Some thoughts on the mechanism of cellular trapping of Cu(II)-ATSM
Some thoughts on the mechanism of cellular trapping of Cu(II)-ATSM
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DOI：
10.1016/j.nucmedbio.2009.11.004
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发表时间：
2010-04-01
影响因子：
3.1
通讯作者：
Packard, Alan B.
中科院分区：
文献类型：
--
作者：
Dearling, Jason L. J.;Packard, Alan B.
Cu（II）-ATSM作为肿瘤缺氧显像剂在实验室和临床上继续被研究。然而，对这些图像的有意义的解释需要更全面地了解示踪剂被捕获在细胞内的机制。Cu（II）-ATSM是一种简单的分子，其与细胞的生物化学相互作用同样简单，主要基于氧化还原化学。在这里，我们认为，捕获机制是双相的。第一阶段是涉及硫醇和分子氧的还原/氧化循环。这之后可以与线粒体中的蛋白质相互作用，导致示踪剂的更永久保留。由于缺氧导致细胞发生变化，例如烟酰胺腺嘌呤二核苷酸（NADH）氧化还原状态的增加以及细胞生物化学和细胞蛋白质组的差异，第二步的摄取机制变得复杂。这些变化可能导致不同细胞类型中（64）Cu的捕获和保留程度的差异。例如，由于金属双（缩氨基硫脲）在酸性条件下的较低稳定性，在具有较低pH的细胞中铜摄取可能增加。与细胞还原剂的反应速率也随pH而变化，pH在细胞器之间不同。对于Cu（II）-ATSM，为了充分发挥其潜力，需要更完整地表征不同细胞类型中的细胞捕获机制。(C)2010年爱思唯尔公司All rights reserved.
Cu(II)-ATSM continues to be investigated, both in the laboratory and in the clinic, as a tumor hypoxia imaging agent. However, meaningful interpretation of these images requires a more complete understanding of the mechanism by which the tracer is trapped within the cell. Cu(II)-ATSM is a simple molecule and its biochemical interaction with cells is similarly simple, mainly based upon redox chemistry. Here we suggest that the trapping mechanism is biphasic. The first phase is a reduction/oxidation cycle involving thiols and molecular oxygen. This can be followed by interaction with proteins in the mitochondria leading to more permanent retention of the tracer. The uptake mechanism is complicated by this second step because of the changes in the cell resulting from hypoxia, such as an increase in nicotinamide adenine dinucleotide (NADH) redox state and differences in cellular biochemistry and cell proteomes. These changes may lead to differences in the extent of trapping and retention of the (64)Cu in different cell types. For example, copper uptake might be increased in cells with lower pH due to the lower stability of metal bis(thiosemicarbazones) under acidic conditions. Reaction rates with cellular reductants also vary with pH, which differs between cellular organelles. For Cu(II)-ATSM to reach its full potential, more complete characterization of the mechanism of cellular trapping in different cell types is required. (C) 2010 Elsevier Inc. All rights reserved.