Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical School, Dallas, TX, USA.
Cancer Res. 2010 Apr 1;70(7):2852-61. doi: 10.1158/0008-5472.CAN-09-3892. Epub 2010 Mar 23.
Failure of chemotherapy in the treatment of pancreatic cancer is often due to resistance to therapy-induced apoptosis. A major mechanism for such resistance is the expression and activity of inhibitors of apoptosis proteins (IAP). Smac (second mitochondria-derived activator of caspase) is a mitochondrial protein that inhibits IAPs. We show that JP1201, a Smac mimetic, is a potent enhancer of chemotherapy in robust mouse models of pancreatic cancer. Combination of JP1201 with gemcitabine reduced primary and metastatic tumor burden in orthotopic xenograft and syngenic tumor models, induced regression of established tumors, and prolonged survival in xenograft and transgenic models of pancreatic cancer. The effect of JP1201 was phenocopied by XIAP small interfering RNA in vitro and correlated with elevated levels of tumor necrosis factor alpha protein in vivo. The continued development of JP1201 and other strategies designed to enhance therapy-induced apoptosis in pancreatic cancer is warranted.
化疗治疗胰腺癌失败的原因通常是对治疗诱导的细胞凋亡产生耐药性。产生这种耐药性的一个主要机制是凋亡抑制蛋白（IAP）的表达和活性。Smac（第二线粒体衍生的半胱天冬酶激活剂）是一种抑制 IAP 的线粒体蛋白。我们发现，Smac 模拟物 JP1201 可增强强大的胰腺癌小鼠模型中的化疗效果。JP1201 与吉西他滨联合使用可减少原位异种移植和同基因肿瘤模型中的原发性和转移性肿瘤负担，诱导已建立的肿瘤消退，并延长胰腺癌异种移植和转基因模型的存活时间。在体外，JP1201 的作用可被 XIAP 小干扰 RNA 模拟，并且与体内肿瘤坏死因子 α 蛋白水平升高相关。有必要继续开发 JP1201 和其他旨在增强胰腺癌治疗诱导细胞凋亡的策略。
