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.
Highlights
Cancer cells possess abnormal metabolic properties, such as aerobic glycolysis, high fatty acid synthesis, and rapid glutamine metabolism [1,2]
We studied the kinetics of binding between malate dehydrogenase 2 (MDH2) and compound 7, as well as the mechanism of compound 7 in the inhibition of hypoxia-inducible factor (HIF)-1α accumulation
Compound 7 reduced the FCCPinduced maximal respiration rate of mitochondria. These results suggest that compound 7 suppresses mitochondrial respiration by inhibiting MDH2 activity in colorectal cancer cells
Summary
Cancer cells possess abnormal metabolic properties, such as aerobic glycolysis, high fatty acid synthesis, and rapid glutamine metabolism [1,2]. These metabolic alterations are associated with cancer progression and therapeutic resistance to cancer treatment [3,4]. Adaptation of cancer cells to hypoxia leads to the alteration of metabolism. A hypoxia-responsive transcription factor, hypoxia-inducible factor (HIF)-1α, has been implicated in the regulation of tumor angiogenesis, metastasis and proliferation in response to hypoxia [5,6,7]. PLOS ONE | DOI:10.1371/journal.pone.0162568 September 9, 2016
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