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Cell Death Dis. 2017 Jun 1;8(6):e2843. doi: 10.1038/cddis.2017.235.

The novel hypoxia-inducible factor-1α inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth.

Author information

1
Metabolic Regulation Research Center, KRIBB, Daejeon 305-806, Korea.
2
Biomolecular Science, University of Science and Technology, Daejeon 305-350, Korea.
3
Personalized Genomic Medicine Research Center, KRIBB, Daejeon 305-806, Korea.
4
Drug Discovery Team, ILDONG Pharmaceutical Co. Ltd, Hwaseong 445-811, Kyungi-do, Korea.
5
College of Pharmacy, Gachon University, Incheon 406-840, Korea.
6
College of Pharmacy, Dongguk University-Seoul, Goyang 410-820, Korea.
7
Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Korea.
8
College of Pharmacy, Korea University, Sejong City 30019, Korea.
9
Functional Genomics, University of Science and Technology, Daejeon 305-350, Korea.

Abstract

HIF-1 is associated with poor prognoses and therapeutic resistance in cancer patients. We previously developed a novel hypoxia-inducible factor (HIF)-1 inhibitor, IDF-11774, a clinical candidate for cancer therapy. We also reported that IDF-1174 inhibited HSP70 chaperone activity and suppressed accumulation of HIF-1α. In this study, IDF-11774 inhibited the accumulation of HIF-1α in vitro and in vivo in colorectal carcinoma HCT116 cells under hypoxic conditions. Moreover, IDF-11774 treatment suppressed angiogenesis of cancer cells by reducing the expression of HIF-1 target genes, reduced glucose uptake, thereby sensitizing cells to growth under low glucose conditions, and decreased the extracellular acidification rate (ECAR) and oxygen consumption rate of cancer cells. Metabolic profiling of IDF-11774-treated cells revealed low levels of NAD+, NADP+, and lactate, as well as of intermediates in glycolysis and the tricarboxylic acid cycle. In addition, we observed elevated AMP and diminished ATP levels, resulting in a high AMP/ATP ratio. The level of AMP-activated protein kinase phosphorylation also increased, leading to inhibition of mTOR signaling in treated cells. In vivo xenograft assays demonstrated that IDF-11774 exhibited substantial anticancer efficacy in mouse models containing KRAS, PTEN, or VHL mutations, which often occur in malignant cancers. Collectively, our data indicate that IDF-11774 suppressed hypoxia-induced HIF-1α accumulation and repressed tumor growth by targeting energy production-related cancer metabolism.

PMID:
28569777
PMCID:
PMC5520894
DOI:
10.1038/cddis.2017.235
[Indexed for MEDLINE]
Free PMC Article

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