser216), Cdc25c, pCdc2 (Tyr15), Cdc2 and cyclin B1 protein levels [29]. Silymarin treatment has been shown to inhibit the growth of androgen dependent (LNCaP) and androgen independent (PC3 and DU145) prostate cancer cells. [12]. Silymarin also induces G1 arrest through an increase in Cip1/p21 and a decrease in the kinase activity of CDK and associated cyclins in human breast cancer MDA-MB 468 cells [26]. Silymarin treatment induced binding of Cip1/p21 with CDK2 and CDK6 paralleled a significant decrease in CDK2-, CDK6-, cyclin D1-, and cyclin E-associated kinase activities, along with a decrease in cyclins D1 and E. Our studies have also shown that silymarin and silibinin modulate G1 phase cyclins-CDKs-CDKIs for G1 arrest, and the Chk2-Cdc25C-Cdc2/cyclin B1 pathway for G2-M arrest, together with an altered subcellular localization of critical cell cycle regulators [18]. Recently, we have shown that silibinin inhibits UVB-caused increase in cell proliferation and microvessel density and down-regulation of inflammatory and angiogenic responses in SKH-1 hairless mice [30]. In other studies, silibinin significantly up-regulated p21/CDK4 and p27/CDK4 complexes and down-regulated Rb-phosphorylation and E2F1/DP1 complex thereby inhibiting human hepatoma HuH7 cell growth [31]. We have also demonstrated the anticancer activity of two pure compounds isosilybin B and isosilybin A, isolated from silymarin, in human prostate carcinoma LNCaP and 22Rv1 cells that is mediated via cell cycle arrest and apoptosis induction [13]. These studies suggested that regulation of cell cycle is one of the mechanisms of action of silymarin in the prevention and therapeutic intervention of cancer.

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