Cargando…
BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I
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...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Science Inc
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3892793/ https://www.ncbi.nlm.nih.gov/pubmed/24403227 http://dx.doi.org/10.1002/cam4.112 |
_version_ | 1782299582456135680 |
---|---|
author | Ellinghaus, Peter Heisler, Iring Unterschemmann, Kerstin Haerter, Michael Beck, Hartmut Greschat, Susanne Ehrmann, Alexander Summer, Holger Flamme, Ingo Oehme, Felix Thierauch, Karlheinz Michels, Martin Hess-Stumpp, Holger Ziegelbauer, Karl |
author_facet | Ellinghaus, Peter Heisler, Iring Unterschemmann, Kerstin Haerter, Michael Beck, Hartmut Greschat, Susanne Ehrmann, Alexander Summer, Holger Flamme, Ingo Oehme, Felix Thierauch, Karlheinz Michels, Martin Hess-Stumpp, Holger Ziegelbauer, Karl |
author_sort | Ellinghaus, Peter |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3892793 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Blackwell Science Inc |
record_format | MEDLINE/PubMed |
spelling | pubmed-38927932014-01-22 BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I Ellinghaus, Peter Heisler, Iring Unterschemmann, Kerstin Haerter, Michael Beck, Hartmut Greschat, Susanne Ehrmann, Alexander Summer, Holger Flamme, Ingo Oehme, Felix Thierauch, Karlheinz Michels, Martin Hess-Stumpp, Holger Ziegelbauer, Karl Cancer Med Cancer Biology 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. Blackwell Science Inc 2013-10 2013-08-20 /pmc/articles/PMC3892793/ /pubmed/24403227 http://dx.doi.org/10.1002/cam4.112 Text en © 2013 Published by John Wiley & Sons Ltd. http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation. |
spellingShingle | Cancer Biology Ellinghaus, Peter Heisler, Iring Unterschemmann, Kerstin Haerter, Michael Beck, Hartmut Greschat, Susanne Ehrmann, Alexander Summer, Holger Flamme, Ingo Oehme, Felix Thierauch, Karlheinz Michels, Martin Hess-Stumpp, Holger Ziegelbauer, Karl BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I |
title | BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I |
title_full | BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I |
title_fullStr | BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I |
title_full_unstemmed | BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I |
title_short | BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I |
title_sort | bay 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex i |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3892793/ https://www.ncbi.nlm.nih.gov/pubmed/24403227 http://dx.doi.org/10.1002/cam4.112 |
work_keys_str_mv | AT ellinghauspeter bay872243ahighlypotentandselectiveinhibitorofhypoxiainducedgeneactivationhasantitumoractivitiesbyinhibitionofmitochondrialcomplexi AT heisleriring bay872243ahighlypotentandselectiveinhibitorofhypoxiainducedgeneactivationhasantitumoractivitiesbyinhibitionofmitochondrialcomplexi AT unterschemmannkerstin bay872243ahighlypotentandselectiveinhibitorofhypoxiainducedgeneactivationhasantitumoractivitiesbyinhibitionofmitochondrialcomplexi AT haertermichael bay872243ahighlypotentandselectiveinhibitorofhypoxiainducedgeneactivationhasantitumoractivitiesbyinhibitionofmitochondrialcomplexi AT beckhartmut bay872243ahighlypotentandselectiveinhibitorofhypoxiainducedgeneactivationhasantitumoractivitiesbyinhibitionofmitochondrialcomplexi AT greschatsusanne bay872243ahighlypotentandselectiveinhibitorofhypoxiainducedgeneactivationhasantitumoractivitiesbyinhibitionofmitochondrialcomplexi AT ehrmannalexander bay872243ahighlypotentandselectiveinhibitorofhypoxiainducedgeneactivationhasantitumoractivitiesbyinhibitionofmitochondrialcomplexi AT summerholger bay872243ahighlypotentandselectiveinhibitorofhypoxiainducedgeneactivationhasantitumoractivitiesbyinhibitionofmitochondrialcomplexi AT flammeingo bay872243ahighlypotentandselectiveinhibitorofhypoxiainducedgeneactivationhasantitumoractivitiesbyinhibitionofmitochondrialcomplexi AT oehmefelix bay872243ahighlypotentandselectiveinhibitorofhypoxiainducedgeneactivationhasantitumoractivitiesbyinhibitionofmitochondrialcomplexi AT thierauchkarlheinz bay872243ahighlypotentandselectiveinhibitorofhypoxiainducedgeneactivationhasantitumoractivitiesbyinhibitionofmitochondrialcomplexi AT michelsmartin bay872243ahighlypotentandselectiveinhibitorofhypoxiainducedgeneactivationhasantitumoractivitiesbyinhibitionofmitochondrialcomplexi AT hessstumppholger bay872243ahighlypotentandselectiveinhibitorofhypoxiainducedgeneactivationhasantitumoractivitiesbyinhibitionofmitochondrialcomplexi AT ziegelbauerkarl bay872243ahighlypotentandselectiveinhibitorofhypoxiainducedgeneactivationhasantitumoractivitiesbyinhibitionofmitochondrialcomplexi |