-
[show abstract]
[hide abstract]
ABSTRACT: Retinoid X receptor (RXR) has been implicated in several neoplastic diseases. Previously, we have shown that RXR-α is downregulated in human and rodent colonic tumors, suggesting a potential target for colon cancer prevention (http://www.cancer.org/Cancer/ColonandRectumCancer/DetailedGuide/colorectal-cancer-key-statistics). Experiments were designed to assess the chemopreventive efficacy of the selective RXR agonist bexarotene for the suppression of intestinal tumorigenesis in Apc(Min/+) mice. Before the efficacy studies, we determined that the maximal tolerated dose in C57BL/6J mice was less than 400 ppm. For the efficacy study, 6-week-old male and female C57BL/6J-Apc(Min/+) mice (nine mice per group) were fed diets containing 0, 30, and 60 ppm of bexarotene or 200 ppm of bexarotene for 80 days before intestinal tumors were evaluated. Dietary administration of 30 and 60 ppm of bexarotene suppressed the intestinal polyp formation by 38% (P < .015) and 60% (P < .0001) in males, respectively, and by 8.5% and 37% (P < .007) in females, respectively. Also, significant inhibition (50%-100%) of colonic tumor formation was observed in both male and female mice with bexarotene treatment. Administration of 200 ppm of bexarotene showed significant suppression of tumor formation (66%, P < .0001); however, it had significant toxicity. Intestinal tumors of bexarotene-fed mice showed significantly reduced expression of proliferating cell nuclear antigen (60%, P < .0001), cyclin D1, and cyclooxygenase 2 and increased RXR-α messenger RNA and uptake of oleate (34%, P < .01). Also, bexarotene-fed mice showed dose-dependent suppression of serum triglycerides (25%-72%, P < .0001) and inflammatory cytokines.
Neoplasia (New York, N.Y.) 02/2012; 14(2):159-68. · 5.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Pancreatic cancer is the one of most common causes of cancer deaths and has the worst prognosis. Clinical observational studies suggest that statins may reduce the risk of pancreatic cancer. The chemopreventive efficacy of the statin atorvastatin (Lipitor(®)) and the role of the phosphatidyl-inositol 3-kinase (PI3/AKT) signaling pathway were evaluated for the progression of pancreatic intraepithelial neoplasms (PanINs) to pancreatic ductal adenocarcinoma (PDAC) in conditional p48(Cre/+) -LSL-Kras(G12D/+) transgenic mice. Six-week-old male p48(Cre/+) -LSL-Kras(G12D/+) (20/group) mice were fed AIN-76A diets containing 0, 200 and 400 ppm atorvastatin for 35 weeks. At termination, pancreata were evaluated histopathologically for PanINs and PDAC, and for various PI3/AKT signaling markers, and inflammatory cytokines, by immunohistochemistry/immunohistoflourscence, ELISA, Western blotting and/or reverse transcription-PCR methods. Control diet-fed mice showed 85% incidence of PDAC; whereas, mice fed with atorvastatin showed PDAC incidence of 65 and 35%, respectively (p < 0.0001). Similarly, significant suppression of PanIN-3 (22.6%) was observed in mice fed 400 ppm atorvastatin. Importantly, pancreata from atorvastatin-treated mice were ∼68% free from ductal lesions. Furthermore, pancreas of mice administered with atorvastatin had significantly reduced expressions levels of PCNA, p2X7, p-ERK, RhoA, cyclin D1, survivin, Akt, pAKT, β-catenin, cyclin E, cdK2 and caveolin-1. Also, atorvastatin-treated mice had shown dose-dependent suppression of inflammatory cytokines and a significant increase in tunnel-positive cells, p21 and PARP expression levels in pancreas. Atorvastatin significantly delays the progression of PanIN-1 and -2 lesions to PanIN-3 and PDAC by modulating PI3/AKT signal molecules in a preclinical model, suggesting potential clinical benefits of statins for high-risk pancreatic cancer patients.
International Journal of Cancer 01/2012; 131(8):1951-62. · 5.44 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Preclinical and clinical studies suggest that 5-lipoxygenase (5-LOX), such as COX-2, is a potential target for colon cancer inhibition and, in part, contributes to cardiovascular side effects associated with COX-2 inhibitors. Experiments were designed to assess the chemopreventive effects of a novel dual 5-LOX/COX inhibitor, licofelone {[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid}, in APC(Min/+) mouse intestinal tumorigenesis. Six-week-old male and female APC(Min/+) mice (n = 10 per group) were fed with control American Institute of Nutrition-76A diet or diets containing 150 or 300 ppm licofelone for 14 weeks (∼100 days), and intestinal tumors were evaluated for tumor multiplicity and size. Licofelone significantly inhibited total intestinal tumor multiplicity and size in a dose-dependent manner (P < 0.0001; mean tumors for 0, 150, and 300 ppm: 48.8, 17, and 8, respectively, in male mice; and 34.3, 8.8, and 5.5, respectively, in female mice). Licofelone at high dose showed more than 83% (P < 0.0001) tumor inhibition in both genders of mice. One hundred and fifty and 300 ppm licofelone resulted in 86% to 97% inhibition of polyps having size greater than 2 mm. One hundred and fifty and 300 ppm licofelone caused more than 72% and 100% inhibition of colonic tumors, respectively. Importantly, in mice fed with licofelone, tumors showed significantly reduced proliferating cell nuclear antigen expression (70%, P < 0.0001), increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells (75%, P < 0.0001), and there was dose-dependent suppression of serum triglycerides (71%-83%, P < 0.0001), decreased inflammatory cytokines; and decreased COX and 5-LOX activities (57%-64%, P < 0.0001). Also, compared with 300 ppm celecoxib, 300 ppm licofelone provided better efficacy in suppressing tumor growth. These observations show that a novel dual 5-LOX/COX inhibitor dramatically suppresses small intestinal and colonic tumor formation in APC(Min/+) mice.
Cancer Prevention Research 09/2011; 4(12):2015-26. · 4.91 Impact Factor
