Jifu Zhao

Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: comparison with silymarin.

Several studies from our laboratory have shown the cancer chemopreventive and anti-carcinogenic effects of silymarin, a flavonoid antioxidant isolated from milk thistle, in long-term tumorigenesis models and in human prostate, breast and cervical carcinoma cells. Since silymarin is composed mainly of silibinin with small amounts of other stereoisomers of silibinin, in the present communication, studies were performed to assess whether the cancer preventive and anti-carcinogenic effects of silymarin are due to its major component silibinin. Treatment of different prostate, breast, and cervical human carcinoma cells with silibinin resulted in a highly significant inhibition of both cell growth and DNA synthesis in a time-dependent manner with large loss of cell viability only in case of cervical carcinoma cells. When compared with silymarin, these effects of silibinin were consistent and comparable in terms of cell growth and DNA synthesis inhibition, and loss of cell viability. Based on the comparable results of silibinin and silymarin, we suggest that the cancer chemopreventive and anti-carcinogenic effects of silymarin reported earlier are due to the main constituent silibinin.

Significant inhibition by the flavonoid antioxidant silymarin against 12-O-tetradecanoylphorbol 13-acetate–caused modulation of antioxidant and inflammatory enzymes, and cyclooxygenase 2 and interleukin-1α expression in SENCAR mouse epidermis: Implications in the prevention of stage I tumor promotion

The flavonoid antioxidant silymarin is used clinically in Europe and Asia for the treatment of liver diseases and is sold in the United States and Europe as a dietary supplement. Recently we showed that silymarin possesses exceptionally high cancer‐preventive effects in different mouse skin carcinogenesis models and affords strong anticancer effects in human skin, cervical, prostate, and breast carcinoma cells. More recently, we showed that the anti–tumor‐promoting effect of silymarin is primarily targeted against stage I tumor promotion in mouse skin (Cancer Res 1999;59:622–632). Based on this recent study, in this report, further investigations were made to identify and define the biochemical and molecular mechanisms of silymarins effect during stage I tumor promotion in mouse skin. A single topical application of silymarin at 3‐, 6‐, and 9‐mg doses onto SENCAR mouse skin followed 30 min later with 12‐O‐tetradecanoylphorbol 13‐acetate (TPA) at a 3‐μg dose resulted in a 76–95% inhibition (P < 0.001) of TPA‐caused skin edema. Similarly, these doses of silymarin also showed 39–90%, 29–85%, and 15–67% protection (P < 0.05 or 0.001), against TPA‐caused depletion of epidermal superoxide dismutase, catalase, and glutathione peroxidase activity, respectively. Pretreatment of mice with silymarin also produced highly significant inhibition of TPA‐caused induction of epidermal lipid peroxidation (47–66% inhibition, P < 0.001) and myeloperoxidase activity (56–100% inhibition, P < 0.001). In additional studies assessing the effect of silymarin on arachidonic acid metabolism pathways involving lipoxygenase and cyclooxygenase (COX), similar doses of silymarin showed highly significant inhibition of TPA‐caused induction of epidermal lipoxygenase (49–77% inhibition, P < 0.001) and COX (35–64% inhibition, P < 0.01 or 0.001) activity. Western immunoblot analysis showed that the observed effect of silymarin on COX activity was due to inhibition of TPA‐inducible COX‐2 with no change in constitutive COX‐1 protein levels. In other studies, silymarin also showed dose‐dependent inhibition of TPA‐caused induction of epidermal interleukin 1α (IL‐1α) protein (39–72% inhibition, P < 0.005 or 0.001) and mRNA expression. Taken together, the results from these biochemical and molecular studies further substantiate our recent observation of silymarins anti–tumor‐promoting effects primarily at stage I tumor promotion. Furthermore, the observed inhibitory effects of silymarin on COX‐2 and IL‐1α should be further explored to develop preventive strategies against those cancers in which these molecular targets play one of the causative roles, such as non‐melanoma skin, colon, and breast cancers in humans. Mol. Carcinog. 26:321–333, 1999.