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.
MeSH terms
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Action Potentials
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Adenosine Triphosphate / metabolism*
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Aldehyde Dehydrogenase / antagonists & inhibitors*
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Aldehyde Dehydrogenase / metabolism
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Animals
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Aspartic Acid / metabolism
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Carcinoma, Non-Small-Cell Lung / drug therapy*
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Carcinoma, Non-Small-Cell Lung / metabolism
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Cell Line, Tumor
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Cytosol / metabolism
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Female
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Gossypol / administration & dosage*
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Humans
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / metabolism
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Malates / metabolism
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Membrane Potential, Mitochondrial
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Mitochondria / metabolism
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NAD / metabolism
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NADP / metabolism
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Neoplasm Transplantation
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Oxidative Phosphorylation
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Oxidoreductases Acting on CH-NH Group Donors
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Phenformin / administration & dosage*
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RNA, Small Interfering / metabolism
Substances
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Malates
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RNA, Small Interfering
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NAD
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Aspartic Acid
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NADP
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malic acid
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Adenosine Triphosphate
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Phenformin
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Aldehyde Dehydrogenase
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Oxidoreductases Acting on CH-NH Group Donors
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formyltetrahydrofolate dehydrogenase
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Gossypol