Sequence-selective DNA binding drugs mithramycin A and chromomycin A3 are potent inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in cortical neurons
Sequence-selective DNA binding drugs mithramycin A and chromomycin A3 are potent inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in cortical neurons
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DOI：
10.1002/ana.71
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发表时间：
2001-03-01
影响因子：
11.2
通讯作者：
Ratan, RR
中科院分区：
文献类型：
--
作者：
Chatterjee, S;Zaman, K;Ratan, RR
放线菌素D或放线菌亚胺等RNA或蛋白质合成的全局抑制剂在体外和体内均可阻断由多种病理刺激诱导的神经细胞凋亡。放线菌素D或放线菌亚胺在人类神经系统疾病中的临床应用受到这些药物毒性的限制。为了克服这些毒性，必须制定策略，选择性地抑制有害的促凋亡蛋白的表达，同时保持抗凋亡、促再生和其他关键的动态平衡蛋白的表达不受干扰。米特拉霉素A(商标为普莱霉素)是一种金黄色抗生素，已用于人类治疗高钙血症和几种癌症。据信，这类药物的作用部分是通过取代与启动子富含G-C区域结合的转录激活剂来选择性地抑制基因表达。在这里，我们证明了米特拉霉素A及其结构类似物色霉素A3是由谷胱甘肽耗竭诱导的DNA损伤剂喜树碱氧化应激诱导的神经元凋亡的有效抑制剂。我们将米特拉霉素A的保护作用与其抑制氧化应激或DNA损伤引起的转录因子Sp1和Sp3与其同源G-C盒的DNA结合增强的能力相关联。米曲霉素A的保护作用不能归因于对蛋白质合成的全面抑制。总之，这些结果表明，米曲霉素A及其结构类似物可能是治疗与细胞凋亡异常激活相关的神经系统疾病的有效药物，并突出了序列选择性DNA结合药物作为神经治疗药物的潜在用途。
Global inhibitors of RNA or protein synthesis such as actinomycin D or cycloheximide abrogate neuronal apoptosis induced by numerous pathological stimuli in vitro and in vivo. The clinical application of actinomycin D or cycloheximide to human neurological disease has been limited by the toxicities of these agents. To overcome these toxicities, strategies must be developed to inhibit selectively the expression of deleterious proapoptotic proteins, while leaving the expression of antiapoptotic, proregeneration, and other critical homeostatic proteins unperturbed. Mithramycin A (trade name Plicamycin) is an aureolic acid antibiotic that has been used in humans to treat hypercalcemia and several types of cancers. This class of agents is believed to act, in part, by selectively inhibiting gene expression by displacing transcriptional activators that bind to G-C-rich regions of promoters. Here we demonstrate that mithramycin A and its structural analog chromomycin A3 are potent inhibitors of neuronal apopotosis induced by glutathione depletion-induced oxidative stress of the DNA-damaging agent camptothecin. We correlate the protective effects of mithramycin A with its ability to inhibit enhanced DNA binding of the transcription factors Sp1 andSp3 to their cognate "G-C" box induced by oxidative stress or DNA damage. The protective effects of mithramycin A cannot be attributed to global inhibition of protein synthesis. Together, these results suggest that mithramycin A and its structural analogs may be effective agents for the treatment of neurological diseases associated with aberrant activation of apoptosis and highlight the potential use of sequence-selective DNA-binding drugs as neurological therapeutics.