Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Cancer Prev Res (Phila). 2010 Nov;3(11):1427-34. doi: 10.1158/1940-6207.CAPR-10-0197. Epub 2010 Oct 19.
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 IκB kinase (IKK) to decrease constitutive interleukin-6 secretion, inhibit constitutive signal transducer and activator of transcription 3 phosphorylation, and block the degradation of IκBα when challenged with tumor necrosis factor α. These results suggest that oleanane triterpenoids and rexinoids have the potential to prevent pancreatic cancer.
胰腺癌是美国第四大致癌相关死亡原因，几乎总是致命的。虽然早期检测为降低这种疾病的死亡率提供了最有希望的方法，但仍需要开发有效的药物来预防和治疗胰腺癌。我们测试了两类有前途的非细胞毒性药物，即合成齐墩果酸三萜和雷西纳德，以预防高度相关的 LSL-Kras(G12D/+);LSL-Trp53(R127H/+);Pdx-1-Cre (KPC) 胰腺癌小鼠模型中的癌变。KPC 转基因小鼠紧密重现了人类胰腺癌的遗传突变、临床症状和组织病理学。从 4 周龄开始，将小鼠喂食粉末对照饮食或含有齐墩果酸甲酯 (CDDO-Me) 或齐墩果酸乙酯酰胺、雷西纳德 LG100268 (LG268) 或组合的饮食，直到小鼠出现明显的胰腺癌症状。CDDO-Me、LG268、CDDO-Me 和 LG268 的组合以及 CDDO-ethyl amide 和 LG268 的组合，均显著（P < 0.05）将 KPC 小鼠的存活率延长了 3 至 4 周。最近的研究表明，吉西他滨是目前治疗人类胰腺癌的标准治疗方法，但不能延长 KPC 小鼠的存活时间。在从 KPC 小鼠中开发的细胞系中，三萜类化合物直接与信号转导和转录激活因子 3 和 IκB 激酶 (IKK) 相互作用，减少白细胞介素-6 的组成性分泌，抑制组成性信号转导和转录激活因子 3 磷酸化，并在受到肿瘤坏死因子 α 挑战时阻止 IκBα 的降解。这些结果表明，齐墩果酸三萜和雷西纳德具有预防胰腺癌的潜力。
