The efficacy of silymarin has been shown against chemically induced carcinogenesis, growth of tumor xenograft, as well as in various transgenic models. We were the first one to demonstrate the activity of silymarin against 12-O
-tetradecanoyl-phorbol-13-acetate (TPA) induced tumor promotion by inhibiting the activity and expression of epidermal ornithine decarboxylase [49
]. Further studies suggested the important role of silymarin in inhibiting the chemical- and UV-induced skin carcinogenesis [18
]. Recently, Gu et al [30
] have shown that topical or dietary silibinin treatment causes a strong protection against UVB-induced photocarcinogenesis by inhibiting cell proliferation, inflammation and angiogenesis in SKH-1 hairless mice. We have also reported that dietary feeding of silibinin prevents UVB radiation-induced skin damages including thymidine dimer-positive cells, proliferating cell nuclear antigen (PCNA) expression and apoptotic sunburn cells. Studies from our laboratory have demonstrated that silibinin can also inhibit the member of MAPKs family (ERK1/2, JNK and p38) and Akt activation induced by either acute or chronic UVB exposure of SKH-1 mouse skin [18
With regard to prostate cancer, it has been shown that dietary administration of silymarin significantly decreased the incidence of 3,2-dimethyl-4-aminobiphenyl (DMBA)-induced prostatic adenocarcinoma in male F344 rats [37
]. Studies from our laboratory have shown that dietary administration of silibinin inhibits the advanced human prostate tumor xenograft growth in athymic nude mice by exhibiting antiproliferative, proapoptotic and antiangiogenic efficacy against prostate tumor [14
]. Recently, we have also demonstrated that dietary silibinin inhibits prostate tumor growth and progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice by modulating the expression of CDKs, CDKIs, and insulin like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 [50
]. In other studies, we have demonstrated that administration of silibinin significantly inhibits N
-(4-hydroxybutyl) nitrosamine induced urinary bladder carcinogenesis in male ICR mice by causing cell cycle arrest and induction of apoptosis [28
]. We also found that silibinin inhibits the growth of human bladder tumor xenograft in athymic nude mice by down-regulating survivin and an increase in p53 expression together with enhanced apoptosis [51
]. Vinh et al [52
] have shown that administration of silymarin reduces the labeling index for BrdU and the cyclin D1-positive cell ratio in various bladder lesions.
Chemopreventive efficacy of silibinin against lung cancer has been extensively studied by our group in both in vitro
and in vivo
systems. Studies from our laboratory have reported that silibinin suppresses the growth of human non-small-cell lung carcinoma A549 xenograft growth in athymic BALB/c nu/nu mice. Silibinin also reduces systemic toxicity of doxorubicin with an enhanced therapeutic efficacy by modulating NF kappa B mediated signaling pathway in this model [53
]. Further studies have carried out to assess the chemopreventive efficacy of silibinin in urethane-induced lung carcinogenesis in A/J mice. Dietary silibinin supplementation significantly inhibited the urethane-induced lung tumorigenesis and tumor size by modulating proteins involved in cell proliferation, inflammation and angiogenesis [41
Anticancer activity of silymarin has also been demonstrated in both in vivo
and in vitro
models of colon cancer. Volate et al [54
] have shown that silymarin significantly decreases the number of aberrant crypt foci (ACF) in an azoxymethane (AOM) induced rat colon cancer model. Kohno et al [55
] have observed that dietary administration of silymarin (100, 500 and 1,000 ppm in diet), either during or after carcinogen exposure (AOM) for 4 weeks, causes significant reduction in the frequency of colonic ACF in a dose-dependent manner. In a long-term experiment, dietary feeding of silymarin (100 and 500 ppm) during the initiation or post-initiation phase of AOM-induced colon carcinogenesis reduced the incidence and multiplicity of colonic adenocarcinoma. They also found that silymarin reduces the PCNA labeling index and increases the number of apoptotic cells associated with decreased levels of beta-glucuronidase activity, PGE2 level and polyamine content in colonic mucosa.
Different laboratories have also investigated the potential of silymarin against breast cancer and there are conflicting reports regarding the chemopreventive efficacy of silymarin/silibinin in mammary carcinogenesis [14
]. Dietary supplementation of silymarin increased the number of mammary tumors in 1-methyl-1- nitrosourea (MNU)-induced mammary carcinogenesis and also increased incidence and multiplicity of mammary tumors in MMTV-neu/HER2 transgenic mice [56
]. On the contrary, silibinin treatment was shown to strongly inhibit development of mammary tumors as well as lung metastasis in HER-2/neu transgenic mice [57
]. Further studies are needed to clearly understand the effect of silymarin and its active constituents against mammary carcinogenesis.
Anticancer effects of silymarin have also been reported in ovarian cancer xenograft models. Gallo et al [40
] have found that administration of Silipide by oral gavage to nude mice bearing tumor xenograft of human ovarian cancer cell line A2780 produces significant tumor inhibition, and the downregulation of VEGF receptor 3 and upregulationof angiopoietin-2 was the possible mechanisms for the antiangiogenic activity. Giacomelli et al [58
] have shown that Silipide was able to potentiate the cytotoxicity of anticancer drug cisplatin (CDDP) under in vitro
conditions, whereas under in vivo
conditions, administration of Silipide significantly enhanced the anti-tumor activity of CDDP in mice along with alleviating the toxicity associated with CDDP.
Anticancer effects of silibinin have been reported in renal cell carcinoma where oral administration of silibinin was found to suppress the growth of local and metastatic tumors in xenograft model of renal cell carcinoma by increasing the plasma levels of IGFBP-3, a binding protein for IGF-1 [59
]. Yanaida et al [60
] have demonstrated that dietary administration of silymarin suppresses 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats by inhibiting cell proliferation and increased apoptotic index. They also found that silymarin decreases the polyamine content and PGE2 level, and that it modifies phase II enzymes’ activity. Overall, these studies strongly suggest the cancer chemopreventive efficacy of silymarin and/or silibinin, and provide a strong rationale for their use in the clinical trials.