Aldehyde dehydrogenase inhibition combined with phenformin treatment reversed NSCLC through ATP depletion

被引：55

作者：

Kang, Joon Hee ^{[1
]}

Lee, Seon-Hyeong ^{[1
]}

Lee, Jae-Seon ^{[1
]}

Nam, Boas ^{[2
]}

Seong, Tae Wha ^{[1
]}

Son, Jaekyoung ^{[2
]}

Jang, Hyonchol ^{[1
]}

Hong, Kyeong Man ^{[1
]}

Lee, Cheolju ^{[3
,4
]}

Kim, Soo-Youl ^{[1
]}

机构：

[1] Natl Canc Ctr, Canc Cell & Mol Biol Branch, Res Inst, Goyang 410769, Gyeonggi Do, South Korea

[2] Univ Ulsan, Coll Med, Dept Biomed Sci, Seoul 138736, South Korea

[3] Korea Inst Sci & Technol, Biomed Res Inst, Ctr Theragnosis, Seoul 136791, South Korea

[4] Univ Sci & Technol, Dept Biol Chem, Daejeon 305333, South Korea

来源：

ONCOTARGET | 2016年 / 7卷 / 31期

关键词：

aldehyde dehydrogenase; NSCLC; gossypol; phenformin; cancer metabolism; CELL LUNG-CANCER; LEUKEMIC HL-60 CELLS; BREAST-CANCER; METABOLISM; GOSSYPOL; DISEASE; TRIAL; GENE; PHARMACOLOGY; CARBOPLATIN;

D O I：

10.18632/oncotarget.10354

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：49397 / 49410

页数：14

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