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Oncotarget. 2016 Aug 2;7(31):49397-49410. doi: 10.18632/oncotarget.10354.

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

Author information

1
Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
2
Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
3
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea.
4
Department of Biological Chemistry, University of Science and Technology, Daejeon 305-333, Republic of Korea.

Abstract

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.

KEYWORDS:

NSCLC; aldehyde dehydrogenase; cancer metabolism; gossypol; phenformin

PMID:
27384481
PMCID:
PMC5226516
DOI:
10.18632/oncotarget.10354
[Indexed for MEDLINE]
Free PMC Article

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