Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome
Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome
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DOI：
10.1006/jsre.2001.6194
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发表时间：
2001-09-01
影响因子：
2.2
通讯作者：
McConkey, DJ
中科院分区：
文献类型：
--
作者：
Bold, RJ;Virudachalam, S;McConkey, DJ
背景。胰腺癌对化疗诱导的细胞凋亡具有极强的耐药性；调节细胞凋亡敏感性的药物可能导致胰腺癌的化学增敏。材料和方法。用26s蛋白酶体抑制剂PS-341体外处理MIA-PaCa-2人胰腺癌细胞。Western blotting检测凋亡调节蛋白（BCL-2、BAK、BAX）水平。利用BCL-2启动子/荧光素酶报告基因构建检测了PS-341对BCL-2基因转录的影响。采用MTT法测定吉西他滨在PS-341存在下（10-1000 nM）的细胞毒作用，确定PS-341的化学增敏作用。在胸腺小鼠体内也进行了相应的异种肿瘤移植实验。PS-341降低BCL-2，对BAX和BAK无影响。PS-341对BCL-2的下调似乎是转录介导的。PS-341高剂量（1000 nM）诱导细胞凋亡，低剂量（10-100 nM）增加吉西他滨的细胞毒性。吉西他滨抑制异种移植物生长59%；PS-341的加入使生长抑制率提高到75%。抑制26S蛋白酶体会破坏细胞周期进程和凋亡控制的关键调节因子的细胞含量，导致胰腺癌对标准化疗药物（如吉西他滨）的敏感性增加。联合治疗可能导致更好的反应率。(C) 2001学术出版社。
Background. Pancreatic cancer is extremely resistant to the induction of apoptosis by chemotherapies; agents that regulate sensitivity to apoptosis may lead to chemosensitization of pancreatic cancer.Materials and methods. MIA-PaCa-2 human pancreatic cancer cells were treated in vitro with the 26S-proteasome inhibitor PS-341. Levels of the apoptosis-regulating proteins (BCL-2, BAK, and BAX) were determined by Western blotting. The effect of PS-341 on BCL-2 gene transcription was examined using a BCL-2 promoter/luciferase reporter construct. The chemosensitizing effect of PS-341 was determined by measurement of the cytotoxic effect of gemcitabine in the presence of PS-341 (10-1000 nM) using the MTT assay. A corresponding in vivo experiment using tumor xenografts in athymic mice was also performed.Results. PS-341 decreased BCL-2, without effect on BAX or BAK. The downregulation of BCL-2 by PS-341 appears to be transcriptionally mediated. PS-341 induced apoptosis at high does (1000 nM) and increased the cytotoxicity of gemcitabine at low doses (10-100 nM). Xenograft growth was inhibited 59% by gemcitabine; the addition of PS-341 increased growth inhibition to 75%.Conclusions. Inhibition of the 26S proteasome disrupts the cellular content of key regulators of cell cycle progression and apoptotic control leading to increased sensitivity to standard chemotherapeutic agents, such as gemcitabine, in pancreatic cancer. Combination therapy may lead to better response rates. (C) 2001 Academic Press.