Carcinogenesis Advance Access originally published online on March 7, 2007
Carcinogenesis 2007 28(7):1446-1454; doi:10.1093/carcin/bgm040
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The suppression of aberrant crypt multiplicity in colonic tissue of 1,2-dimethylhydrazine-treated C57BL/6J mice by dietary flavone is associated with an increased expression of Krebs cycle enzymes
Molecular Nutrition Unit, Department of Food and Nutrition, Technical University of Munich, Am Forum 5, D-85350 Freising, Germany
1 Institute of Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilian-University of Munich, Feodor-Lynen-Strasse 25, D-81377 Munich, Germany
2 Institute of Toxicology, GSF-National Research Center for Environment and Health, Ingolstädter Landstrasse 1, D-85764 Neuherberg, Germany
3 Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany
* To whom correspondence should be addressed. Tel: +49 641/99-39220; Fax: +49 641/99-39229; Email: uwe.wenzel{at}ernaehrung.uni-giessen.de
Colorectal cancer is the second leading cause of cancer deaths worldwide with diet playing a prominent role in disease initiation and progression. Flavonoids are secondary plant compounds that are suggested as protective ingredients of a diet rich in fruits and vegetables. We here tested whether flavone, a flavonoid that proved to be an effective apoptosis inducer in colon cancer cells in culture, can affect the development of aberrant crypt foci (ACFs) in C57BL/6J mice in vivo when preneoplastic lesions were induced by the carcinogen 1,2-dimethylhydrazine (DMH). Flavone applied at either a low dose (15 mg/kg body wt per day) or a high dose (400 mg/kg body wt per day) reduced the numbers of ACFs significantly, independent of whether it was supplied simultaneously with the carcinogen (blocking group) or subsequent to the tumor induction phase (suppressing group). Proteome analysis performed in colonic tissue samples revealed that flavone treatment increased the expression of a number of Krebs cycle enzymes in the suppressing group and this was associated with reduced crypt multiplicity. It suggests that mitochondrial substrate oxidation is increased by flavone in colonic cells in vivo as already observed in HT-29 cells in vitro as the prime mechanism underlying tumor cell apoptosis induction by flavone. In conclusion, flavone reduces the number of ACFs in DMH-treated mice at doses that can be achieved for flavonoids by a diet rich in fruits and vegetables. Moreover, reduction in crypt multiplicity by flavone is most probably due to the preservation of a normal oxidative metabolism.
Abbreviations: AC, aberrant crypt; ACF, aberrant crypt focus; DMH, 1,2-dimethylhydrazine; IPG, immobilized pH gradient; ROS, reactive oxygen species
Received November 23, 2006; revised February 5, 2007; accepted February 9, 2007.