BAY 87‐2243, a highly potent and selective inhibitor of hypoxia‐induced gene activation has antitumor activities by inhibition of mitochondrial complex I

Autor: Ingo Flamme, Iring Heisler, Michael Haerter, Peter Ellinghaus, Alexander Ehrmann, Susanne Greschat, Felix Oehme, Hartmut Beck, Martin Michels, Holger Summer, Karl Ziegelbauer, Holger Hess-Stumpp, Karl-Heinz Thierauch, Kerstin Unterschemmann
Rok vydání: 2013
Předmět:
Cancer Research
Lung Neoplasms
Mice
Genes
Reporter
Drug Discovery
Tumor Cells
Cultured
Molecular Targeted Therapy
RNA
Small Interfering
Cancer Biology
Carbonic Anhydrases
Regulation of gene expression
Oxadiazoles
mitochondrial complex 1
Cell Hypoxia
Tumor Burden
Gene Expression Regulation
Neoplastic
Oncology
Von Hippel-Lindau Tumor Suppressor Protein
Female
Hypoxia-Inducible Factor 1
medicine.symptom
Energy source
Molecular Sequence Data
Mice
Nude
Biology
Hypoxia-Inducible Factor-Proline Dioxygenases
Small Molecule Libraries
Antigens
Neoplasm
In vivo
medicine
Animals
Humans
Radiology
Nuclear Medicine and imaging
Carbonic Anhydrase IX
Transcription factor
Cell Proliferation
Electron Transport Complex I
Dose-Response Relationship
Drug
hypoxia
Cell growth
Hypoxia (medical)
Xenograft Model Antitumor Assays
Molecular biology
hypoxia-inducible factor-1
Tumor progression
Cell culture
Cancer research
Pyrazoles
Antitumor activity
Genes
Neoplasm
Zdroj: Cancer Medicine
ISSN: 2045-7634
DOI: 10.1002/cam4.112
Popis: The activation of the transcription factor hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumor development, tumor progression, and resistance to chemo- and radiotherapy. In order to identify compounds targeting the HIF pathway, a small molecule library was screened using a luciferase-driven HIF-1 reporter cell line under hypoxia. The high-throughput screening led to the identification of a class of aminoalkyl-substituted compounds that inhibited hypoxia-induced HIF-1 target gene expression in human lung cancer cell lines at low nanomolar concentrations. Lead structure BAY 87-2243 was found to inhibit HIF-1α and HIF-2α protein accumulation under hypoxic conditions in non-small cell lung cancer (NSCLC) cell line H460 but had no effect on HIF-1α protein levels induced by the hypoxia mimetics desferrioxamine or cobalt chloride. BAY 87-2243 had no effect on HIF target gene expression levels in RCC4 cells lacking Von Hippel-Lindau (VHL) activity nor did the compound affect the activity of HIF prolyl hydroxylase-2. Antitumor activity of BAY 87-2243, suppression of HIF-1α protein levels, and reduction of HIF-1 target gene expression in vivo were demonstrated in a H460 xenograft model. BAY 87-2243 did not inhibit cell proliferation under standard conditions. However under glucose depletion, a condition favoring mitochondrial ATP generation as energy source, BAY 87-2243 inhibited cell proliferation in the nanomolar range. Further experiments revealed that BAY 87-2243 inhibits mitochondrial complex I activity but has no effect on complex III activity. Interference with mitochondrial function to reduce hypoxia-induced HIF-1 activity in tumors might be an interesting therapeutic approach to overcome chemo- and radiotherapy-resistance of hypoxic tumors.
Databáze: OpenAIRE
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