Anticancer Potential of Silymarin: From Bench to Bed Side

RAJESH AGARWAL; CHARU AGARWAL; HARUYO ICHIKAWA; RANA P. SINGH; BHARAT B. AGGARWAL

Abstract

Silymarin consists of a family of flavonoids (silybin, isosilybin, silychristin, silydianin and taxifoline) commonly found in the dried fruit of the milk thistle plant Silybum marianum. Although silymarin's role as an antioxidant and hepatoprotective agent is well known, its role as an anticancer agent has begun to emerge. Extensive research within the last decade has shown that silymarin can suppress the proliferation of a variety of tumor cells (e.g., prostate, breast, ovary, colon, lung, bladder); this is accomplished through cell cycle arrest at the G1/S-phase, induction of cyclin-dependent kinase inhibitors (such as p15, p21 and p27), down-regulation of anti-apoptotic gene products (e.g., Bcl-2 and Bcl-xL), inhibition of cell-survival kinases (AKT, PKC and MAPK) and inhibition of inflammatory transcription factors (e.g., NF-κB). Silymarin can also down-regulate gene products involved in the proliferation of tumor cells (cyclin D1, EGFR, COX-2, TGF-β, IGF-IR), invasion (MMP-9), angiogenesis (VEGF) and metastasis (adhesion molecules). The anti-inflammatory effects of silymarin are mediated through suppression of NF-κB-regulated gene products, including COX-2, LOX, inducible iNOS, TNF and IL-1. Numerous studies have indicated that silymarin is a chemopreventive agent in vivo against a variety of carcinogens/tumor promoters, including UV light, 7,12-dimethylbenz(a)anthracene (DMBA), phorbol 12-myristate 13-acetate (PMA) and others. Silymarin has also been shown to sensitize tumors to chemotherapeutic agents through down-regulation of the MDR protein and other mechanisms. It binds to both estrogen and androgen receptors, and down-regulates PSA. In addition to its chemopreventive effects, silymarin exhibits antitumor activity against human tumors (e.g., prostate and ovary) in rodents. Various clinical trials have indicated that silymarin is bioavailable and pharmacologically safe. Studies are now in progress to demonstrate the clinical efficacy of silymarin against various cancers.

Footnotes

Abbreviations: AAP, alanine-aminopeptidase; AAF, acrylamino-fluorene; ACTH, adrenocorticotropic hormone; ADP, adenosine diphosphate; Aica-P, 4,5-amino-imidazole-carboxamide-phosphate; AP, alkaline phosphatase; sASG, ascorbigen; AR, androgen receptor; B(α)P, benzo(α)pyrene; BPO, benzoyl peroxide; CAH, chronic active hepatitis; CAPD, continuous ambulatory peritoneal dialysis; CCl₄, carbon tetrachloride, CDK, cyclin-dependent kinase; CDDP, cisplatin; COX, cyclooxygenase; CP, cyclophosphamide; CYP, cytochrome P450; CV, cyclic voltammetry; DHT, dihydrotestosterone; DMBA, 7,12-dimethylbenz(α)anthracene; DNM, daunomycin; DPH, 16-diphenyl-1,3,5-hexan; DR, TRAIL death receptor; DTD, DT-diaphorase=NAD(P)H-quinone reductase; DOX, doxorubicin; EBO, extrahepatic biliary obstruction; EDC, ethanol-derived calories; EROD, ethoxyresorufin O-deethylase; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ER, estrogen receptor; ERK, extracellular signal-regulated kinase; GGTP, γ glutamyl transpeptidase; GSH, glutathione; GSHPx, glutathione peroxidase; GST, glutathione S-transferase; HaCaT, human epithelial cell; HD, high-dose; HbA1c, glycosylated hemoglobin; HFK, human foreskin keratinocyte; HMBC, heteronuclear multiple bond correlation; HMC, human mesangial cell; HOCl, hypochlorous acid; HUVEC, human umbilical vein endothelial cells; IAP, inhibitor-of-apoptosis protein; IBI/S, silybin-β-cyclodextrin; IGF-IR, insulin; IκB, inhibitory subunit of NF-κB; IKK, IκBα kinase; IL, interleukin; iNOS, inducible nitric oxide synthase; HPLC, high performance liquid chromatography; OC, osteocalcin; PCA, prostate cancer; PMA, phorbol 12-myristate 13-acetate; LPS, lipopolysaccharide; JNK, c-Jun NH₂-terminal kinase; LC/MS, liquid chromatography/mass spectrometry; LCK, log10 cell kill; LDH, lactate dehydrogenase; LOX, lipooxygenase; LT, leukotriene; MAPK, mitogen-activated protein kinase: MDA, malondialdehyde; MDR, multidrug resistance; MMP, matrixmetalloproteinase; MRP, multidrug resistance-associated protein; MTDQ, 6,6-methylene-bis(2,2,4-trimethyl)-1,2-dihydroquinoline; NAG, non-steroidal anti-inflammatory drug-activated gene-1; NBT, nitro blue tetrazolium; NNK, 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone; NQO, 4-nitroquinoline 1-oxide; NSAIDS, non-steroidal anti-inflammatory drugs; PARP, poly (ADP ribose) polymerase; P-gp, P-glycoprotein; PG, prostaglandin; Akt, protein kinase B; PIIINP, propeptide of procollagen; PMLNs, polymorphonuclear leukocytes; PMS, phenazine methoxysulfate; PSA, prostate-specific antigen; OA, okadaic acid; ODC, ornithine decarboxylase; 3-OH-BP, 3-OH-benzo(α)pyrene; QR, quinone reductase; Rb, retinoblastoma; ROS, reactive oxygen species; SAR, structure activity relationship; SDH, silibin dihemisussinate; SOD, superoxide dismutase; STAT, signal transducer and activator of transcription; TBARS, thiobarbituric acid reactive substance; T2DM, non-insulin-dependent diabetes mellitus; TGF, transforming growth factor; TNBF, trinitrobenzenesulphonic acid; TPA, 7,12-tetradecanoyl phorbol-13-acetate; TRAP, tartrate resistant acid phosphatase; UDPGA, UDP-glucuronic acid; UDP-GDH, UDP-glucose dehydrogenase; TRAIL, tumour necrosis factor-related apoptosis-inducing ligand; VEGF, vascular endothelial growth factor; VBL, vinblastin. Silibinin is also called silybin.