Synthetic Triterpenoids Prolong Survival in a Transgenic Mouse Model of Pancreatic Cancer
Synthetic Triterpenoids Prolong Survival in a Transgenic Mouse Model of Pancreatic Cancer
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DOI：
10.1158/1940-6207.capr-10-0197
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发表时间：
2010-11-01
影响因子：
3.3
通讯作者：
Sporn, Michael B.
中科院分区：
文献类型：
--
作者：
Liby, Karen T.;Royce, Darlene B.;Sporn, Michael B.
胰腺癌是美国癌症相关死亡的第四大原因，几乎总是致命的。虽然早期发现提供了降低胰腺癌死亡率的最有希望的方法，但仍有必要开发有效的药物来预防和治疗胰腺癌。在高度相关的LSL-Kras(G12D/+)、LSL-Trp53(R127H/+)和PDX-1-Cre(KPC)小鼠模型中，我们测试了两类有希望的非细胞毒性药物，合成齐墩果烷三萜类化合物和rexinoid类化合物，用于预防胰腺癌的发生。KPC转基因小鼠与人类胰腺癌中发现的基因突变、临床症状和组织病理学密切相关。从4周大的小鼠开始，喂食粉状对照饲料或含有三萜类CDDO-甲酯(CDDO-Me)或CDDO-乙酰胺、rexinid LG100268(LG268)或其组合的饲料，直到小鼠表现出明显的胰腺癌症状。CDDO-Me、LG268、CDDO-Me与LG268联用、CDDO-乙胺与LG268联用均能显著提高KPC小鼠3~4周的存活率(P<；0.05)。最近的研究表明，目前治疗人类胰腺癌的标准药物吉西他滨并不能延长KPC小鼠的存活时间。在KPC小鼠发展的细胞系中，三萜类化合物直接与信号转导和转录激活子3和I kappa B激酶(IKK)相互作用，减少组成性白介素6的分泌，抑制组成性信号转导和转录激活子3的磷酸化，并在肿瘤坏死因子α作用下阻断I kappa Bα的降解。这些结果表明齐墩果烷、三萜类和类维A酸类化合物具有预防胰腺癌的潜力。癌症前传；3(11)；1427-34。(C)2010年AACR。
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and is nearly always fatal. Whereas early detection offers the most promising approach for reducing the mortality of this disease, there is still a need to develop effective drugs for the prevention and treatment of pancreatic cancer. We tested two promising classes of noncytotoxic drugs, synthetic oleanane triterpenoids and rexinoids, for the prevention of carcinogenesis in the highly relevant LSL-Kras(G12D/+); LSL-Trp53(R127H/+); Pdx-1-Cre (KPC) mouse model of pancreatic cancer. KPC transgenic mice closely recapitulate the genetic mutations, clinical symptoms, and histopathology found in human pancreatic cancer. Beginning at 4 weeks of age, mice were fed powdered control diet or a diet containing the triterpenoids CDDO-methyl ester (CDDO-Me) or CDDO-ethyl amide, the rexinoid LG100268 (LG268), or the combination, until the mice displayed overt symptoms of pancreatic cancer. CDDO-Me, LG268, the combination of CDDO-Me and LG268, and the combination of CDDO-ethyl amide and LG268, all significantly (P < 0.05) increased survival in the KPC mice by 3 to 4 weeks. Recent studies have shown that gemcitabine, the current standard of care for human pancreatic cancer, does not extend survival in KPC mice. In cell lines developed from the KPC mice, the triterpenoids directly interact with both signal transducer and activator of transcription 3 and I kappa B kinase (IKK) to decrease constitutive interleukin-6 secretion, inhibit constitutive signal transducer and activator of transcription 3 phosphorylation, and block the degradation of I kappa B alpha when challenged with tumor necrosis factor alpha. These results suggest that oleanane triterpenoids and rexinoids have the potential to prevent pancreatic cancer. Cancer Prev Res; 3(11); 1427-34. (C) 2010 AACR.