Sodium salicylate is a novel catalytic inhibitor of human DNA topoisomerase II alpha
Sodium salicylate is a novel catalytic inhibitor of human DNA topoisomerase II alpha
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DOI：
10.1016/j.bcp.2010.10.009
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发表时间：
2011-02-01
影响因子：
5.8
通讯作者：
Kurz, Ebba U.
中科院分区：
文献类型：
--
作者：
Bau, Jason T.;Kurz, Ebba U.
我们以前曾报道，预处理的人淋巴母细胞与羟基自由基清除剂，N-乙酰半胱氨酸，减弱阿霉素诱导的DNA损伤信号通过ATM蛋白激酶。我们试图扩展这些研究，以检查其他羟基自由基清除剂在人类乳腺癌细胞中的作用。使用MCF-7细胞，我们观察到阿霉素处理触发ATM在丝氨酸1981上的自磷酸化及其下游效应子p53、Chk 2和SMC 1的ATM依赖性激活。此外，我们证明，用羟基自由基清除剂苯甲酸钠、水杨酸钠和较小程度的N-乙酰半胱氨酸预处理细胞可以减弱这种作用，但Trolox（TM）则不然。有趣的是，这些效果是独立的阿霉素的氧化还原循环的能力，观察到多种类型的拓扑异构酶II毒药，但并不代表一般的损伤衰减响应。此外，观察到的效应与水杨酸钠抑制环氧合酶-2或NF κ B的能力无关。我们证明，水杨酸钠防止阿霉素诱导的DNA双链断裂的产生，这是由于抑制阿霉素稳定的拓扑异构酶II α-DNA可切割的复合物在体内形成。使用拓扑异构酶II α-DNA切割和去连环化测定，我们确定水杨酸钠是拓扑异构酶II α的催化抑制剂。与观察到的双链断裂形成的抑制一致，用水杨酸钠预处理细胞减弱了阿霉素和依托泊苷的细胞毒性。这些结果表明水杨酸钠的一种新的作用机制，并建议进一步研究拓扑异构酶II抑制机制和相关治疗对阿霉素和依托泊苷细胞毒性的影响是必要的。(C)2010年爱思唯尔公司All rights reserved.
We have previously reported that pretreatment of human lymphoblastoid cells with the hydroxyl radical scavenger, N-acetyl cysteine, attenuates doxorubicin-induced DNA damage signalling through the ATM protein kinase. We sought to extend these studies to examine the effects of other hydroxyl radical scavengers in human breast cancer cells. Using MCF-7 cells, we observed that doxorubicin treatment triggered autophosphorylation of ATM on serine 1981 and the ATM-dependent activation of its downstream effectors p53, Chk2, and SMC1. Furthermore, we demonstrate that this effect was attenuated by pretreatment of cells with the hydroxyl radical scavengers sodium benzoate, sodium salicylate and, to a lesser extent, N-acetyl cysteine, but not Trolox(TM). Intriguingly, these effects were independent of doxorubicin's ability to redox cycle, were observed with multiple classes of topoisomerase II poisons, but did not represent a general damage-attenuating response. In addition, the observed effects were independent of the ability of sodium salicylate to inhibit cyclooxygenase-2 or NF kappa B. We demonstrate that sodium salicylate prevented doxorubicin-induced DNA double-strand break generation, which was attributable to inhibition of doxorubicin-stabilized topoisomerase II alpha-DNA cleavable complex formation in vivo. Using topoisomerase II alpha-DNA cleavage and decatenation assays, we determined that sodium salicylate is a catalytic inhibitor of topoisomerase II alpha. Consistent with the observed inhibition of double-strand break formation, pretreatment of cells with sodium salicylate attenuated doxorubicin and etoposide cytotoxicity. These results demonstrate a novel mechanism of action for sodium salicylate and suggest that further study on the mechanism of topoisomerase II inhibition and the effects of related therapeutics on doxorubicin and etoposide cytotoxicity are warranted. (C) 2010 Elsevier Inc. All rights reserved.