抗氧化酶在羟基脲诱导实验性转移增加中的作用。

Role of antioxidant enzymes in the induction of increased experimental metastasis by hydroxyurea.

作者信息

Eskenazi A E, Pinkas J, Whitin J C, Arguello F, Cohen H J, Frantz C N

机构信息

Department of Pediatrics, University of Maryland School of Medicine, Baltimore.

出版信息

J Natl Cancer Inst. 1993 May 5;85(9):711-21. doi: 10.1093/jnci/85.9.711.

DOI:10.1093/jnci/85.9.711

PMID:8478957

Abstract

BACKGROUND

Treatment of tumor cells with hydroxyurea and other DNA-damaging agents has been shown to increase the experimental metastatic potential of these cells.

PURPOSE

We sought to elucidate some of the biochemical and genetic changes that promote tumor cell metastasis in hydroxyurea-treated cells. We hypothesized that drug treatment induces resistance to oxidative damage and that elimination of this resistance reverses the drug-induced experimental metastatic capabilities of tumor cells.

METHODS

We examined the effect of hydroxyurea treatment on B16 melanoma cells with respect to experimental metastatic potential, resistance to hydrogen peroxide (H2O2), glutathione peroxidase activity and messenger RNA (mRNA) level, glutathione reductase activity, glutathione levels, glutathione-S-transferase activity, and catalase activity and mRNA level.

RESULTS

Hydroxyurea-treated cells were transiently more metastatic following intravenous injection in syngeneic mice and transiently more resistant than untreated cells to exogenous H2O2. Hydroxyurea-induced experimental metastases and H2O2 resistance were eliminated by depletion of intracellular glutathione with buthionine sulfoximine. Glutathione peroxidase activity and mRNA level, glutathione reductase activity, and reduced glutathione levels were all transiently increased in hydroxyurea-treated cells, whereas the increase in glutathione-S-transferase activity was sustained. Catalase activity was modestly increased with no increase in its mRNA levels.

CONCLUSIONS

In B16 melanoma cells, experimental metastasis induced by hydroxyurea appears to depend on a process that requires glutathione. Hydroxyurea treatment also induces resistance to exogenous H2O2, which may be due to induction of glutathione and antioxidant enzyme activity.

IMPLICATIONS

The role of antioxidants in B16 melanoma cells offers new insights into the metastatic process and the cellular response to chemotherapy.

摘要

背景

已证明用羟基脲和其他DNA损伤剂处理肿瘤细胞可增加这些细胞的实验性转移潜能。

目的

我们试图阐明在羟基脲处理的细胞中促进肿瘤细胞转移的一些生化和基因变化。我们假设药物处理诱导对氧化损伤的抗性，并且消除这种抗性可逆转药物诱导的肿瘤细胞实验性转移能力。

方法

我们研究了羟基脲处理对B16黑色素瘤细胞在实验性转移潜能、对过氧化氢（H2O2）的抗性、谷胱甘肽过氧化物酶活性和信使核糖核酸（mRNA）水平、谷胱甘肽还原酶活性、谷胱甘肽水平、谷胱甘肽-S-转移酶活性以及过氧化氢酶活性和mRNA水平方面的影响。

结果

在同基因小鼠中静脉注射后，经羟基脲处理的细胞短暂性地具有更高的转移能力，并且比未处理的细胞对外源H2O2具有更高的抗性。用丁硫氨酸亚砜胺耗尽细胞内谷胱甘肽可消除羟基脲诱导的实验性转移和H2O2抗性。在经羟基脲处理的细胞中，谷胱甘肽过氧化物酶活性和mRNA水平、谷胱甘肽还原酶活性以及还原型谷胱甘肽水平均短暂升高，而谷胱甘肽-S-转移酶活性的升高则持续存在。过氧化氢酶活性适度增加，但其mRNA水平未升高。