Polyethylene glycol inhibits intestinal neoplasia and induces epithelial apoptosis in Apcmin mice

Roy, Hemant K.; Gulizia, James M.; DiBaise, John K.; Karolski, William J.; Ansari, Sajid Ali; Madugula, Madhavi; Hart, John; Bissonnette, Marc; Wali, Ramesh K.

doi:10.1016/j.canlet.2004.05.012

Cited by 19 publications

(20 citation statements)

References 18 publications

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“…1, PEG significantly decreased tumorigenesis by 76% (P < 0.001), total ACF by 74% (P < 0.001), and complex ACF by 64% (P < 0.001; n = 12 from each group). These results are in agreement with numerous other reports showing remarkable efficacy of PEG in suppressing ACF and tumor development (17,35).…”

Section: Peg Inhibits Initiation Of Colon Carcinogenesis In Azoxymethsupporting

confidence: 93%

“…Our results from the cell culture, in keeping with the study from Corpet's laboratory (26), indicate that PEG has a marked cytoprotective effect. Furthermore, antiproliferative effect of PEG complements its proapoptotic effect that we have previously reported in cell culture, azoxymethane-treated rat, and the MIN mouse (17,41).…”

Section: Discussionsupporting

confidence: 71%

“…Epidermal growth factor receptor is known to induce SNAIL (49). Another point that needs to be emphasized is that whereas our article focuses on proliferation, we have previously shown that PEG also induces apoptosis in animal models and cell culture (17,41). Clearly, both SNAIL and h-catenin have important effects on apoptosis.…”

Section: Discussionmentioning

confidence: 86%

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Chemoprevention of colon carcinogenesis by polyethylene glycol: suppression of epithelial proliferation via modulation of SNAIL/β-catenin signaling

Roy

Kunte

Koetsier

et al. 2006

Molecular Cancer Therapeutics

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Polyethylene glycol (PEG) is one of the most potent chemopreventive agents against colorectal cancer; however, the mechanisms remain largely unexplored. In this study, we assessed the ability of PEG to target cyclin D1 -B-catenin -mediated hyperproliferation in the azoxymethane-treated rat model and the human colorectal cancer cell line, HT-29. Azoxymethane-treated rats were randomized to AIN-76A diet alone or supplemented with 5% PEG-8000. After 30 weeks, animals were euthanized and biopsies of aberrant crypt foci and uninvolved crypts were subjected to immunohistochemical and immunoblot analyses. PEG markedly suppressed both early and late markers of azoxymethane-induced colon carcinogenesis (fractal dimension by 80%, aberrant crypt foci by 64%, and tumors by 74%). In both azoxymethane-treated rats and HT-29 cells treated with 5% PEG-3350 for 24 hours, PEG decreased proliferation (45% and 52%, respectively) and cyclin D1 (78% and 56%, respectively). Because B-catenin is the major regulator of cyclin D1 in colorectal cancer, we used the T-cell factor (Tcf) -TOPFLASH reporter assay to show that PEG markedly inhibited B-catenin transcriptional activity. PEG did not alter total B-catenin expression but rather its nuclear localization, leading us to assess E-cadherin expression (a major determinant of B-catenin subcellular localization), which was increased by 73% and 71% in the azoxymethane-rat and HT-29 cells, respectively. We therefore investigated the effect of PEG treatment on levels of the negative regulator of E-cadherin, SNAIL, and observed a 50% and 75% decrease, respectively. In conclusion, we show, for the first time, a molecular mechanism through which PEG imparts its antiproliferative and hence profound chemopreventive effect.

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Section: Peg Inhibits Initiation Of Colon Carcinogenesis In Azoxymethsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 71%

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Chemoprevention of colon carcinogenesis by polyethylene glycol: suppression of epithelial proliferation via modulation of SNAIL/β-catenin signaling

Roy

Kunte

Koetsier

et al. 2006

Molecular Cancer Therapeutics

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“…To keep these results in perspective, PEG outperformed all other chemopreventive agents including well established agents such as NSAIDs. Our group confirmed that this was not model-specific by demonstrating the efficacy of PEG 3350 in the MIN (multiple intestinal neoplasias) mouse model, a genetically driven model of intestinal neoplasia (23). While definitive (randomized placebo-controlled) studies are ongoing, it is heartening to note a 52% neoplasia risk reduction with PEG in a casecontrol study (15).…”

Section: Discussionmentioning

confidence: 59%

Involvement of p21cip1/waf1 in the anti-proliferative effects of polyethylene glycol in colon carcinogenesis

Roy

Koetsier²,

Tiwari³

et al. 2011

Int J Oncol

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Abstract. Polyethylene glycol (PEG) is a safe and effective chemopreventive agent against colorectal carcinogenesis in cell culture, animal models and human subjects. Although the precise molecular mechanism is unclear, we previously reported that PEG suppresses colonic epithelial proliferation. As cellular proliferation is driven by complex G1-S phase transition, we now characterize the role of PEG on cell cycle regulation. We focused our attention on the effect of PEG on the CDK inhibitor p21 cip1/waf1 , which is implicated in early colon carcinogenesis and is upregulated by non-steroidal anti-inflammatory drugs. These studies were done in the azoxymethane-treated (AOM) rat model as well as in HT-29 colon cancer cells. Immunohistochemical analysis revealed that while AOM decreased the p21 expression (75%, p<0.01) in the premalignant colonic mucosa, PEG induced p21 levels back to normal. These findings paralleled a decreased BrdUrd incorporation (78%, p<0.001) and hypophosphorylated retinoblastoma protein (Rb; by 47%) signifying PEG's antiproliferative activity. Furthermore, in HT-29 cells, PEG decreased proliferation as measured by PCNA (68% reduction), increased p21 expression (2.3-fold), induced cell cycle arrest during G0/G1 phase (45% reduction in S phase cells) and inhibited the phosphorylation of Rb (by 52% compared to untreated). PEG caused greater than a 2-fold induction of protein and mRNA level of p21 cip1/waf1 in HT-29 cells. These results demonstrate for the first time that PEG is involved in p21 regulation concomitant with G1➝S phase cell cycle arrest and it is through these effects that it can exert its anti-proliferative and hence chemopreventive role.

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“…O medicamento polietilenoglicol tem a capacidade de reprimir EGFR, funcionando como um quimiopreventivo eficaz contra o câncer colorretal (158)(159)(160) .…”

Section: Ciclina D1unclassified

Análise da expressão e mecanismos de ação das proteínas Akt, Hsp90, mTOR e ciclina D1 em cultura de células de carcinoma epidermoide humano e células displásicas após irradiação com laser em baixa intensidade

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Polyethylene glycol inhibits intestinal neoplasia and induces epithelial apoptosis in Apcmin mice

Cited by 19 publications

References 18 publications

Chemoprevention of colon carcinogenesis by polyethylene glycol: suppression of epithelial proliferation via modulation of SNAIL/β-catenin signaling

Chemoprevention of colon carcinogenesis by polyethylene glycol: suppression of epithelial proliferation via modulation of SNAIL/β-catenin signaling

Involvement of p21cip1/waf1 in the anti-proliferative effects of polyethylene glycol in colon carcinogenesis

Análise da expressão e mecanismos de ação das proteínas Akt, Hsp90, mTOR e ciclina D1 em cultura de células de carcinoma epidermoide humano e células displásicas após irradiação com laser em baixa intensidade

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