Samimi Goli, Howell Stephen B
Department of Medicine, The Rebecca and John Moores UCSD Cancer Center, Mail code 0819, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Cancer Chemother Pharmacol. 2006 Jun;57(6):781-8. doi: 10.1007/s00280-005-0121-5. Epub 2005 Sep 17.
Satraplatin is an orally bioavailable platinum analog that has activity in prostate cancer. JM118 is the most abundant species found in the plasma following the oral ingestion of satraplatin and has anti-tumor activity in vitro against cell lines that are resistant to cisplatin (DDP). The goal of the current study was to determine whether the activity of JM118 in some DDP-resistant cells can be explained by differences in the cellular pharmacology of the two drugs. The effect of each of the Cu transporters CTR1, ATP7A and ATP7B on sensitivity to the growth inhibitory effect of JM118 and its cellular pharmacology was examined to identify the characteristics of JM118 that distinguish it from DDP. These studies were performed using wild type and CTR1-/- homozygous knockout mouse embryo cells, and human Me32a Menkes disease fibroblasts that do not express either ATP7A or ATP7B plus sublines molecularly engineered to express either ATP7A (MeMNK cells) or ATP7B (MeWND cells). Knockout of the Cu influx transporter CTR1 in murine embryo cells increased their resistance to DDP and reduced its cellular accumulation but had no effect on sensitivity to JM118 or its uptake. In the case of DDP, forced expression of either of the two Cu efflux transporters, ATP7A or ATP7B, in Me32a cells rendered them resistant to DDP, increased whole cell accumulation of Pt but reduced the amount of Pt in DNA. In the case of JM118, forced expression of either ATP7A or ATP7B rendered Me32a cells resistant, increased not only whole cell Pt accumulation but also increased rather than decreased the amount of Pt in DNA. These results demonstrate that both ATP7A and ATP7B mediate resistance to JM118 as well as DDP and suggest that they sequester both DDP and JM118 into vesicular compartments within the cell resulting in enhanced whole cell accumulation and reduced cytotoxicity. We conclude that there are two important differences between DDP and JM118 with respect to the effect of Cu transporters on their cellular pharmacology. First, whereas CTR1 is involved in DDP accumulation it does not play a role in the uptake of JM118. Second, ATP7A and ATP7B, while they both mediate resistance, have opposite effects on the accumulation of Pt in DNA following exposure to the two drugs. ATP7A and ATP7B appear to be able to modulate the toxicity of the Pt that accumulates in DNA following exposure to JM118. These results suggest that JM118 will retain activity in cells in which DDP resistance is due to the loss of CTR1, but not in cells in which resistance is due to enhanced expression of ATP7A or ATP7B.
沙铂是一种口服生物可利用的铂类似物，对前列腺癌具有活性。JM118是口服沙铂后血浆中发现的最丰富的物质，对顺铂（DDP）耐药的细胞系具有体外抗肿瘤活性。本研究的目的是确定JM118在某些DDP耐药细胞中的活性是否可以通过两种药物细胞药理学的差异来解释。研究了铜转运蛋白CTR1、ATP7A和ATP7B对JM118生长抑制作用敏感性及其细胞药理学的影响，以确定JM118与DDP不同的特征。这些研究使用野生型和CTR1-/-纯合敲除小鼠胚胎细胞，以及不表达ATP7A或ATP7B的人类Me32a门克斯病成纤维细胞，外加经分子工程改造以表达ATP7A（MeMNK细胞）或ATP7B（MeWND细胞）的亚系。敲除小鼠胚胎细胞中的铜流入转运蛋白CTR1增加了它们对DDP的抗性并减少了其细胞内积累，但对JM118的敏感性或其摄取没有影响。就DDP而言，在Me32a细胞中强制表达两种铜流出转运蛋白ATP7A或ATP7B之一使它们对DDP产生抗性，增加了全细胞铂的积累，但减少了DNA中的铂含量。就JM118而言，强制表达ATP7A或ATP7B使Me32a细胞产生抗性，不仅增加了全细胞铂的积累，而且增加而不是减少了DNA中的铂含量。这些结果表明，ATP7A和ATP7B均介导对JM118以及DDP的抗性，并表明它们将DDP和JM118都隔离到细胞内的囊泡区室中，导致全细胞积累增强和细胞毒性降低。我们得出结论，就铜转运蛋白对其细胞药理学的影响而言，DDP和JM118之间存在两个重要差异。第一，虽然CTR1参与DDP的积累，但它在JM118的摄取中不起作用。第二，ATP7A和ATP7B虽然都介导抗性，但在暴露于两种药物后对DNA中铂的积累有相反的影响。ATP7A和ATP7B似乎能够调节暴露于JM118后在DNA中积累的铂的毒性。这些结果表明，JM118在DDP抗性是由于CTR1缺失的细胞中仍将保持活性，但在抗性是由于ATP7A或ATP7B表达增强的细胞中则不然。
