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 Citations (Scopus)

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 - Feb 2003
Externally publishedYes

Fingerprint

Catenins
Chlorophyll
Colon
Carcinogenesis
Cell Proliferation
Apoptosis
Mutation
Dimethylhydrazines
Aberrant Crypt Foci
Azoxymethane
2-amino-3-methylimidazo(4,5-f)quinoline
chlorophyllin
Phytol
Proto-Oncogene Proteins c-jun
1,2-Dimethylhydrazine
Glycogen Synthase Kinase 3
Amino Acids
Neoplasms
DNA Nucleotidylexotransferase
In Situ Nick-End Labeling

Keywords

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

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Molecular Biology

Cite this

Promotion versus suppression of rat colon carcinogenesis by chlorophyllin and chlorophyll : Modulation of apoptosis, cell proliferation, and β-catenin/Tcf signaling. / Blum, Carmen A.; Xu, Meirong; Orner, Gayle A.; Díaz, G. Darío; Li, Qingjie; Dashwood, Wan Mohaiza; Bailey, George S.; Dashwood, Roderick H.

In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 523-524, 02.2003, p. 217-223.

Research output: Contribution to journalArticle

Blum, Carmen A. ; Xu, Meirong ; Orner, Gayle A. ; Díaz, G. Darío ; Li, Qingjie ; Dashwood, Wan Mohaiza ; Bailey, George S. ; Dashwood, Roderick H. / Promotion versus suppression of rat colon carcinogenesis by chlorophyllin and chlorophyll : Modulation of apoptosis, cell proliferation, and β-catenin/Tcf signaling. In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. 2003 ; Vol. 523-524. pp. 217-223.
@article{149d365c9a1a45bc8d5551553158e5b0,
title = "Promotion versus suppression of rat colon carcinogenesis by chlorophyllin and chlorophyll: Modulation of apoptosis, cell proliferation, and β-catenin/Tcf signaling",
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.",
keywords = "β-Catenin, 1,2-Dimethylhydrazine, 2-Amino-3-methylimidazo [4,5-f]quinoline (IQ), Aberrant crypt foci, Apoptosis, Azoxymethane, Colon tumors",
author = "Blum, {Carmen A.} and Meirong Xu and Orner, {Gayle A.} and D{\'i}az, {G. Dar{\'i}o} and Qingjie Li and Dashwood, {Wan Mohaiza} and Bailey, {George S.} and Dashwood, {Roderick H.}",
year = "2003",
month = "2",
doi = "10.1016/S0027-5107(02)00338-X",
language = "English (US)",
volume = "523-524",
pages = "217--223",
journal = "Mutation Research",
issn = "0027-5107",
publisher = "Elsevier",

}

TY - JOUR

T1 - Promotion versus suppression of rat colon carcinogenesis by chlorophyllin and chlorophyll

T2 - Modulation of apoptosis, cell proliferation, and β-catenin/Tcf signaling

AU - Blum, Carmen A.

AU - Xu, Meirong

AU - Orner, Gayle A.

AU - Díaz, G. Darío

AU - Li, Qingjie

AU - Dashwood, Wan Mohaiza

AU - Bailey, George S.

AU - Dashwood, Roderick H.

PY - 2003/2

Y1 - 2003/2

N2 - 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.

AB - 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.

KW - β-Catenin

KW - 1,2-Dimethylhydrazine

KW - 2-Amino-3-methylimidazo [4,5-f]quinoline (IQ)

KW - Aberrant crypt foci

KW - Apoptosis

KW - Azoxymethane

KW - Colon tumors

UR - http://www.scopus.com/inward/record.url?scp=0037294022&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037294022&partnerID=8YFLogxK

U2 - 10.1016/S0027-5107(02)00338-X

DO - 10.1016/S0027-5107(02)00338-X

M3 - Article

VL - 523-524

SP - 217

EP - 223

JO - Mutation Research

JF - Mutation Research

SN - 0027-5107

ER -