A Novel Malate Dehydrogenase 2 Inhibitor Suppresses Hypoxia-Inducible Factor-1 by Regulating Mitochondrial Respiration.
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.
Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.|Biomolecular Science, University of Science and Technology, Daejeon, Korea.
Hyun Seung
HS
Ban
College of Pharmacy, Dongguk University-Seoul, Goyang, Korea.
Xuezhen
X
Xu
College of Pharmacy, Dongguk University-Seoul, Goyang, Korea.
Kusik
K
Jang
Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.|Functional Genomics, University of Science and Technology, Daejeon, Korea.
Inhyub
I
Kim
Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
Bo-Kyung
BK
Kim
College of Pharmacy, Dongguk University-Seoul, Goyang, Korea.
Kyeong
K
Lee
Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.|Functional Genomics, University of Science and Technology, Daejeon, Korea.
Misun
M
Won
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008291:Malate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C000619306:MDH2 protein, human; D008291:Malate Dehydrogenase