title: Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats.
abstract: Colorectal cancer is a common cancer with high mortality rate. Despite being the standard anti-colorectal cancer drug, 5-fluorouracil (5-FU) exhibits only limited therapeutic benefits. Herein, we investigated whether paricalcitol, a synthetic vitamin D analogue with potential antitumor properties, would enhance the chemopreventive efficacy of 5-FU on an intermediate-term (15 weeks) model of colorectal tumors induced by azoxymethane (AOM) in rats. After 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), whereas paricalcitol (2.5 μg/kg/day; 3 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, HSP90, and VEGF. IHC was additionally used to measure β-catenin, HSP90, and inducible nitric oxide synthase (iNOS). Compared with their individual therapy, combination of 5-FU and paricalcitol showed more significant reducing effect on numbers of grown tumors and large aberrant crypts foci. Mechanistically, paricalcitol and 5-FU had cooperated together to repress the expression of procancerous Wnt, β-catenin, NF-κB, COX-2, iNOS, VEGF, and HSP-90 more, and to upregulate the expression of antitumorigenesis DKK-1 and CDNK-1A, compared with their monotherapies. Our findings suggest that combined use of paricalcitol with 5-FU exhibits an augmenting chemopreventive effect against colorectal tumors, and might potentially be useful for chemoprevention in colorectal cancer patients. Cancer Prev Res; 9(6); 491-501. ©2016 AACR.
authors.affiliation: Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Holy Makkah, Saudi Arabia. Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt. agshemi@uqu.edu.sa.
authors.forename: Adel Galal
authors.initials: AG
authors.lastname: El-Shemi
authors.affiliation: Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Holy Makkah, Saudi Arabia.
authors.forename: Bassem
authors.initials: B
authors.lastname: Refaat
authors.affiliation: Department of Clinical Nutrition, Faculty of Applied Medical Sciences, Umm Al-Qura University, Holy Makkah, Saudi Arabia.
authors.forename: Osama Adnan
authors.initials: OA
authors.lastname: Kensara
authors.affiliation: Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Holy Makkah, Saudi Arabia. Department of Animal Medicine, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt.
authors.forename: Amr Mohamed
authors.initials: AM
authors.lastname: Mohamed
authors.affiliation: Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Holy Makkah, Saudi Arabia.
authors.forename: Shakir
authors.initials: S
authors.lastname: Idris
authors.affiliation: Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Holy Makkah, Saudi Arabia.
authors.forename: Jawwad
authors.initials: J
authors.lastname: Ahmad
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001397:Azoxymethane / Q000633:toxicity; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D015179:Colorectal Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D004872:Ergocalciferols / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar; D059467:Transcriptome / Q000187:drug effects
chemical_list: D002273:Carcinogens; D004872:Ergocalciferols; C084656:paricalcitol; D001397:Azoxymethane; D005472:Fluorouracil