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首页> 外文期刊>Cell cycle >Novel combination of celecoxib and proteasome inhibitor MG132 provides synergistic antiproliferative and proapoptotic effects in human liver tumor cells.
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Novel combination of celecoxib and proteasome inhibitor MG132 provides synergistic antiproliferative and proapoptotic effects in human liver tumor cells.

机译：塞来昔布和蛋白酶体抑制剂MG132的新型组合在人肝肿瘤细胞中提供了协同的抗增殖和凋亡作用。

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Molecular targeted therapy has shown promise as a treatment for advanced hepatocellular carcinoma (HCC). Celecoxib (Celebrex((R))) exhibits antitumor effects in human HCC cells, and its mechanism of action is mediated either by its ability to inhibit cyclooxygenase 2 (COX-2) or by a number of various other COX-2 independent effects. Proteasome inhibitors (PIs) can exert cell growth inhibitory and apoptotic effects in different tumor cell types, including HCC cells. The present study examined the interaction between celecoxib and the PI MG132 in two human liver tumor cell lines HepG2 and HA22T/VGH. Our data showed that each inhibitor reduced proliferation and induced apoptosis in a dose-dependent manner in both cell lines. Moreover, the combination of celecoxib with MG132 synergistically inhibited cell viability and increased apoptosis, as documented by caspase 3 and 7 activation, PARP cleavage, and downregulation of Bcl-2. Celecoxib and MG132, both alone and synergistically in combination, induced expression of the endoplasmic reticulum (ER) stress genes ATF4, CHOP, TRB3 and promoted the splicing of XBP1 mRNA. Knockdown of TRB3 mRNA expression by small interference RNA significantly decreased combination-induced cell death in HA22T/VGH cells, whereas it increased combination-induced cell death in HepG2 cells, suggesting that activation of the ER stress response might have either a detrimental or a protective role in liver tumor cell survival. In conclusion, our data indicate that combination treatment with celecoxib and MG132 resulted in synergistic antiproliferative and proapoptotic effects against liver cancer cells, providing a rational basis for the clinical use of this combination in the treatment of liver cancer.
机译：分子靶向治疗已显示出有望作为晚期肝细胞癌（HCC）的治疗方法。塞来昔布（Celebrex（R））在人HCC细胞中表现出抗肿瘤作用，其作用机制是由其抑制环氧合酶2（COX-2）的能力或许多其他独立于COX-2的作用介导的。蛋白酶体抑制剂（PI）可以在包括HCC细胞在内的不同肿瘤细胞类型中发挥细胞生长抑制和凋亡作用。本研究检查了塞来昔布和PI MG132在两种人肝肿瘤细胞HepG2和HA22T / VGH中的相互作用。我们的数据表明，每种抑制剂在两种细胞系中均以剂量依赖性方式减少增殖并诱导凋亡。此外，塞来昔布与MG132的组合协同抑制了细胞活力并增加了细胞凋亡，这由caspase 3和7激活，PARP裂解和Bcl-2的下调证明。塞来昔布和MG132单独或协同组合诱导内质网（ER）应激基因ATF4，CHOP，TRB3的表达并促进XBP1 mRNA的剪接。通过小干扰RNA抑制TRB3 mRNA表达可显着降低HA22T / VGH细胞中联合诱导的细胞死亡，而增加HepG2细胞中联合诱导的细胞死亡，这表明ER应激反应的激活可能具有有害或保护性作用在肝肿瘤细胞存活中的作用。总之，我们的数据表明，塞来昔布和MG132的联合治疗可产生针对肝癌细胞的协同抗增殖和促凋亡作用，为该联合治疗肝癌的临床应用提供了合理的依据。

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