Pyridoxal isonicotinoyl hydrazone analogs induce apoptosis in hematopoietic cells due to their iron-chelating properties
Pyridoxal isonicotinoyl hydrazone analogs induce apoptosis in hematopoietic cells due to their iron-chelating properties
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DOI：
10.1016/s0006-2952(02)01512-5
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发表时间：
2003-01-15
影响因子：
5.8
通讯作者：
Ponka, P
中科院分区：
文献类型：
--
作者：
Buss, JL;Neuzil, J;Ponka, P
吡哆醛异烟酰肼(PIH)的类似物被认为是治疗继发性铁超载和癌症的铁络合剂。选择毒性在两个数量级以上的妊高征、水杨醛异烟酰肼(SIH)和2-羟基-1-萘醛异烟肼(NIH)作为研究对象，对其毒性机理进行了研究。PIH类似物及其铁络合物可诱导Jurkat T淋巴细胞和K562细胞发生浓度和时间依赖性的凋亡。Bcl2的过表达部分抑制了细胞的凋亡，提示线粒体参与了细胞的凋亡。由于泛caspase抑制剂zVAD-fmk不能减少溶酶体和线粒体的失稳，这些事件发生在caspase激活的上游。相反，磷脂酰丝氨酸外化和凋亡形态的发展被显著抑制，表明caspase在这些后期事件中的作用。由于CrmA的过度表达对细胞凋亡没有影响，caspase-8可能不参与其中。SiH和NIH的Fe3+络合物在与螯合剂孵育过程中积累在Fe-59标记的小鼠网织红细胞中，也引起了细胞凋亡。促进细胞释放复合物的BSA降低了SiH和NIH的毒性，提示PIH类似物诱导细胞凋亡涉及其Fe3+配合物介导的毒性效应。此外，缺乏铁螯合部分的这些试剂的类似物是无毒的。(C)2002年，爱思唯尔科学公司出版。
Analogs of pyridoxal isonicotinoyl hydrazone (PIH) are of interest as iron chelators for the treatment of secondary iron overload and cancer. PIH, salicylaldehyde isonicotinoyl hydrazone (SIH), and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (NIH), the toxicity of which vary over two orders of magnitude, were selected for a study of their mechanisms of toxicity. PIH analogs and their iron complexes caused concentration- and time-dependent apoptosis in Jurkat T lymphocytes and K562 cells. Bcl-2 overexpression was partially anti-apoptotic, suggesting mitochondrial mediation of apoptosis. Since the pan-caspase inhibitor zVAD-fmk did not reduce lysosomal and mitochondrial destabilization, these events occur upstream of caspase activation. In contrast, phosphatidylserine externalization and the development of apoptotic morphology were inhibited significantly, indicating the role of caspases in mediating these later events. Since overexpression of CrmA had no effect on apoptosis, caspase-8 is not likely involved. Fe3+ complexes of SIH and NIH, which accumulated in Fe-59-labeled mouse reticulocytes during incubation with the chelators, also caused apoptosis. BSA, which promotes release of the complexes from cells, reduced the toxicity of SIH and NIH, suggesting that the induction of apoptosis by PIH analogs involves toxic effects mediated by their Fe3+ complexes. Moreover, analogs of these agents lacking the iron-chelating moiety were non-toxic. (C) 2002 Published by Elsevier Science Inc.