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Anticarcinogenic effect of a flavonoid antioxidant, silymarin, in human breast cancer cells MDA-MB 468: induction of
1Department of Dermatology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Abstract:
There is an increasing interest in identifying potent cancer preventive and therapeutic agents against breast cancer. Silymarin, a flavonoid antioxidant isolated from milk thistle, exerts exceptionally high to complete anticarcinogenic effects in tumorigenesis models of epithelial origin. In this study, we investigated the anticarcinogenic effect of silymarin and associated molecular mechanisms, using human breast carcinoma cells MDA-MB 468. Silymarin treatment resulted in a significantly high to complete inhibition of both anchorage-dependent and anchorage-independent cell growth in a dose- and time-dependent manner. The inhibitory effects of silymarin on cell growth and proliferation were associated with a G1 arrest in cell cycle progression concomitant with an induction of up to 19-fold in the protein expression of cyclin-dependent kinase (CDK) inhibitor Cip1/p21. Following silymarin treatment of cells, an incremental binding of Cip1/p21 with CDK2 and CDK6 paralleled a significant decrease in CDK2-, CDK6-, cyclin D1-, and cyclin E-associated kinase activity with no change in CDK2 and CDK6 expression but a decrease in G1 cyclins D1 and E. Taken together, these results suggest that silymarin may exert a strong anticarcinogenic effect against breast cancer and that this effect possibly involves an induction of Cip1/p21 by silymarin, which inhibits the threshold kinase activities of CDKs and associated cyclins, leading to a G1 arrest in cell cycle progression.
Insights
Silymarin, a milk thistle extract, effectively inhibits breast cancer cell growth by halting cell cycle progression. This natural compound shows promise as a potent cancer preventive and therapeutic agent.
Area of Science:
- Phytochemistry
- Molecular Biology
- Cancer Research
Background:
- Increasing interest in natural compounds for cancer prevention and therapy.
- Silymarin, a flavonoid from milk thistle, demonstrates significant anticarcinogenic effects in epithelial models.
Purpose of the Study:
- To investigate the anticarcinogenic effects of silymarin on human breast carcinoma cells (MDA-MB 468).
- To elucidate the molecular mechanisms underlying silymarin's anti-cancer activity.
Main Methods:
- Treatment of MDA-MB 468 cells with silymarin.
- Assessment of cell growth (anchorage-dependent and -independent).
- Analysis of cell cycle progression, protein expression (CDK inhibitor Cip1/p21), and kinase activity (CDK2, CDK6, cyclins D1, E).
Main Results:
- Silymarin significantly inhibited breast cancer cell growth in a dose- and time-dependent manner.
- Silymarin induced G1 cell cycle arrest, upregulating Cip1/p21 protein expression by 19-fold.
- Cip1/p21 binding increased with CDK2 and CDK6, decreasing their kinase activity and that of cyclins D1 and E.
Conclusions:
- Silymarin exhibits a potent anticarcinogenic effect against breast cancer.
- The mechanism involves silymarin-induced Cip1/p21, which inhibits CDK/cyclin activity, leading to G1 cell cycle arrest.