Paricalcitol Enhances the Chemopreventive Efficacy of 5-Flurouracil on an Intermediate-term Model of Azoxymethane- Induced Colorectal Tumors in Rats
Menée sur un modèle murin de tumeur colorectale induite chimiquement, cette étude montre que le paricalcitol, un analogue de synthèse de la vitamine D, augmente l'efficacité chimiopréventive du 5-fluorouracile
Colorectal cancer (CRC) is a common cancer with high mortality rate. Despite it is the standard anti-CRC drug, 5-Fluorouracil (5-FU) exhibits only limited therapeutic benefits. Herein, we investigated would paricalcitol (Pcal), a synthetic vitamin D analog with potential antitumor properties, enhance the chemopreventive efficacy of 5-FU on an intermediate-term (15 weeks) model of colorectal tumors induced by azoxymethane (AOM) in rats. Post-AOM injection, 5-FU was administered during the 9th and 10th weeks (12 mg/kg/day for 4 days, then 6 mg/kg every other day for another 4 doses), while Pcal (2.5 μg/kg/day; three days/week) was given from the 7th to the 15th week. At week 15, the animals were euthanized and their resected colons were examined macroscopically and microscopically. Quantitative RT-PCR was used to measure the transcription activities of Wnt, β-catenin, DKK-1, CDNK-1A, NF-κB, and COX-2 genes; and ELISA was used to quantify the protein levels of β-catenin, COX-2, HSP-90, and VEGF. Immunohistochemistry was additionally used to measure β-catenin, HSP90, and iNOS. Compared with their individual therapy, combination of 5-FU and Pcal showed more significant reducing effect on numbers of grown tumors and large aberrant crypts foci. Mechanistically, Pcal and 5-FU had cooperated together to more repress the expression of pro-cancerous Wnt, β-catenin, NF-κB, COX-2, iNOS, VEGF and HSP-90, and to upregulate the expression of anti-tumorigenesis DKK-1 and CDNK-1A, compared with their monotherapies. Our findings suggest that combined use of Pcal with 5-FU exhibits an augmenting chemopreventive effect against colorectal tumors, and might potentially be useful for chemoprevention in CRC patients.