Promotion versus suppression of rat colon carcinogenesis by chlorophyllin and chlorophyll: Modulation of apoptosis, cell proliferation, and β-catenin/Tcf signaling

Carmen A. Blum, Meirong Xu, Gayle A. Orner, G. Darío Díaz, Qingjie Li, Wan Mohaiza Dashwood, George S. Bailey, Roderick H. Dashwood

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

The carcinogens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 1,2-dimethylhydrazine (DMH) induce colon tumors in the rat that contain mutations in β-catenin, but the mutation pattern can be influenced by exposure to dietary phytochemicals, such as the water-soluble derivative of chlorophyll called chlorophyllin. Whereas chlorophyllin is an effective blocking agent during the initiation phase, post-initiation responses depend upon the exposure protocol, and can be influenced by the initiating agent and the concentration of chlorophyllin. Post-initiation treatment with 0.001% chlorophyllin (w/v) in the drinking water promoted colon carcinogenesis in the rat, but much higher concentrations (1.0% chlorophyllin) led to suppression. Bromodeoxyuridine and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) indices revealed that the promotional concentration of 0.001% chlorophyllin increased the ratio of cell proliferation to apoptosis in the colonic crypts, whereas concentrations in the range 0.0l-1.0% chlorophyllin modestly reduced this ratio. Molecular studies showed that the spectrum of β-catenin mutations was markedly different in chlorophyllin-promoted colon tumors - many of the mutations led to direct substitutions of critical Ser/Thr residues within the glycogen synthase kinase-3β (GSK-3β) region, whereas in all other groups, including DMH and IQ controls, the mutations typically affected amino acids adjacent to Ser33. Substitution of critical Ser/Thr residues caused β-catenin and c-Jun proteins to be markedly over-expressed compared with tumors in which the mutations substituted amino acid residues flanking these critical Ser/Thr sites. In a separate study, rats were exposed to IQ or azoxymethane (AOM), a metabolite of DMH, and they were treated post-initiation with chlorophyllin, chlorophyll, copper, or phytol in the diet. Natural chlorophyll (0.08%) suppressed AOM- and IQ-induced aberrant crypt foci (ACF), whereas chlorophyllin had no effect and copper promoted the number of small ACF induced by IQ. The results suggest that further investigation of the dose-response for suppression versus promotion by chlorophyll and chlorophyllin is warranted, including studies of the β-catenin/Tcf signaling pathway and its influence on cell proliferation and apoptosis in the colonic crypt.

Original languageEnglish (US)
Pages (from-to)217-223
Number of pages7
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume523-524
DOIs
StatePublished - Jan 1 2003

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Keywords

  • 1,2-Dimethylhydrazine
  • 2-Amino-3-methylimidazo [4,5-f]quinoline (IQ)
  • Aberrant crypt foci
  • Apoptosis
  • Azoxymethane
  • Colon tumors
  • β-Catenin

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Health, Toxicology and Mutagenesis

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