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首页> 外文期刊>Biochemical Pharmacology >COX-2 inhibitors block chemotherapeutic agent-induced apoptosis prior to commitment in hematopoietic cancer cells.
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COX-2 inhibitors block chemotherapeutic agent-induced apoptosis prior to commitment in hematopoietic cancer cells.

机译：在定型于造血癌细胞之前，COX-2抑制剂可阻断化学治疗剂诱导的凋亡。

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Enzymatic inhibitors of pro-inflammatory cyclooxygenase-2 (COX-2) possess multiple anti-cancer effects, including chemosensitization. These effects are not always linked to the inhibition of the COX-2 enzyme. Here we analyze the effects of three COX-2 enzyme inhibitors (nimesulide, NS-398 and celecoxib) on apoptosis in different hematopoietic cancer models. Surprisingly, COX-2 inhibitors strongly prevent apoptosis induced by a panel of chemotherapeutic agents. We selected U937 cells as a model of sensitive cells for further studies. Here, we provide evidence that the protective effect is COX-independent. No suppression of the low basal prostaglandin (PG)E(2) production may be observed upon treatment by COX-2 inhibitors. Besides, the non-active celecoxib analog 2,5-dimethyl-celecoxib is able to protect from apoptosis as well. We demonstrate early prevention of the stress-induced apoptotic signaling, prior to Bax/Bak activation. This preventive effect fits with an impairment of the ability of chemotherapeutic agents to trigger apoptogenic stress. Accordingly, etoposide-induced DNA damage is strongly attenuated in the presence of COX-2 inhibitors. In contrast, COX-2 inhibitors do not exert any anti-apoptotic activity when cells are challenged with physiological stimuli (anti-Fas, TNFalpha or Trail) or with hydrogen peroxide, which do not require internalization and/or are not targeted by chemoresistance proteins. Altogether, our findings show a differential off-target anti-apoptotic effect of COX-2 inhibitors on intrinsic vs. extrinsic apoptosis at the very early steps of intracellular signaling, prior to commitment. The results imply that an exacerbation of the chemoresistance phenomena may be implicated.
机译：促炎性环氧合酶2（COX-2）的酶抑制剂具有多种抗癌作用，包括化学增敏作用。这些作用并不总是与抑制COX-2酶有关。在这里，我们分析了三种COX-2酶抑制剂（尼美舒利，NS-398和塞来昔布）对不同造血癌症模型中细胞凋亡的影响。出人意料的是，COX-2抑制剂强烈阻止了一组化学治疗剂诱导的细胞凋亡。我们选择U937细胞作为敏感细胞的模型进行进一步研究。在这里，我们提供了保护作用与COX无关的证据。经COX-2抑制剂治疗后，未见低基底前列腺素（PG）E（2）产生的抑制作用。此外，非活性塞来昔布类似物2，5-二甲基塞来昔布也能够防止细胞凋亡。我们展示了在Bax / Bak激活之前对应激诱导的细胞凋亡信号的早期预防。这种预防作用与化学治疗剂触发凋亡的能力的损害相吻合。因此，在COX-2抑制剂存在下，依托泊苷诱导的DNA损伤被大大减轻。相反，当细胞受到生理刺激（抗Fas，TNFalpha或Trail）或过氧化氢攻击时，COX-2抑制剂不发挥任何抗凋亡活性，而后者不需要内在化和/或不受化学抗性蛋白的靶向。总而言之，我们的发现表明，在承诺之前，COX-2抑制剂对细胞内信号传导的非常早期步骤的内在和外在凋亡均具有不同的脱靶抗凋亡作用。结果暗示可能牵涉到化学抗性现象的恶化。

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