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.