Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Eur J Pharmacol. 2010 Jul 25;638(1-3):13-20. doi: 10.1016/j.ejphar.2010.04.012. Epub 2010 Apr 18.
Chemopreventive non-steroidal anti-inflammatory drugs (NSAIDs) exhibit diverse pharmacological and biological activities mainly through their inhibitory effect on cyclooxygenase (COX). However, COX-independent mechanisms involving kinase inhibition have been proposed to explain certain therapeutic effects of NSAIDs. Here, we explored the potential relationship between chemopreventive NSAIDs and DNA damage responses induced by treatment with topoisomerase-targeting drugs. (1) Sodium salicylate, a non-COX-selective NSAID, was shown to reduce DNA damage-induced RPA and p53 phosphorylation. (2) The formation of enzyme cleavable complexes by topoisomerase-targeting drugs was not affected in the presence of sodium salicylate. (3) The attenuating effect of NSAIDs on the DNA damage responses is COX-2-independent, since COX-2-selective inhibitors failed to inhibit DNA damage-induced phosphorylation of replication protein A (RPA) and p53. (4) This COX-2-independent attenuating effect was mediated through interference of neither nuclear factor kappa B nor extracellular signal-regulated kinase pathways. (5) The activation of ataxia telangiectasia mutated (ATM) kinase and DNA-dependent protein kinase (DNA-PK), two key signal transducers upstream of RPA and p53, was found to be significantly reduced with sodium salicylate treatment. (6) Most importantly, sodium salicylate and other NSAIDs directly inhibited kinase activity of ATM and DNA-PK. The extent of inhibition on the kinase activity also correlated with the degree of attenuation on the DNA damage responses. (7) Unexpectedly, sodium salicylate showed a p53-independent protection effect on topoisomerase-mediated cell killing. Together, our study provides evidence that NSAIDs exhibit a novel COX-independent modulating activity of NSAIDs on the DNA damage responses and it is through inhibition of phosphoinositide 3-kinase-like kinases.
化学预防非甾体抗炎药 (NSAIDs) 通过抑制环氧化酶 (COX) 表现出多种药理学和生物学活性。然而，已经提出了涉及激酶抑制的 COX 非依赖性机制来解释 NSAIDs 的某些治疗效果。在这里，我们探讨了化学预防 NSAIDs 与拓扑异构酶靶向药物治疗诱导的 DNA 损伤反应之间的潜在关系。(1) 非 COX 选择性 NSAID 水杨酸钠被证明可减少 DNA 损伤诱导的 RPA 和 p53 磷酸化。(2) 拓扑异构酶靶向药物形成酶可切割复合物的情况在存在水杨酸钠时不受影响。(3) COX-2 选择性抑制剂不能抑制 DNA 损伤诱导的复制蛋白 A (RPA) 和 p53 磷酸化，表明 NSAIDs 对 DNA 损伤反应的减弱作用与 COX-2 无关。(4) 这种 COX-2 非依赖性减弱作用不是通过核因子 kappa B 或细胞外信号调节激酶途径的干扰介导的。(5) 发现 ATM 激酶和 DNA 依赖性蛋白激酶 (DNA-PK) 的激活，RPA 和 p53 的两个关键信号转导物在上游，明显减少了水杨酸钠处理。(6) 最重要的是，水杨酸钠和其他 NSAIDs 直接抑制 ATM 和 DNA-PK 的激酶活性。对激酶活性的抑制程度也与对 DNA 损伤反应的减弱程度相关。(7) 出乎意料的是，水杨酸钠对拓扑异构酶介导的细胞杀伤表现出 p53 独立的保护作用。总之，我们的研究提供了证据，表明 NSAIDs 表现出一种新型的 COX 独立调节作用，可调节 DNA 损伤反应，这是通过抑制磷酸肌醇 3-激酶样激酶来实现的。
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