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 structure-based 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 transporter 1 (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.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Cell Hypoxia / drug effects
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Cell Line, Tumor
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Citric Acid Cycle / drug effects
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Glucose Transporter Type 1 / genetics
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Glucose Transporter Type 1 / metabolism
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HCT116 Cells
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HeLa Cells
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Hep G2 Cells
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Malate Dehydrogenase / antagonists & inhibitors*
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Malate Dehydrogenase / metabolism*
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Mice
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Mitochondria / drug effects
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Mitochondria / metabolism*
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Signal Transduction / drug effects
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Antineoplastic Agents
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Glucose Transporter Type 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Vascular Endothelial Growth Factor A
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MDH2 protein, human
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Malate Dehydrogenase
Grants and funding
This work was supported by grant 2015M3A9A8032460 by Korea National Research Foundation (NRF) (
https://ernd.nrf.re.kr) to MW, grant 2014R1A2A2A01005455 by National Research Foundation (NRF) (
https://ernd.nrf.re.kr) to KL, grant HI13C2162 by Health Technology R&D (
https://www.htdream.kr) to MW, and grant KGM4751612 by KRIBB Initiative of the Korea Research Council of Fundamental Science and Technology (
https://www.kribb.re.kr) to MW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.