Suppression of tumor formation by a cyclooxygenase-2 inhibitor and a peroxisome proliferator-activated receptor gamma agonist in an in vivo mouse model of spontaneous breast cancer.
Suppression of tumor formation by a cyclooxygenase-2 inhibitor and a peroxisome proliferator-activated receptor gamma agonist in an in vivo mouse model of spontaneous breast cancer.
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DOI：
10.1158/1078-0432.ccr-08-0958
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发表时间：
2008-08-01
期刊：
影响因子：
--
通讯作者：
Kruger WD
中科院分区：
文献类型：
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作者：
Mustafa A;Kruger WD
在人和动物乳腺癌模型中，已观察到环氧合酶-2(COX-2)的激活和过氧化体增殖物激活受体γ(PPARγ)的抑制。抑制COX-2和激活PPARγ在体外均能抑制乳腺癌细胞的增殖。在这里，我们检测了环氧合酶-2抑制剂塞来昔布和PPARγ激动剂F-L-亮氨酸在体外和体内对小鼠乳腺癌细胞的作用。我们从C3(1)-SV40T抗原小鼠建立并鉴定了小鼠乳腺癌细胞系，以研究COX-2和PPARγ的表达以及对塞来昔布和F-L-亮氨酸的体外反应。为了研究C3(1)SV40T抗原小鼠的体内效应，给C3(1)SV40T抗原小鼠喂以对照饲料或含有三种不同浓度的塞来昔布和F-L亮氨酸的饲料，以及两种制剂的组合。随后对小鼠进行了长达一年的肿瘤形成跟踪调查。MMAC1细胞同时表达COX-2和PPARγ，塞来昔布和F-L-亮氨酸联合应用对MMAC1细胞有协同生长抑制作用。在小鼠中，在所有三种浓度的塞来昔布治疗的动物中，因乳腺肿瘤而死亡的中位年龄显著推迟，但单独使用F-L-亮氨酸治疗并没有显著影响。塞来昔布联合F-L亮氨酸的疗效明显优于单用塞来昔布。我们的发现表明，COX-2抑制剂和PPARγ激动剂的组合可以延迟小鼠模型中的乳腺癌，并建议这些药物应该在人类高乳腺癌风险人群的背景下进行研究。
Activation of cyclooxygenase-2 (COX-2) and inhibition of peroxisome proliferators-activated receptor γ (PPARγ) have been observed in human and animal models of breast cancer. Both inhibition of COX-2 and activation of PPARγ can inhibit proliferation of breast cancer cells in vitro. Here we examine the effects of the COX-2 inhibitor celecoxib and the PPARγ agonist F-L-Leu on mouse breast tumor cells in vitro and in vivo. We created and characterized a mouse mammary adenocarcinoma cell (MMAC1) line from C3 (1)-SV40 T-antigen mice to study COX-2 and PPARγ expression and response to celecoxib and F-L-Leu in vitro. To study the in vivo effects, C3 (1) SV40 T-antigen mice were given either control diet or diets containing three different concentrations of celecoxib and F-L-Leu as well as a combination of both agents. Mice were then followed for tumor formation up to one year. MMAC1 cells express both COX-2 and PPARγ mRNA and exhibited cooperative growth inhibition with a combination of celecoxib and F-L-Leu. In mice, the median age of death due to mammary tumors was significantly delayed in celecoxib treated animals at all three concentrations, but was not significantly affected by F-L-Leu treatment alone. A combination of celecoxib and F-L-Leu was significantly more effective than celecoxib alone. Our findings suggest that a combination of a COX-2 inhibitor and PPARγ agonist can delay breast cancer in a mouse model and suggest these agents should be studied in the context of human populations with high breast cancer risk.