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

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.

• Authors: Hyun Seung Ban, Bo-Kyung Kim, Hongsub Lee, Hwan Mook Kim, Dipesh Harmalkar, Miso Nam, Song-Kyu Park, Kiho Lee, Joon-Tae Park, Inhyub Kim, Kyeong Lee, Geum-Sook Hwang, Misun Won
• Journal: Cell death & disease (Cell Death Dis) Vol. 8 Issue 6 Pg. e2843 (06 01 2017) ISSN: 2041-4889 [Electronic] England
• PMID: 28569777 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• IDF-11774
• KRAS protein, human
• Piperazines
• NAD
• Lactic Acid
• Cyclic AMP
• Von Hippel-Lindau Tumor Suppressor Protein
• MTOR protein, human
• TOR Serine-Threonine Kinases
• PTEN Phosphohydrolase
• PTEN protein, human
• Proto-Oncogene Proteins p21(ras)
• VHL protein, human
• Glucose
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Proliferation
• Colorectal Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cyclic AMP (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Glucose (metabolism)
• Glycolysis (drug effects)
• HCT116 Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, genetics, metabolism)
• Lactic Acid (metabolism)
• Mice
• Mice, Nude
• NAD (metabolism)
• Neovascularization, Pathologic (genetics, metabolism, pathology, prevention & control)
• PTEN Phosphohydrolase (genetics, metabolism)
• Piperazines (pharmacology)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (genetics, metabolism)
• Von Hippel-Lindau Tumor Suppressor Protein (genetics, metabolism)
• Xenograft Model Antitumor Assays