Oncotarget

Research Papers:

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

Joon Hee Kang, Seon-Hyeong Lee, Jae-Seon Lee, Boas Nam, Tae Wha Seong, Jaekyoung Son, Hyonchol Jang, Kyeong Man Hong, Cheolju Lee and Soo-Youl Kim _

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Oncotarget. 2016; 7:49397-49410. https://doi.org/10.18632/oncotarget.10354

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Abstract

Joon Hee Kang1,*, Seon-Hyeong Lee1,*, Jae-Seon Lee1, Boas Nam2, Tae Wha Seong1, Jaekyoung Son2, Hyonchol Jang1, Kyeong Man Hong1, Cheolju Lee3,4, Soo-Youl Kim1

1Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea

2Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea

3Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea

4Department 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.


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