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Carcinogenesis Advance Access originally published online on September 7, 2007
Carcinogenesis 2008 29(3):585-593; doi:10.1093/carcin/bgm198
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Apple procyanidins induce tumor cell apoptosis through mitochondrial pathway activation of caspase-3

Tomisato Miura*, Mitsuru Chiba, Kosuke Kasai, Hiroyuki Nozaka, Toshiya Nakamura, Toshihiko Shoji1, Tomomasa Kanda1, Yasuyuki Ohtake1 and Tatsusuke Sato

Department of Pathologic analysis, Hirosaki University Graduate School of Health Sciences, 66-1, Hon-cho, Hirosaki, Aomori 036-8564, Japan
1 Fundamental Research Laboratory, ASAHI Breweries, Ltd, 1-21 Midori 1-chome, Moriya, Ibaraki 302-0106, Japan

* To whom correspondence should be addressed. Tel: +81 172 39 5966; Fax: +81 172 39 5966; Email: tomisato{at}cc.hirosaki-u.ac.jp

Correspondence may also be addressed to Toshihiko Shoji. Tel: +81 297 46 1504; Fax: +81 297 46 1506;Email: 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 lifestyle diseases, such as cardiovascular disorders and cancer. Apples are a major dietary source of polyphenols. Here we investigated the antitumor activity of apple polyphenols (APs) and procyanidins, namely condensed tannins, both in vitro and in vivo studies. APs 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 APs, 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-tumor 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.

Abbreviations: ACT, apple condensed tannin; AP, apple polyphenol; PBS, phosphate-buffered saline; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling

Received June 11, 2007; revised August 16, 2007; accepted August 18, 2007.


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