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Growth Inhibitory and Antimetastatic Effect of Green Tea Polyphenols on Metastasis-Specific Mouse Mammary Carcinoma 4T1 Cells In vitro and In vivo Systems

Departments of ¹ Dermatology, ² Comprehensive Cancer Center, ³ Clinical Nutrition Research Center, and ⁴ Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, Alabama

Requests for reprints: Santosh K. Katiyar, Department of Dermatology, University of Alabama at Birmingham, 1670, University Boulevard, Volker Hall 557, P.O. Box 202, Birmingham, AL 35294. Phone: 205-975-2608; Fax: 205-934-5745; E-mail: skatiyar{at}uab.edu.

Purpose: Breast cancer is the second leading cause of cancer-related deaths among females. Dietary habits may have a role in breast cancer risk and prevention as well. Here, we examined the effect of green tea polyphenols (GTP) on growth and metastasis of highly metastatic mouse mammary carcinoma 4T1 cells in vitro and in vivo systems.

Experimental Design: 4T1 cells were treated with (–)-epigallocatechin-3-gallate (EGCG), and the effect was determined on cellular proliferation, induction of apoptosis, proapoptosis, and antiapoptotic proteins of Bcl-2 family, and caspase 3 and poly(ADP-ribose) polymerase activation following 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry, and Western blot analysis. Anticarcinogenic and antimetastatic effect of GTP in 4T1 cells was assessed in immunocompetent BALB/c mice.

Results: Treatment of 4T1 cells with EGCG resulted in inhibition of cell proliferation, induction of apoptosis in dose- and time-dependent manner. The increase in apoptosis was accompanied with decrease in the protein expression of Bcl-2 concomitantly increase in Bax, cytochrome c release, Apaf-1, and cleavage of caspase 3 and PARP proteins. Treatment of EGCG-rich GTP in drinking water to 4T1 cells bearing BALB/c mice resulted in reduction of tumor growth accompanied with increase in Bax/Bcl-2 ratio, reduction in proliferating cell nuclear antigen and activation of caspase 3 in tumors. Metastasis of tumor cells to lungs was inhibited and survival period of animals was increased after green tea treatment.

Conclusion: This study suggests that GTP have the ability to prevent the development of breast cancer and its metastasis; however, further in vivo studies are required to identify the molecular targets.

Key Words: breast cancer • chemoprevention • antimetastasis • green tea polyphenols • epigallocatechin-3-gallate • apoptosis • 4T1 cells

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