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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.
Highlights
Most cancer cells produce energy by glycolysis rather than mitochondrial oxidative phosphorylation, regardless of oxygen availability; this phenomenon is termed the Warburg effect.[1]
These HIF-1α/β heterodimers subsequently bind to hypoxia-response elements (HREs) (5′-RCGTG-3′, where R is A or G) in the promoters of target genes involved in angiogenesis, metastasis, and resistance to apoptosis, thereby activating their transcription.[4]
We found that IDF-11774 reduced the HRE-luciferase activity of HIF-1α (IC50 = 3.65 μM) and blocked HIF-1α accumulation under hypoxic conditions in HCT116 human colon cancer cells (Figure 1a and Supplementary Figure S1a)
Summary
Most cancer cells produce energy by glycolysis rather than mitochondrial oxidative phosphorylation, regardless of oxygen availability; this phenomenon is termed the Warburg effect.[1] this metabolic phenotype of cancer is regulated by the HIF-1, PI3K, p53, MYC, and AMP-activated protein kinase (AMPK)-liver kinase B1 pathways. Received 06.1.17; revised 15.4.17; accepted 20.4.17; Edited by M Agostini developed an orally administered HIF-1 inhibitor, IDF-11774, which has been approved as a clinical candidate for a phase I study by the Korea Food and Drug Administration.[17] Using chemical probes, we previously demonstrated that IDF-11774 inhibits HSP70 chaperone activity by binding to its allosteric pocket, rather than the ATP-binding site in its nucleotidebinding domain.[18] The HSP70 family is reported to be associated with malignancy, clinical cancer stage, and poor prognosis of various cancers.[19,20]. IDF-11774 showed significant antitumor efficacy in xenograft assays of various cancer models bearing drug resistance mutations, suggesting that IDF-11774 may be used by itself or in combination with other agents in cancer therapeutics
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