Synergistic antipancreatic tumor effect by simultaneously targeting hypoxic cancer cells with HSP90 inhibitor and glycolysis inhibitor
Synergistic antipancreatic tumor effect by simultaneously targeting hypoxic cancer cells with HSP90 inhibitor and glycolysis inhibitor
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DOI：
10.1158/1078-0432.ccr-07-1607
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发表时间：
2008-03-15
影响因子：
11.5
通讯作者：
Sun, Duxin
中科院分区：
文献类型：
--
作者：
Cao, Xianhua;Bloomston, Mark;Sun, Duxin
目的：我们试图研究协同抗胰腺癌的作用，同时针对缺氧癌细胞与热休克蛋白90（HSP 90）抑制剂和封锁的能源production.Experimental Design：在胰腺细胞中的HSP 90抑制剂（格尔德霉素）的抗癌作用进行了研究，在缺氧和常氧。研究了己糖激酶11抑制剂3-溴丙酮酸（3BrPA）作为HSP 90抑制剂的增敏剂对胰腺癌的选择性糖酵解抑制作用。Western blot检测HSP 90客户蛋白降解情况。格尔德霉素和3BrPA的协同抗肿瘤作用进行了评估，在异种移植胰腺癌模型和监测的非侵入性动态对比增强magnetic resonance imaging.Results：缺氧增强HIF-1 α的表达在胰腺癌细胞的11倍，和HSP 90抑制剂表现出7 - 8倍高的抗癌效果，缺氧相比，常氧通过HSP 90客户端蛋白降解。3BrPA通过HSP 90客户蛋白降解选择性地抑制糖酵解并使格尔德霉素对胰腺癌细胞的致敏性提高17至400倍。在异种移植模型中，通过超过75%的肿瘤生长抑制作用证实了减少剂量的格尔德霉素和3-BrPA的协同抗癌作用。结论：HSP 90抑制剂和糖酵解抑制剂的组合通过HSP 90客户端蛋白降解和选择性糖酵解抑制提供了在缺氧中对癌细胞的优先抑制。这可能提供一种新的治疗方案，通过增强协同治疗效果和减少剂量限制性毒性来对抗化疗耐药性胰腺癌。
Purpose: We sought to examine the synergistic antipancreatic cancer effect by simultaneously targeting hypoxic cancer cells with heat-shock protein 90 (HSP90) inhibitor and blockade of energy production.Experimental Design: The anticancer effects of an HSP90 inhibitor (geldanamycin) in pancreatic cells were investigated in hypoxia and normoxia. A hexokinase 11 inhibitor, 3-broma-pyruvate (3BrPA), was evaluated for selective glycolysis inhibition in hypoxia as a sensitizer of HSP90 inhibitor against pancreatic cancer. The HSP90 client protein degradation was monitored by Western blot. The synergistic antitumor effect of geldanamycin and 3BrPA was evaluated in a xenograft pancreatic cancer model and monitored by a noninvasive dynamic contrast-enhanced magnetic resonance imaging.Results: Hypoxia enhanced HIF-1 alpha expression by 11-fold in pancreatic cancer cells, and HSP90 inhibitor exhibited a seven- to eightfold higher anticancer effect in hypoxia compared with normoxia via HSP90 client protein degradation. 3BrPA selectively inhibited glycolysis and sensitized geldanamycin against pancreatic cancer cells by 17- to 400-fold through HSP90 client protein degradation. The synergistic anticancer effect of reduced doses of geldanamycin and 3-BrPA was confirmed in xenograft models in vivo by more than 75% tumor growth inhibition.Conclusions: The combination of HSP90 inhibitors and glycolysis inhibitors provides preferential inhibition of cancer cells in hypoxia through HSP90 client protein degradation and selective glycolysis inhibition. This may provide a new therapeutic regimen to battle chemotherapy-resistant pancreatic cancers, by enhancing the synergistic therapeutic efficacy and reducing dose-limiting toxicity.