A novel malate dehydrogenase 2 inhibitor suppresses hypoxia-inducible factor-1 by regulating mitochondrial respiration = 미토콘드리아 호흡을 저해함으로써 HIF-1을 억제하는 신규 MDH2 저해제

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Title
A novel malate dehydrogenase 2 inhibitor suppresses hypoxia-inducible factor-1 by regulating mitochondrial respiration = 미토콘드리아 호흡을 저해함으로써 HIF-1을 억제하는 신규 MDH2 저해제
Author(s)
Hyun Seung Ban; X Xu; K Jang; Inhyub Kim; Bo Kyung Kim; K Lee; Mi Sun Won
Bibliographic Citation
PLoS One, vol. 11, no. 9, pp. e0162568-e0162568
Publication Year
2016
Abstract
We previously reported that hypoxia-inducible factor (HIF)-1 inhibitor LW6, an aryloxyacetylamino benzoic acid derivative, inhibits malate dehydrogenase 2 (MDH2) activity during the mitochondrial tricarboxylic acid (TCA) cycle. In this study, we present a novel MDH2 inhibitor compound 7 containing benzohydrazide moiety, which was identified through structurebased virtual screening of chemical library. Similar to LW6, compound 7 inhibited MDH2 activity in a competitive fashion, thereby reducing NADH level. Consequently, compound 7 reduced oxygen consumption and ATP production during the mitochondrial respiration cycle, resulting in increased intracellular oxygen concentration. Therefore, compound 7 suppressed the accumulation of HIF-1α and expression of its target genes, vascular endothelial growth factor (VEGF) and glucose transporter1 (GLUT1). Moreover, reduction in ATP content activated AMPK, thereby inactivating ACC and mTOR the downstream pathways. As expected, compound 7 exhibited significant growth inhibition of human colorectal cancer HCT116 cells. Compound 7 demonstrated substantial anti-tumor efficacy in an in vivo xenograft assay using HCT116 mouse model. Taken together, a novel MDH2 inhibitor, compound 7, suppressed HIF-1α accumulation via reduction of oxygen consumption and ATP production, integrating metabolism into anti-cancer efficacy in cancer cells.
ISSN
1932-6203
Publisher
Public Library of Science
DOI
http://dx.doi.org/10.1371/journal.pone.0162568
Type
Article
Appears in Collections:
Division of Biomedical Research > Biotherapeutics Translational Research Center > 1. Journal Articles
Division of Biomedical Research > Personalized Genomic Medicine Research Center > 1. Journal Articles
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