We investigated the chemopreventive effect of celecoxib on 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumours and also the expression and immunolocalization of cyclooxygenase-1 (COX-1) and COX-2 in the various stages of rat mammary carcinogenesis. Rats were divided into normal control group, DMBA-control group, 500 p.p.m. celecoxib-treated group, and 1500 p.p.m. celecoxib-treated group. Both incidence and multiplicity values of tumour for rats treated with celecoxib were less than those in rats of the DMBA-control group. The level of prostaglandin E2 was higher in tumours of the DMBA-control and both celecoxib-treated groups compared to normal mammary glands of each group. In Western blot analysis, all tumours of the DMBA-control group expressed COX-1, whereas normal mammary glands showed insignificant expression. COX-2 expression was observed in 67% of the DMBA-control group and 20% of both celecoxib-treated groups and was absent in normal mammary glands. COX-1 protein was localized in the nuclear membrane and cytoplasm of epithelial tumour cells abutting on glandular lumen, stromal cells, and endothelial cells. COX-2 protein was detected in the perinuclear cytoplasm of tumour cells bordering on glandular lumen and surrounding stroma, stromal cells, and vascular smooth muscle. In the DMBA-control group, invasive carcinoma cells showed higher positive immunoreactivity of COX-2 than carcinomas in situ and atypical tumours. Tumours displayed an increased number of mast-like cells with COX-2 expression in comparison to carcinomas in situ. Our results suggest that COX-1 and COX-2 expression in tumour cells and stromal cells play an important role in the various stages of DMBA-induced rat mammary carcinogenesis. In addition, we reconfirm that celecoxib reduces the growth of DMBA-induced rat mammary tumours.
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[Show abstract][Hide abstract] ABSTRACT: Background
During the last few years it has been shown in several laboratories that Celecoxib (Cx), a non-steroidal anti-inflammatory agent (NSAID) normally used for pain and arthritis, mediates antitumor and antiangiogenic effects. However, the effects of this drug on a tumor cell line resistant to chemotherapeutical drugs used in cancer have not been described.
Herein we evaluate the angiogenic and antitumor effects of Cx in the development of a drug-resistant mammary adenocarcinoma tumor (TA3-MTXR).
Cx reduces angiogenesis in the chick embryonic chorioallantoic membrane assay (CAM), inhibits the growth and microvascular density of the murine TA3-MTXR tumor, reduces microvascular density of tumor metastases, promotes apoptosis and reduces vascular endothelial growth factor (VEGF) production and cell proliferation in the tumor.
The antiangiogenic and antitumor Cx effects correlate with its activity on other tumor cell lines, suggesting that Prostaglandins (PGs) and VEGF production are involved. These results open the possibility of using Celecoxib combined with other experimental therapies, ideally aiming to get synergic effects.
Full-text · Article · Jun 2014 · Biological research
"Consistent with the chemopreventive effects on hormonally responsive mammary carcinomas observed in our model, celecoxib has been shown highly efficacious for the prevention of mammary cancer in chemically induced rat models. Two different groups using 9,10-dimethylbenz-a-anthracene as the carcinogen in rats reported reductions in tumor multiplicity of 69% and of 86% associated with celecoxib administration at a dose of 1,500 ppm [5,6]. This effect is more dramatic than that observed in our model. "
[Show abstract][Hide abstract] ABSTRACT: While current breast cancer chemoprevention strategies using selective estrogen response modulators and aromatase inhibitors are quite successful, their effects are limited to hormonally responsive breast cancer. Hormonally nonresponsive breast cancer (including estrogen receptor-negative cancer) is associated with poor prognosis for patients, and few chemoprevention agents exist for this type of cancer. The cyclooxygenase-2 inhibitor celecoxib (Celebrex) is a nonsteroidal anti-inflammatory drug and as such is a potential candidate for the prevention of hormonally nonresponsive breast cancer.
The chemopreventive effects of celecoxib were evaluated in the neu-induced retroviral rat mammary carcinogenesis model, to assess the efficacy of celecoxib on hormonally responsive and hormonally nonresponsive mammary carcinomas.
Dietary celecoxib at 1,200 mg/kg diet was highly efficacious in the prevention of hormonally responsive mammary carcinomas in intact rats, decreasing tumor multiplicity by 56% (P < 0.0001) and by 74% (P = 0.0002) in two independent experiments. No significant effect was found, however, on hormonally nonresponsive mammary carcinomas of ovariectomized rats. Treatment with a combination diet, consisting of tamoxifen at 2 mg/kg diet and celecoxib at 1,200 mg/kg diet, reduced tumor multiplicity by 72% (P = 0.0002) in intact rats. This reduction was not statistically different from that observed with celecoxib alone. Furthermore, long-term treatment with celecoxib was not associated with reductions in tumor volume in either intact rats or ovariectomized rats. In contrast, tamoxifen treatment and the combination regimen caused significant reductions in tumor volumes in intact rats (P = 0.01 and P = 0.004, respectively). Consistent with these data, decreases in proliferation and increases in apoptosis were detected in tamoxifen-treated and combination diet-treated tumors. No such modulations were observed in celecoxib-treated tumors.
The chemopreventive effects of celecoxib appear to be limited to modulations in multiplicity of hormonally responsive mammary carcinomas. The fact that no synergistic or additive effects were observed in combination diet-treated rats raises the question of whether celecoxib is suitable for the prevention of hormonally nonresponsive breast cancer or for use in combination therapy with selective estrogen response modulators or aromatase inhibitors.
Full-text · Article · Feb 2008 · Breast cancer research: BCR
[Show abstract][Hide abstract] ABSTRACT: Based on our studies demonstrating first time evidence that the cyclooxygenase-2 (Cox-2) enzyme is abundant within invasive human breast tumors, we developed a clonally derived human breast tumor cell clone designated as MCF-7/Cox-2 Clone 10 by transfection of human Cox-2 cDNA into slow growing, Cox-2 null, non-metastatic MCF-7 human breast tumor cells. The present studies evaluated the biological characteristics of the MCF-7/Cox-2 Clone 10 human breast tumors compared to the characteristics of MCF-7/empty vector control tumors when grown in vivo following injection of 5x10(6) tumor cells into mammary fat pads of ovariectomized female Crl:Nu-Foxn1(nu) mice implanted with slow release 17-beta estradiol pellets. At 60 days after tumor cell injection, MCF-7/Cox-2 Clone 10 human breast tumors were 4-fold greater (p < 0.01) in volume than MCF-7/empty vector control tumors. MCF-7/Cox-2 Clone 10 human breast tumor xenografts were highly angiogenic based on histological observation of large-bore blood vessels, which was confirmed by immunohistochemical staining with anti-CD-31 antibody and quantitation of mean vessel density. MCF-7/Cox-2 Clone 10 human breast tumor cells were present within regional lymph nodes adjacent to mammary fat pads with their local invasion confirmed by Western blotting of Cox-2-protein. This unique Cox-2-dependent breast tumor model rapidly produces large, angiogenic, locally invasive human breast tumor xenografts in mammary fat pads of ovariectomized female Crl:Nu-Foxn1(nu) mice at 42-60 days which recapitulate human breast ductal carcinomas. This unique model may be invaluable as a means to evaluate preclinical safety and efficacy of novel adjuvant therapies for women with metastastic breast cancer including prostanoid receptor antagonists, newly developed anti-angiogenic therapies, as well as other novel approaches for targeting and destruction of human breast tumors and their vasculature.
Full-text · Article · Mar 2007 · Anticancer research