Carcinogenesis Advance Access published online on September 7, 2007
Carcinogenesis, doi:10.1093/carcin/bgm198
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Apple Procyanidins Induce Tumor-Cell Apoptosis through Mitochondrial Pathway Activation of Caspase-3
1 Department of Medical Technology, Hirosaki University School of Health Sciences, Aomori, Japan
2 Fundamental Research Laboratory, ASAHI Breweries, LTD, Ibaraki, Japan
* To whom correspondence should be addressed at: Tomisato Miura, Department of Medical Technology, Hirosaki University School of Health Sciences, 66-1, Hon-cho, Hirosaki, Aomori 036-8564, Japan Tel: +81-172-39-5966; E-mail: tomisato{at}cc.hirosaki-u.ac.jp, and Toshihiko Shoji, Fundamental Research Laboratory, ASAHI Breweries, LTD, 1-21 Midori 1-chome, Moriya, Ibaraki 302-0106, Japan Tel: +81-297-46-1504; E-mail: toshihiko.shoji{at}asahibeer.co.jp.
Various epidemiologic and experimental in vivo and in vitro studies have suggested that polyphenols derived from fruits, vegetables, and beverages might decrease the risk of developing life-style diseases, such as cardiovascular disorders and cancer. Apples are a major dietary source of polyphenols. Here we investigated the anti-tumor activity of apple polyphenols and procyanidins, namely condensed tannins, both in vitro and in vivo studies. The apple polyphenols and procyanidins inhibited the growth of transplanted B16 mouse melanoma cells and BALB–MC.E12 mouse mammary tumor cells, and increased the survival rate of the host mice transplanted B16 cells. Among the apple polyphenols, the apple procyanidins specifically, rather than other polyphenols such as chlorogenic acid, (–)-epicatechin, phloridzin and procyanidin B2, had a major effect on cell proliferation, and induced apoptosis in vitro. The apple procyanidins increased mitochondrial membrane permeability and cytochrome c release from mitochondria, and activated caspase-3 and caspase-9 within the tumor cells. In addition, we separated eight procyanidin fractions according to the degree of polymerization using normal-phase chromatography, and detected strong anti-apoptotic activity in the procyanidin pentamer and higher degree fractions. Our results indicate that the oral administration of apple procyanidins inhibits the proliferation of tumor cells by inducing apoptosis through the intrinsic mitochondrial pathway.
Key Words: apple procyanidin • caspase • cytochrome c • mitochondrial membrane • tumor-cell apoptosis
Received June 11, 2007; revised August 16, 2007; accepted August 18, 2007.