title: Resveratrol enhances the chemopreventive effect of celecoxib in chemically induced breast cancer in rats.
abstract: Resveratrol and celecoxib were used as chemopreventive agents in animal models of carcinogenesis, and exert antiproliferative and proapoptotic effects on cancer cells. Therefore, the aim of this study was to evaluate whether combining resveratrol with celecoxib may exert more potent anticarcinogenic effects than the single agents. Mammary carcinogenesis was initiated in 70 female Sprague-Dawley rats with N-methyl-N-nitrosourea (NMU). The chemoprevention with resveratrol, celecoxib, and their combination started 2 weeks before the first carcinogen dose and lasted until the end of the experiment. Tumor incidence and frequency, latency period, tumor volume, the expression of cyclooxygenase 2 (COX2) and growth differentiation factor 15 (GDF15), and also the formation of reactive oxygen species were analyzed using different methods. In addition, the levels of resveratrol and its metabolites in blood and selected tumor tissues were determined by high-performance liquid chromatography. Finally, the anticancer effects of the reagents were studied in the human breast cancer cell line MCF-7. Celecoxib as a single agent significantly decreased tumor frequency, prolonged tumor latency, and decreased the total number of malignant tumors compared with the NMU conditions. Tumor volume was nonsignificantly reduced (0.68±0.25 vs. 0.93±0.28 cm3). Importantly, the addition of resveratrol to celecoxib reduced tumor volume by 60% compared with celecoxib alone (from 0.68±0.25 to 0.27±0.07 cm3, P<0.05). Furthermore, the combination of resveratrol and celecoxib reduced tumor frequency by 29% compared with celecoxib alone (P=0.53). Tumor latency was not influenced by this combination compared with celecoxib alone (126.56±3.45 vs. 120.71±4.08 days). In addition, COX2 mRNA and immunoreactive protein stained on tumor sections were reduced and GDF15 protein increased significantly by the combination studied compared with the NMU conditions. In agreement with these data, a significant reduction in reactive oxygen species in blood lymphocytes of the combination was detected, which may have contributed toward the cancer-preventive effects of this application. This study showed that in NMU-induced mammary cancer in rats, the combination of resveratrol and celecoxib led to a significant reduction in all tumor parameters. In addition, in terms of tumor volume, the combination was more efficient than celecoxib as a single agent.
authors.affiliation: Departments of aAnimal Physiology bCell Biology, Institute of Biology and Ecology, Faculty of Science, P.J. Šafárik University in Košice, Košice cDepartment of Pathology, Jessenius Faculty of Medicine, Commenius University, Martin, Slovak Republic dDepartment of Pathophysiology and Allergy Research, Center for Pathophysiology, Medical University of Vienna eDepartment of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna fInstitute of Environmental Health, Centre for Public Health, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Terézia
authors.initials: T
authors.lastname: Kisková
authors.forename: Rastislav
authors.initials: R
authors.lastname: Jendželovský
authors.forename: Erdenetsetsek
authors.initials: E
authors.lastname: Rentsen
authors.forename: Alexandra
authors.initials: A
authors.lastname: Maier-Salamon
authors.forename: Natália
authors.initials: N
authors.lastname: Kokošová
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Papčová
authors.forename: Jaromír
authors.initials: J
authors.lastname: Mikeš
authors.forename: Peter
authors.initials: P
authors.lastname: Orendáš
authors.forename: Bianka
authors.initials: B
authors.lastname: Bojková
authors.forename: Peter
authors.initials: P
authors.lastname: Kubatka
authors.forename: Martin
authors.initials: M
authors.lastname: Svoboda
authors.forename: Karol
authors.initials: K
authors.lastname: Kajo
authors.forename: Peter
authors.initials: P
authors.lastname: Fedoročko
authors.forename: Walter
authors.initials: W
authors.lastname: Jäger
authors.forename: Cem
authors.initials: C
authors.lastname: Ekmekcioglu
authors.forename: Monika
authors.initials: M
authors.lastname: Kassayová
authors.forename: Theresia
authors.initials: T
authors.lastname: Thalhammer
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D002273:Carcinogens; D000068579:Celecoxib; D018890:Chemoprevention / Q000379:methods; D004357:Drug Synergism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D008770:Methylnitrosourea; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D011720:Pyrazoles; D013267:Stilbenes; D013449:Sulfonamides; D008770:Methylnitrosourea; D000068579:Celecoxib; D000077185:Resveratrol