title: Aldehyde dehydrogenase inhibition combined with phenformin treatment reversed NSCLC through ATP depletion.
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.
authors.affiliation: Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Joon Hee
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Seon-Hyeong
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Jae-Seon
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Boas
authors.initials: B
authors.lastname: Nam
authors.affiliation: Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Tae Wha
authors.initials: TW
authors.lastname: Seong
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Jaekyoung
authors.initials: J
authors.lastname: Son
authors.affiliation: Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Hyonchol
authors.initials: H
authors.lastname: Jang
authors.affiliation: Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Kyeong Man
authors.initials: KM
authors.lastname: Hong
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea.|Department of Biological Chemistry, University of Science and Technology, Daejeon 305-333, Republic of Korea.
authors.forename: Cheolju
authors.initials: C
authors.lastname: Lee
authors.affiliation: Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Soo-Youl
authors.initials: SY
authors.lastname: Kim
mesh_terms: D000200:Action Potentials; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D005260:Female; D006072:Gossypol / Q000008:administration & dosage*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008293:Malates / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009368:Neoplasm Transplantation; D010085:Oxidative Phosphorylation; D000587:Oxidoreductases Acting on CH-NH Group Donors; D010629:Phenformin / Q000008:administration & dosage*; D034741:RNA, Small Interfering / Q000378:metabolism; D000099295:Formyltetrahydrofolate Dehydrogenase
chemical_list: D000255:Adenosine Triphosphate; D000444:Aldehyde Dehydrogenase; D001224:Aspartic Acid; D006072:Gossypol; D008293:Malates; D009243:NAD; D009249:NADP; D000587:Oxidoreductases Acting on CH-NH Group Donors; D010629:Phenformin; D034741:RNA, Small Interfering; D000099295:Formyltetrahydrofolate Dehydrogenase; C030298:malic acid
keywords: NSCLC; aldehyde dehydrogenase; cancer metabolism; gossypol; phenformin