Department of Medicine, Dartmouth Medical School, Hanover, NH 03755, USA.
Cancer Prev Res (Phila). 2012 May;5(5):726-34. doi: 10.1158/1940-6207.CAPR-11-0404. Epub 2012 Mar 8.
Novel drugs are needed for the prevention and treatment of breast cancer. Synthetic triterpenoids are a promising new class of compounds with activity in a variety of preclinical cancer models. We tested activity of the methyl ester derivative of the synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me), in a relevant model of estrogen receptor-negative breast cancer, the polyoma-middle T (PyMT), in which the oncoprotein drives carcinogenesis. The developing tumors recapitulate key features of the human disease. Mice were fed CDDO-Me (50 mg/kg diet), starting at 4 weeks of age. CDDO-Me significantly increased the age of mice at onset of first tumor (P < 0.001) by an average of 4.3 weeks and overall survival (P < 0.001) by 5.2 weeks. The drug also inhibited the infiltration of tumor-associated macrophages into mammary glands of PyMT mice at 12 weeks of age and reduced levels of the chemokines CXCL12 and CCL2 in primary PyMT mammary tumor cells. Treatment with this multifunctional drug also inhibited secretion of matrix metalloproteinase-9 in primary tumor cells from PyMT mice and decreased proliferation of these cells by inhibiting cyclin D1 and decreasing phosphorylation of epidermal growth factor receptor and STAT3.
需要新型药物来预防和治疗乳腺癌。合成三萜类化合物是一类很有前途的新型化合物，在多种临床前癌症模型中均具有活性。我们在一种与雌激素受体阴性乳腺癌相关的模型（多瘤病毒-中 T 基因（PyMT））中测试了合成三萜类化合物 2-氰基-3,12-二氧代齐墩果烷-1,9(11)-二烯-28-酸甲酯（CDDO-Me）的活性，在该模型中，致癌蛋白驱动癌症发生。正在发育的肿瘤再现了人类疾病的关键特征。从 4 周龄开始，用 CDDO-Me（50mg/kg 饮食）喂养小鼠。CDDO-Me 显著增加了首次肿瘤发病的小鼠年龄（P < 0.001），平均增加了 4.3 周，总生存时间（P < 0.001）增加了 5.2 周。该药物还抑制了 12 周龄 PyMT 小鼠乳腺中肿瘤相关巨噬细胞的浸润，并降低了原发性 PyMT 乳腺肿瘤细胞中趋化因子 CXCL12 和 CCL2 的水平。用这种多功能药物治疗还抑制了来自 PyMT 小鼠的原发性肿瘤细胞中基质金属蛋白酶-9 的分泌，并通过抑制周期蛋白 D1 和降低表皮生长因子受体和 STAT3 的磷酸化来抑制这些细胞的增殖。
