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

// Joon Hee Kang 1, * , Seon-Hyeong Lee 1, * , Jae-Seon Lee 1 , Boas Nam 2 , Tae Wha Seong 1 , Jaekyoung Son 2 , Hyonchol Jang 1 , Kyeong Man Hong 1 , Cheolju Lee 3, 4 , Soo-Youl Kim 1 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 * These authors contributed equally to this work Correspondence to: Soo-Youl Kim, email: kimsooyoul@gmail.com Keywords: aldehyde dehydrogenase, NSCLC, gossypol, phenformin, cancer metabolism Received: April 20, 2016      Accepted: June 17, 2016      Published: June 30, 2016 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.