Targeting SOD1 reduces experimental non-small-cell lung cancer
Targeting SOD1 reduces experimental non-small-cell lung cancer
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DOI：
10.1172/jci71714
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发表时间：
2014-01-01
影响因子：
15.9
通讯作者：
Chandel, Navdeep S.
中科院分区：
文献类型：
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作者：
Glasauer, Andrea;Sena, Laura A.;Chandel, Navdeep S.
大约85%的肺癌是非小细胞肺癌（nsclc），通常在晚期被诊断出来，预后较差。目前，由于非小细胞肺癌的顽固性，治疗非小细胞肺癌的方法很少。在20%到30%的非小细胞肺癌中发现了激活小GTPase KRAS的突变。在这里，我们报道了小分子ATN-224对超氧化物歧化酶1 （SOD1）的抑制可诱导多种非小细胞肺癌细胞死亡，包括那些携带KRAS突变的细胞。atn -224依赖性SOD1抑制增加了超氧化物，从而降低了抗氧化剂谷胱甘肽过氧化物酶的酶活性，导致细胞内过氧化氢（H2O2）水平增加。我们发现atn -224诱导的细胞死亡是通过h2o2依赖性激活P38 MAPK介导的，P38激活导致抗凋亡因子MCL1的降低，MCL1在NSCLC中经常上调。ATN-224和ABT-263（一种凋亡调节因子BCL2/BCLXL的抑制剂）均可增强细胞死亡。此外，我们证明ATN-224在非小细胞肺癌小鼠模型中降低了肿瘤负荷。我们的研究结果表明，ATN-224的抗氧化抑制作用具有潜在的临床应用，可单独使用或与其他药物联合使用，用于治疗各种形式的非小细胞肺癌，包括kras驱动的癌症。
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.