Flavone induces changes in intermediary metabolism that prevent microadenoma formation in colonic tissue of carcinogen-treated mice.
METHODS
Colorectal cancer is a major cause of cancer deaths worldwide with the need for improved therapeutics and adjuvants.


RESULTS
We here tested whether the secondary plant compound flavone affects the development of aberrant crypt foci and microadenomas triggered in C57BL/6J mice by 1,2-dimethylhydrazine. Ten weeks after the last 1,2-dimethylhydrazine injection, flavone was applied at 400 mg/kg body weight over 4 wk by gavage. Flavone was found to increase apoptosis and to reduce the rate of proliferation and aberrant crypt formation. More importantly, development of microadenomas was completely suppressed by flavone. Proteome analysis by 2-DE with mass spectrometric identification of regulated proteins suggests a downregulation of tricarboxylic acid cycle activity in colonocytes with compensation by increased FADH(2) production via a partial beta-oxidation of long-chain fatty acids to meet energy demands. Transcriptome analysis, using a Gene Chip expression array with 24,000 gene probes confirmed the proteome data and moreover revealed the increased expression of various solute transporters, suggesting increased substrate supply to be used for tricarboxylic acid cycle-independent energy production.


CONCLUSIONS
In conclusion, changes in the levels of proteins from intermediary metabolism or their encoding mRNAs are linked to flavone-induced apoptosis and the prevention of microadenoma formation in transformed colonocytes of mice.
Winkelmann
Isabel
I
Department of Food and Nutrition, Technical University of Munich, Freising, Germany.
Diehl
Daniela
D
Oesterle
Doris
D
Daniel
Hannelore
H
Wenzel
Uwe
U
D019813:1,2-Dimethylhydrazine / Q000633:toxicity; D058739:Aberrant Crypt Foci / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000236:Adenoma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D002952:Citric Acid Cycle / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D047309:Flavones / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D020543:Proteome / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000972:Antineoplastic Agents, Phytogenic; D002273:Carcinogens; D047309:Flavones; D020543:Proteome; D012333:RNA, Messenger; D019813:1,2-Dimethylhydrazine; C043562:flavone