The Effect of Glutathione Peroxidase-1 Knockout on Anticancer Drug Sensitivities and Reactive Oxygen Species in Haploid HAP-1 Cells
The Effect of Glutathione Peroxidase-1 Knockout on Anticancer Drug Sensitivities and Reactive Oxygen Species in Haploid HAP-1 Cells
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DOI：
10.3390/antiox9121300
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发表时间：
2020-12-18
期刊：
影响因子：
7
通讯作者：
Bednarski PJ
中科院分区：
文献类型：
--
作者：
Behnisch-Cornwell S;Wolff L;Bednarski PJ
谷胱甘肽过氧化物酶(GPX)在肿瘤中的作用及其对肿瘤预后和抗癌耐药性发展的影响一直是人们广泛而有争议的讨论。本研究的目的是评价GPX1的表达对抗癌药物细胞毒作用的影响。为此，我们获得了近单倍体人类癌细胞系HAP-1的GPX1基因敲除，并在形态、生长和代谢率以及氧化应激防御能力方面与天然细胞系进行了比较。此外，还测定了两种过氧化氢和16种常用抗癌药物在两种细胞系中的IC50值。在此，我们报告了在HAP-1细胞中敲除GPX1对细胞大小、活力、生长和代谢率没有显著影响。过氧化氢和叔丁基氢过氧化氢、抗癌药物顺铂和卡铂以及烷化剂洛莫司汀和替莫唑胺的细胞毒力显著增加。在顺铂、洛莫司汀或替莫唑胺处理的HAP-1细胞株中，细胞内的ROS水平均呈浓度依赖性升高，而GPX1基因敲除的HAP-1细胞株中，除最高浓度替莫唑胺外，与天然细胞株相比，ROS水平没有显著升高。另一方面，与天然系相比，在GPX1基因敲除中发现谷胱甘肽水平下降了约50%，这表明除了ROS水平之外的其他因素单独在这些药物在GPX1基因敲除细胞中增强细胞毒活性中起作用。
The role of glutathione peroxidases (GPx) in cancer and their influence on tumor prognosis and the development of anticancer drug resistance has been extensively and controversially discussed. The aim of this study was to evaluate the influence of GPx1 expression on anticancer drug cytotoxicity. For this purpose, a GPx1 knockout of the near-haploid human cancer cell line HAP-1 was generated and compared to the native cell line with regards to morphology, growth and metabolic rates, and oxidative stress defenses. Furthermore, the IC50 values of two peroxides and 16 widely used anticancer drugs were determined in both cell lines. Here we report that the knockout of GPx1 in HAP-1 cells has no significant effect on cell size, viability, growth and metabolic rates. Significant increases in the cytotoxic potency of hydrogen peroxide and tert-butylhydroperoxide, the anticancer drugs cisplatin and carboplatin as well as the alkylating agents lomustine and temozolomide were found. While a concentration dependent increases in intracellular reactive oxygen species (ROS) levels were observed for both HAP-1 cell lines treated with either cisplatin, lomustine or temozolamide, no significant enhancement in ROS levels was observed in the GPx1 knockout compared to the native cell line except at the highest concentration of temozolamide. On the other hand, a ca. 50% decrease in glutathione levels was noted in the GPx1 knockout relative to the native line, suggesting that factors other than ROS levels alone play a role in the increased cytotoxic activity of these drugs in the GPx1 knockout cells.
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影响因子：
3.6
作者：
Oancea-Castillo LR;Klein C;Abdollahi A;Weber KJ;Régnier-Vigouroux A;Dokic I
通讯作者：
Dokic I
影响因子：
2.8
作者：
Jerome-Morais, Anita;Wright, Margaret E.;Liu, Rui;Yang, Wancai;Jackson, Matthew I.;Combs, Gerald F., Jr.;Diamond, Alan M.
通讯作者：
Diamond, Alan M.
影响因子：
2.9
作者：
Rusolo, Fabiola;Capone, Francesca;Costantini, Susan
通讯作者：
Costantini, Susan
影响因子：
2.9
作者：
Colella, Alex D.;Chegenii, Nusha;Chataway, Tim K.
通讯作者：
Chataway, Tim K.
影响因子：
7.4
作者：
Fu, YX;Cheng, WH;Lei, XG
通讯作者：
Lei, XG