TY - JOUR
T1 - Chemopreventive efficacy of raloxifene, bexarotene, and their combination on the progression of chemically induced colon adenomas to adenocarcinomas in rats
AU - Janakiram, Naveena B.
AU - Mohammed, Altaf
AU - Zhang, Yuting
AU - Brewer, Misty
AU - Bryant, Taylor
AU - Lightfoot, Stan
AU - Steele, Vernon E.
AU - Rao, Chinthalapally V.
PY - 2013/12
Y1 - 2013/12
N2 - Estrogen receptor (ER)-β signaling is associated positively in colon tumor progression, whereas down-regulation or loss of function of retinoid X receptor (RXR)-α occurs in colon tumors. The chemopreventive efficacies of the estrogen antagonist raloxifene and the selective RXR agonist bexarotene were tested individually and in combination, during promotion and progression stages of colon tumorigenesis. Colon tumors were induced in male F344 rats with azoxymethane and at early adenoma stage, groups of rats (36 or 45 per group) were fed diets containing raloxifene (1.5 or 3 ppm), bexarotene (50 or 100 ppm), or their low-dose combinations for 40 weeks. Raloxifene or bexarotene alone significantly suppressed colon adenocarcinoma formation in terms of multiplicities (mean ± SE): control, 3.59 ± 0.25; 1.5 ppm raloxifene, 2.51 ± 0.29 (P < 0.004); 3 ppm raloxifene, 2.14 ± 0.28 (P < 0.0001); 50 ppm bexarotene, 2.25 ± 0.32 (P < 0.001); 100 ppm bexarotene, 2.1 ± 0.27 (P < 0.0001); and 1.5 ppm raloxifene + 50 ppm bexarotene, 1.57 ± 0.21 (P < 0.0001). The low-dose combination caused significant (56%) inhibition of adenocarcinomas as compared with control diet fed rats. Tumors exposed to raloxifene, bexarotene and/or the combination showed significant suppression of proliferating cell nuclear antigen, cyclin D1, and b-catenin with an increased apoptotic cells (3-fold) and p21 expression (3.8-fold) as compared tumors of rats fed control diet. The combination of low doses of raloxifene and bexarotene significantly suppressed the progression of colonic adenomas to adenocarcinomas and may be useful for colon cancer prevention and/or treatment in high-risk individuals.
AB - Estrogen receptor (ER)-β signaling is associated positively in colon tumor progression, whereas down-regulation or loss of function of retinoid X receptor (RXR)-α occurs in colon tumors. The chemopreventive efficacies of the estrogen antagonist raloxifene and the selective RXR agonist bexarotene were tested individually and in combination, during promotion and progression stages of colon tumorigenesis. Colon tumors were induced in male F344 rats with azoxymethane and at early adenoma stage, groups of rats (36 or 45 per group) were fed diets containing raloxifene (1.5 or 3 ppm), bexarotene (50 or 100 ppm), or their low-dose combinations for 40 weeks. Raloxifene or bexarotene alone significantly suppressed colon adenocarcinoma formation in terms of multiplicities (mean ± SE): control, 3.59 ± 0.25; 1.5 ppm raloxifene, 2.51 ± 0.29 (P < 0.004); 3 ppm raloxifene, 2.14 ± 0.28 (P < 0.0001); 50 ppm bexarotene, 2.25 ± 0.32 (P < 0.001); 100 ppm bexarotene, 2.1 ± 0.27 (P < 0.0001); and 1.5 ppm raloxifene + 50 ppm bexarotene, 1.57 ± 0.21 (P < 0.0001). The low-dose combination caused significant (56%) inhibition of adenocarcinomas as compared with control diet fed rats. Tumors exposed to raloxifene, bexarotene and/or the combination showed significant suppression of proliferating cell nuclear antigen, cyclin D1, and b-catenin with an increased apoptotic cells (3-fold) and p21 expression (3.8-fold) as compared tumors of rats fed control diet. The combination of low doses of raloxifene and bexarotene significantly suppressed the progression of colonic adenomas to adenocarcinomas and may be useful for colon cancer prevention and/or treatment in high-risk individuals.
UR - http://www.scopus.com/inward/record.url?scp=84890514017&partnerID=8YFLogxK
U2 - 10.1158/1940-6207.CAPR-13-0249
DO - 10.1158/1940-6207.CAPR-13-0249
M3 - Article
C2 - 24080207
AN - SCOPUS:84890514017
SN - 1940-6207
VL - 6
SP - 1251
EP - 1261
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 12
ER -