Aldehyde dehydrogenase inhibition combined with phenformin treatment reversed NSCLC through ATP depletion.
Aldehyde dehydrogenase inhibition combined with phenformin treatment reversed NSCLC through ATP depletion.
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DOI：
10.18632/oncotarget.10354
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发表时间：
2016-08-02
期刊：
影响因子：
--
通讯作者：
Kim SY
中科院分区：
文献类型：
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作者：
Kang JH;Lee SH;Lee JS;Nam B;Seong TW;Son J;Jang H;Hong KM;Lee C;Kim SY
在ALDH亚型中，叶酸通路中的ALDH1L1在非小细胞肺癌细胞（NSCLC）中表达高度增加。基于ALDH通过副产物NADH将醛转化为羧酸的基本机制，我们认为ALDH1L1可能通过氧化磷酸化利用NADH产生ATP。在非小细胞肺癌中，ALDH1L1敲低可使ATP产生减少60%，同时NADH降低。ALDH抑制剂棉酚也以剂量依赖的方式减少ATP的产生，同时降低NSCLC的NADH水平。棉酚与线粒体复合物I抑制剂苯双胍联合处理，协同ATP耗竭，有效诱导细胞死亡。使用人非小细胞肺癌的临床前异种移植模型对棉酚和苯双胍联合治疗显示出显著的治疗反应。
Among ALDH isoforms, ALDH1L1 in the folate pathway showed highly increased expression in non-small-cell lung cancer cells (NSCLC). Based on the basic mechanism of ALDH converting aldehyde to carboxylic acid with by-product NADH, we suggested that ALDH1L1 may contribute to ATP production using NADH through oxidative phosphorylation. ALDH1L1 knockdown reduced ATP production by up to 60% concomitantly with decrease of NADH in NSCLC. ALDH inhibitor, gossypol, also reduced ATP production in a dose dependent manner together with decrease of NADH level in NSCLC. A combination treatment of gossypol with phenformin, mitochondrial complex I inhibitor, synergized ATP depletion, which efficiently induced cell death. Pre-clinical xenograft model using human NSCLC demonstrated a remarkable therapeutic response to the combined treatment of gossypol and phenformin.