Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.
Sci Transl Med. 2012 Oct 17;4(156):156ra139. doi: 10.1126/scitranslmed.3004334.
Pancreatic cancer is one of the most lethal human malignancies with an all-stage 5-year survival frequency of <5%, which highlights the urgent need for more effective therapeutic strategies. We have previously shown that triptolide, a diterpenoid, is effective against pancreatic cancer cells in vitro as well as in vivo. However, triptolide is poorly soluble in water, limiting its clinical use. We therefore synthesized a water-soluble analog of triptolide, named Minnelide. The efficacy of Minnelide was tested both in vitro and in multiple independent yet complementary in vivo models of pancreatic cancer: an orthotopic model of pancreatic cancer using human pancreatic cancer cell lines in athymic nude mice, a xenograft model where human pancreatic tumors were transplanted into severe combined immunodeficient mice, and a spontaneous pancreatic cancer mouse model (KRas(G12D); Trp53(R172H); Pdx-1Cre). In these multiple complementary models of pancreatic cancer, Minnelide was highly effective in reducing pancreatic tumor growth and spread, and improving survival. Together, our results suggest that Minnelide shows promise as a potent chemotherapeutic agent against pancreatic cancer, and support the evaluation of Minnelide in clinical trials against this deadly disease.
胰腺癌是人类最致命的恶性肿瘤之一，各期 5 年生存率均<5%，这凸显了迫切需要更有效的治疗策略。我们之前已经表明，雷公藤红素是一种二萜类化合物，对体外和体内的胰腺癌细胞均有效。然而，雷公藤红素在水中的溶解度很差，限制了其临床应用。因此，我们合成了雷公藤红素的水溶性类似物，命名为 Minnelide。Minnelide 的疗效在多个独立但互补的胰腺癌体内模型中进行了测试：在免疫缺陷裸鼠中用人胰腺癌细胞系建立的胰腺癌原位模型、将人胰腺肿瘤移植到严重联合免疫缺陷小鼠中的异种移植模型，以及自发性胰腺癌小鼠模型（KRas(G12D); Trp53(R172H); Pdx-1Cre）。在这些互补的胰腺癌模型中，Minnelide 能有效抑制胰腺肿瘤的生长和扩散，并提高存活率。总之，我们的研究结果表明，Minnelide 有望成为一种针对胰腺癌的有效化疗药物，并支持在临床试验中评估 Minnelide 治疗这种致命疾病。
