Carcinogenesis Advance Access published online on April 5, 2006
Carcinogenesis, doi:10.1093/carcin/bgl030
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1 Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
* To whom correspondence should be addressed. The strategies available for the treatment of metastatic breast cancer are limited. Dietary botanicals may have a better chemotherapeutic effect on this disease. We therefore investigated the effects of grape seed proanthocyanidins (GSPs) on a highly metastatic mouse mammary carcinoma cell line. In vitro treatment of 4T1 cells with GSPs resulted in significant inhibition of cellular proliferation and viability, and induction of apoptosis in a time- and dose-dependent manner. Further analysis indicated an alteration in the ratio of Bax/Bcl-2 proteins in favor of apoptosis, and the knockdown of Bax using Bax siRNA transfection of 4T1 cells resulted in blocking of GSPs-induced apoptosis. Induction of apoptosis was associated with the release of cytochrome c, increased expression of Apaf-1 and activation of caspase-3 and poly (ADP-ribose) polymerase. Treatment with the pan-caspase inhibitor (Z-VAD-FMK) resulted in partial but significant inhibition of apoptosis in 4T1 cells suggesting the involvement of both caspase activation-dependent and -independent pathways in the apoptosis of 4T1 cells induced by GSPs. The effects of dietary GSPs were then examined using an in vivo model in which 4T1 cells were implanted subcutaneously in Balb/c mice. Dietary GSPs (0.2 and 0.5%, w/w) significantly inhibited the growth of the implanted 4T1 tumor cells and increased the ratio of Bax:Bcl-2 proteins, cytochrome c release, induction of Apaf-1 and activation of caspase-3 in the tumor microenvironment. Notably, the metastasis of tumor cells to the lungs was inhibited significantly and the survival of the mice enhanced. These data suggest that GSPs possess chemotherapeutic efficacy against breast cancer including inhibition of metastasis.
Received January 4, 2006
Revised February 26, 2006
Accepted March 19, 2006
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Grape seed proanthocyanidins induce apoptosis and inhibit metastasis of highly metastatic breast carcinoma cells
Sudheer K. Mantena 1,
Manjeshwar S. Baliga 1,
and
Santosh K. Katiyar 2 *
2 Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Clinical Nutrition Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Santosh K. Katiyar, E-mail: skatiyar{at}uab.edu
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