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首页> 外文期刊>British Journal of Cancer >Do altering in ornithine decarboxylase activity and gene expression contribute to antiproliferative properties of COX inhibitors?
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Do altering in ornithine decarboxylase activity and gene expression contribute to antiproliferative properties of COX inhibitors?

机译：鸟氨酸脱羧酶活性和基因表达的改变是否有助于COX抑制剂的抗增殖特性？

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Two isoforms of cyclooxygenase (COX) participate in growth control; COX-1 is constitutively expressed in most cells, and COX-2 is an inducible enzyme in response to cellular stimuli. An induction of COX-2 found in neoplastic tissues results in increased cell growth, inhibition of apoptosis, activation of angiogenesis, and decreased immune responsiveness. Although both COX-1 and COX-2 inhibitors are suppressors of cell proliferation and appear to be chemopreventive agents for tumorigenesis, the molecular mechanisms mediating antiproliferative effect of COX inhibitors are still not well defined. This study contrasts and compares the effects of aspirin and celecoxib, inhibitors of COX-1 and COX-2, in rat hepatoma HTC-IR cells. The following were assessed: cell proliferation and apoptosis, ornithine decarboxylase (ODC) activity, and pattern expression of three immediate-early genes, c-myc, Egr-1, and c-fos. We have shown that the treatment of hepatocytes in vitro with the selective COX-2 inhibitor, celecoxib, was associated with induction of apoptosis and complete inhibition of cellular proliferation. Aspirin exhibited a small antiproliferative effect that was not associated with apoptosis. Treatment with celecoxib produced dose- and time-dependent decrease in ODC activity. In addition, at higher drug concentration the decrease in ODC activity was greater in proliferating than in resting cells. Much lesser inhibitory effect on ODC activity was observed in aspirin-treated cells. The two COX inhibitors did not change c-myc expression, significantly decreased the expression of Egr-1, and differentially altered expression of c-fos; aspirin did not change, but celecoxib dramatically decreased the levels of c-fos-mRNA. Our study revealed that celecoxib and aspirin share the ability to inhibit ODC activity and alter the pattern of immediate-early gene expression. It seems that some of the observed effects are likely to be related to COX-independent pathways. The precise mechanisms of action of COX inhibitors should be defined before using these drugs for cancer chemopreventive therapy.
机译：环氧合酶（COX）的两种同工型参与生长控制。 COX-1在大多数细胞中组成性表达，而COX-2是响应细胞刺激的可诱导酶。在肿瘤组织中发现的COX-2诱导导致细胞生长增加，细胞凋亡抑制，血管生成激活和免疫应答降低。尽管COX-1和COX-2抑制剂均是细胞增殖的抑制剂，并且似乎是肿瘤发生的化学预防剂，但介导COX抑制剂抗增殖作用的分子机制仍不清楚。这项研究对比并比较了阿司匹林和塞来昔布（COX-1和COX-2的抑制剂）在大鼠肝癌HTC-IR细胞中的作用。评估了以下内容：细胞增殖和凋亡，鸟氨酸脱羧酶（ODC）活性以及三个即早基因c-myc，Egr-1和c-fos的模式表达。我们已经表明，在体外用选择性COX-2抑制剂塞来昔布治疗肝细胞与诱导凋亡和完全抑制细胞增殖有关。阿司匹林显示出小的抗增殖作用，与细胞凋亡无关。塞来昔布治疗导致ODC活性的剂量和时间依赖性降低。此外，在较高的药物浓度下，ODC活性的下降比在静息细胞中更大。在阿司匹林处理的细胞中观察到对ODC活性的抑制作用要小得多。两种COX抑制剂均未改变c-myc表达，显着降低了Egr-1的表达，并差异地改变了c-fos的表达。阿司匹林没有改变，但是塞来昔布显着降低了c-fos-mRNA的水平。我们的研究表明，塞来昔布和阿司匹林具有抑制ODC活性和改变即刻早期基因表达模式的能力。似乎某些观察到的作用可能与COX非依赖性途径有关。在将这些药物用于癌症化学预防治疗之前，应定义COX抑制剂的确切作用机理。

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