Unexpected Enhancement of Cytotoxicity of Cisplatin in a Rat Kidney Proximal Tubular Cell Line Overexpressing Mitochondrial Glutathione Transport Activity.
Unexpected Enhancement of Cytotoxicity of Cisplatin in a Rat Kidney Proximal Tubular Cell Line Overexpressing Mitochondrial Glutathione Transport Activity.
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顺铂在过度表达线粒体谷氨酸转运活性的大鼠肾近端小管细胞系中的细胞毒性意外增强。
DOI：
10.3390/ijms23041993
复制
发表时间：
2022-02-11
影响因子：
5.6
通讯作者：
Lash LH
中科院分区：
文献类型：
--
作者：
Lash LH
在以前的研究中，我们确定了两个主要的转运蛋白介导的谷胱甘肽（GSH）从细胞质的摄取到线粒体基质的大鼠肾近端小管细胞。我们假设转运蛋白表达的遗传调节可以显著改变肾近端小管细胞对一系列氧化剂和线粒体毒物的敏感性。事实上，我们以前表明，这些转运蛋白的过度表达导致对几种化学物质的敏感性降低。在目前的工作中，我们研究了线粒体2-酮戊二酸载体（OGC）在NRK-52 E细胞中的过表达对顺铂细胞毒性的影响。与先前的结果显示线粒体OGC的过表达提供了NRK-52 E细胞免受几种毒物损伤的实质性保护相反，我们发现与野生型NRK-52 E细胞相比，暴露于顺铂的细胞损伤显著增强。尽管已知顺铂在肾近端小管中引起氧化应激，但与OGC过表达相关的线粒体GSH浓度增加可能导致顺铂向分子靶点的递送增加和细胞损伤增加，而不是先前工作中观察到的典型保护。
In previous studies, we identified the two principal transporters that mediate the uptake of glutathione (GSH) from cytoplasm into the mitochondrial matrix of rat kidney proximal tubular cells. We hypothesized that genetic modulation of transporter expression could markedly alter susceptibility of renal proximal tubular cells to a broad array of oxidants and mitochondrial toxicants. Indeed, we previously showed that overexpression of either of these transporters resulted in diminished susceptibility to several chemicals. In the present work, we investigated the influence of overexpression of the mitochondrial 2-oxoglutarate carrier (OGC) in NRK-52E cells on the cytotoxicity of the antineoplastic drug cisplatin. In contrast to previous results showing that overexpression of the mitochondrial OGC provided substantial protection of NRK-52E cells from injury due to several toxicants, we found a remarkable enhancement of cellular injury from exposure to cisplatin as compared to wild-type NRK-52E cells. Despite the oxidative stress that cisplatin is known to cause in the renal proximal tubule, the increased concentrations of mitochondrial GSH associated with OGC overexpression likely resulted in increased delivery of cisplatin to molecular targets and increased cellular injury rather than the typical protection observed in the previous work.
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DOI：
10.1124/jpet.103.060541
发表时间：
2004-03-01
影响因子：
3.5
作者：
Cummings, BS;McHowat, J;Schnellmann, RG
通讯作者：
Schnellmann, RG
影响因子：
5.1
作者：
Lash, Lawrence H.
通讯作者：
Lash, Lawrence H.
单功能铂(II)抗癌剂
DOI：
10.3390/ph14020133
发表时间：
2021-02-07
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Jin S;Guo Y;Guo Z;Wang X
通讯作者：
Wang X
DOI：
10.1080/15287394.2021.1969305
发表时间：
2021-08-29
影响因子：
2.6
作者：
Kim, Hae Ri;Park, Jae Hyeon;Kim, Hyung Sik
通讯作者：
Kim, Hyung Sik
影响因子：
13.6
作者：
Bolisetty, Subhashini;Traylor, Amie M.;Agarwal, Anupam
通讯作者：
Agarwal, Anupam