Suppression of pancreatic tumor growth by combination chemotherapy with sulindac and LC-1 is associated with cyclin D1 inhibition in vivo
Suppression of pancreatic tumor growth by combination chemotherapy with sulindac and LC-1 is associated with cyclin D1 inhibition in vivo
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DOI：
10.1158/1535-7163.mct-06-0794
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发表时间：
2007-06-01
影响因子：
5.7
通讯作者：
Schmidt, C. Max
中科院分区：
文献类型：
--
作者：
Yip-Schneider, Michele T.;Wu, Huangbing;Schmidt, C. Max
新的靶向或联合疗法的设计可能会改善胰腺癌的治疗选择。最近感兴趣的两个靶点是核因子-kappaB(NF-kappa B)和环氧合酶(COX)，它们在胰腺癌中分别被激活或过度表达。我们先前已经证明，与抑制核因子-kappa B相关的促凋亡药物巴特内酯在体外增强了环氧合酶抑制剂舒林酸对胰腺癌细胞的生长抑制。在本研究中，利用人胰腺癌异种移植模型，在活体内评价了菊内酯、LC-1和舒林酸的生物利用度类似物。治疗组包括安慰剂，低剂量/高剂量LC-1(20和40 mg/kg)，低剂量/高剂量舒林酸(20和60 mg/kg)，以及低剂量LC-1/舒林酸(20 mg/kg)。在MiaPaCa-2异种移植瘤中，高剂量舒林酸或LC-1抑制肿瘤生长。在BxPC-3移植瘤中，小剂量LC-1/舒林酸联合治疗或大剂量舒林酸单独治疗可显著缩小肿瘤体积(P<；0.05)。免疫组织化学结果显示，大剂量舒林酸可显著降低BxPC-3肿瘤细胞Ki-67和CD31的表达，而对COX-1/COX-2的表达和活性无明显影响。大剂量LC-1可显著降低核因子-kappaB的DNA结合活性。小剂量LC-1/舒林酸联合应用或大剂量舒林酸单独应用均可降低Cyclin D1蛋白水平，与BxPC-3肿瘤抑制相关。这些结果表明，LC-1和舒林酸可能部分通过改变细胞周期蛋白D1的水平来调节其抗肿瘤作用。此外，这项研究为这些药物的治疗效果提供了临床前证据。
The design of novel targeted or combination therapies may improve treatment options for pancreatic cancer. Two targets of recent interest are nuclear factor-kappa B (NF-kappa B) and cyclooxygenase (COX), known to be activated or overexpressed, respectively, in pancreatic cancer. We have previously shown that parthenolide, a proapoptotic drug associated with NF-kappa B inhibition, enhanced the growth suppression of pancreatic cancer cells by the COX inhibitor sulindac in vitro. In the present study, a bioavailable analogue of parthenolide, LC-1, and sulindac were evaluated in vivo using a xenograft model of human pancreatic cancer. Treatment groups included placebo, low-dose/high-dose LC-1 (20 and 40 mg/kg), low-dose/high-dose sulindac (20 and 60 mg/kg), and low-dose combination LC-1/sulindac (20 mg/kg each). In MiaPaCa-2 xenografts, tumor growth was inhibited by either high-dose sulindac or LC-1. In BxPC-3 xenografts, tumor size was significantly reduced by treatment with the low-dose LC-1/sulindac combination or high-dose sulindac alone (P < 0.05). Immunohistochemistry of BxPC-3 tumors revealed a significant decrease in Ki-67 and CD31 staining by high-dose sulindac, with no significant changes in COX-1/COX-2 levels or activity in any of the treatment groups. NF-kappa B DNA-binding activity was significantly decreased by high-dose LC-1. Cyclin D1 protein levels were reduced by the low-dose LC-1/sulindac combination or high-dose sulindac alone, correlating with BxPC-3 tumor suppression. These results suggest that LC-1 and sulindac may mediate their antitumor effects, in part, by altering cyclin D1 levels. Furthermore, this study provides preclinical evidence for the therapeutic efficacy of these agents.