Polyethylene glycol inhibits intestinal neoplasia and induces epithelial apoptosis in Apc(min) mice.
Efficacy of a safe and clinically utilized polyethylene glycol formulation (PEG-3350) to suppress intestinal tumors was investigated in the Apc(min) mouse-model of experimental carcinogenesis. Furthermore, based on our previous finding on the induction of apoptosis in HT-29 cells by PEG, we evaluated its ability to stimulate epithelial cell apoptosis in both Apc(min) mouse as well as AOM-treated rat as a potential molecular mechanism of chemoprevention. Twenty-two Apc(min) mice were randomized equally to PEG or vehicle (control) supplementation. Tumors were scored and uninvolved intestinal mucosal apoptosis was assayed using a modified terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) assay and by immunohistochemical detection of cleaved caspase-3. Supplementation of Apc(min) mice with 10% PEG 3350 (in drinking water) resulted in a 48% (P<0.05) reduction in intestinal tumor burden and induced 2-3 fold increase in mucosal apoptosis. Dietary supplementation of polyethylene glycol (5%) also stimulated colonic mucosal apoptosis 4-5 fold in AOM-treated rats, the regimen that we previously reported to reduce tumor burden by 76% (P<0.05). In summary, we demonstrate, for the first time, that PEG does protect against Apc(min) mouse tumorigenesis. The correlation between pro-apoptotic actions and chemopreventive efficacy of PEG in these models strongly implicates induction of apoptosis as one of the impending mechanisms of chemoprevention.
Roy
Hemant K
HK
Department of Medicine, Evanston-Northwestern Healthcare Research Institute, 1001 University Place, Evanston, IL 60201, USA.
Gulizia
James
J
DiBaise
John K
JK
Karolski
William J
WJ
Ansari
Sajid
S
Madugula
Madhavi
M
Hart
John
J
Bissonnette
Marc
M
Wali
Ramesh K
RK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001397:Azoxymethane / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D019587:Dietary Supplements; D004847:Epithelial Cells / Q000187:drug effects*; D017491:Genes, APC / Q000502:physiology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D013501:Surface-Active Agents / Q000627:therapeutic use*; D014867:Water
D002273:Carcinogens; D013501:Surface-Active Agents; D014867:Water; D011092:Polyethylene Glycols; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D001397:Azoxymethane