打开APP

JCI:超氧化物歧化酶抑制剂阻断非小细胞肺癌细胞生长

  1. SOD
  2. 非小细胞肺癌

来源:生物谷 2013-12-12 21:18

2013年12月13日讯 /生物谷BIOON/--许多癌症已经适应应付高浓度的自由基(由免疫系统产生),也被称为活性氧,其机制为肿瘤细胞能过量产生具有抗氧化作用的蛋白质。

这些蛋白质之一,超氧化物歧化酶1(SOD1)在肺腺癌细胞中过量产生,已经是化疗药物的作用对象之一。发表在Journal of Clinical Investigation杂志上的一项研究中,Navdeep Chandel和美国西北大学同事们报告SOD1药理抑制剂对非小细胞肺癌(NSCLC)细胞的作用。

抑制剂--ATN-224阻断培养的人非小细胞肺癌细胞生长,并诱导其死亡。研究人员还发现,ATN-224抑制其他抗氧化蛋白,导致细胞内高浓度的过氧化氢。

过氧化氢的生成对于ATN-224的抑制效应是必需的,因为过氧化氢激活细胞的死亡途径。另外,ATN-224能诱导癌细胞死亡,减少肺腺癌小鼠模型的肿瘤大小。当该抑制剂与另一种药物(激活程序性细胞死亡)组合使用时,ATN-224在动物中的抑制作用被加强。(生物谷Bioon.com)

Targeting SOD1 reduces experimental non-small-cell lung cancer

Andrea Glasauer, et al.

Approximately 85% of lung cancers are non–small-cell lung cancers (NSCLCs), which are often diagnosed at an advanced stage and associated with poor prognosis. Currently, there are very few therapies available for NSCLCs due to the recalcitrant nature of this cancer. Mutations that activate the small GTPase KRAS are found in 20% to 30% of NSCLCs. Here, we report that inhibition of superoxide dismutase 1 (SOD1) by the small molecule ATN-224 induced cell death in various NSCLC cells, including those harboring KRAS mutations. ATN-224–dependent SOD1 inhibition increased superoxide, which diminished enzyme activity of the antioxidant glutathione peroxidase, leading to an increase in intracellular hydrogen peroxide (H2O2) levels. We found that ATN-224–induced cell death was mediated through H2O2-dependent activation of P38 MAPK and that P38 activation led to a decrease in the antiapoptotic factor MCL1, which is often upregulated in NSCLC. Treatment with both ATN-224 and ABT-263, an inhibitor of the apoptosis regulators BCL2/BCLXL, augmented cell death. Furthermore, we demonstrate that ATN-224 reduced tumor burden in a mouse model of NSCLC. Our results indicate that antioxidant inhibition by ATN-224 has potential clinical applications as a single agent, or in combination with other drugs, for the treatment of patients with various forms of NSCLC, including KRAS-driven cancers.

 

版权声明 本网站所有注明“来源:生物谷”或“来源:bioon”的文字、图片和音视频资料,版权均属于生物谷网站所有。非经授权,任何媒体、网站或个人不得转载,否则将追究法律责任。取得书面授权转载时,须注明“来源:生物谷”。其它来源的文章系转载文章,本网所有转载文章系出于传递更多信息之目的,转载内容不代表本站立场。不希望被转载的媒体或个人可与我们联系,我们将立即进行删除处理。

87%用户都在用生物谷APP 随时阅读、评论、分享交流 请扫描二维码下载->