Abstract

Hypoxia is one of the most important biological phenomena that influences cancer agressiveness and che-motherapy resistance. Cancer cells display dysregulated pathways notably resulting from oncogene expression.Tumors also show modifications in extracellular pH, extracellular matrix remodeling, neo-angiogenesis, hypoxiacompared to normal tissues. Classically, the conventional anticancer therapies are efficient in cancer cells innormoxic conditions but under hypoxia, chemoresistance may occur. The addition of compounds that potentiatetheir activity in low oxygen environment could be a strategy to counteract this resistance. To identify newcompounds active in hypoxia, we screened one hundred molecules with different chemical structures from aninternal chemolibrary. Their potential ability to increase the activity of taxol and etoposide independently oftheir mechanism of action has been assayed. After afirst step of selection, based on biological/pharmacologicalproperties and chemical structure analysis, we identified three potential hits. Two hits are closely relatedamides/ureas and the third is a thiosemicarbazone. The compounds present no activity in cancer and normalcells when used alone but demonstrate chemosensitizing activity under hypoxia. Finally, by analyzing cell death,the indole thiosemicarbazone was shown to be able to significantly potentiate apoptosis induced by taxol andetoposide in two models of cancer cell lines. This new compound could lead to the development of an originalseries of chemosensitizers active under hypoxia
Original languageEnglish
Pages (from-to)224-236
Number of pages13
JournalBiochemical Pharmacology
Volume162
DOIs
Publication statusPublished - 2019

Keywords

  • Cancer
  • Chemosensitizer
  • Etoposide
  • Hypoxia
  • Taxol

Cite this

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title = "Potentialization of anticancer agents by identification of new chemosensitizers active under hypoxia",
abstract = "Hypoxia is one of the most important biological phenomena that influences cancer agressiveness and che-motherapy resistance. Cancer cells display dysregulated pathways notably resulting from oncogene expression.Tumors also show modifications in extracellular pH, extracellular matrix remodeling, neo-angiogenesis, hypoxiacompared to normal tissues. Classically, the conventional anticancer therapies are efficient in cancer cells innormoxic conditions but under hypoxia, chemoresistance may occur. The addition of compounds that potentiatetheir activity in low oxygen environment could be a strategy to counteract this resistance. To identify newcompounds active in hypoxia, we screened one hundred molecules with different chemical structures from aninternal chemolibrary. Their potential ability to increase the activity of taxol and etoposide independently oftheir mechanism of action has been assayed. After afirst step of selection, based on biological/pharmacologicalproperties and chemical structure analysis, we identified three potential hits. Two hits are closely relatedamides/ureas and the third is a thiosemicarbazone. The compounds present no activity in cancer and normalcells when used alone but demonstrate chemosensitizing activity under hypoxia. Finally, by analyzing cell death,the indole thiosemicarbazone was shown to be able to significantly potentiate apoptosis induced by taxol andetoposide in two models of cancer cell lines. This new compound could lead to the development of an originalseries of chemosensitizers active under hypoxia",
keywords = "Hypoxia, Etoposide, Chemosensitizer, Taxol, Cancer, Cancer, Chemosensitizer, Etoposide, Hypoxia, Taxol",
author = "S{\'e}bastien Marx and {Van Gysel}, M{\'e}gane and Aur{\'e}lie Breuer and {Dal Maso}, Thomas and Carine Michiels and Johan Wouters and {Le Calve}, Benjamin",
year = "2019",
doi = "10.1016/j.bcp.2019.01.004",
language = "English",
volume = "162",
pages = "224--236",
journal = "Biochemical Pharmacology",
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T1 - Potentialization of anticancer agents by identification of new chemosensitizers active under hypoxia

AU - Marx, Sébastien

AU - Van Gysel, Mégane

AU - Breuer, Aurélie

AU - Dal Maso, Thomas

AU - Michiels, Carine

AU - Wouters, Johan

AU - Le Calve, Benjamin

PY - 2019

Y1 - 2019

N2 - Hypoxia is one of the most important biological phenomena that influences cancer agressiveness and che-motherapy resistance. Cancer cells display dysregulated pathways notably resulting from oncogene expression.Tumors also show modifications in extracellular pH, extracellular matrix remodeling, neo-angiogenesis, hypoxiacompared to normal tissues. Classically, the conventional anticancer therapies are efficient in cancer cells innormoxic conditions but under hypoxia, chemoresistance may occur. The addition of compounds that potentiatetheir activity in low oxygen environment could be a strategy to counteract this resistance. To identify newcompounds active in hypoxia, we screened one hundred molecules with different chemical structures from aninternal chemolibrary. Their potential ability to increase the activity of taxol and etoposide independently oftheir mechanism of action has been assayed. After afirst step of selection, based on biological/pharmacologicalproperties and chemical structure analysis, we identified three potential hits. Two hits are closely relatedamides/ureas and the third is a thiosemicarbazone. The compounds present no activity in cancer and normalcells when used alone but demonstrate chemosensitizing activity under hypoxia. Finally, by analyzing cell death,the indole thiosemicarbazone was shown to be able to significantly potentiate apoptosis induced by taxol andetoposide in two models of cancer cell lines. This new compound could lead to the development of an originalseries of chemosensitizers active under hypoxia

AB - Hypoxia is one of the most important biological phenomena that influences cancer agressiveness and che-motherapy resistance. Cancer cells display dysregulated pathways notably resulting from oncogene expression.Tumors also show modifications in extracellular pH, extracellular matrix remodeling, neo-angiogenesis, hypoxiacompared to normal tissues. Classically, the conventional anticancer therapies are efficient in cancer cells innormoxic conditions but under hypoxia, chemoresistance may occur. The addition of compounds that potentiatetheir activity in low oxygen environment could be a strategy to counteract this resistance. To identify newcompounds active in hypoxia, we screened one hundred molecules with different chemical structures from aninternal chemolibrary. Their potential ability to increase the activity of taxol and etoposide independently oftheir mechanism of action has been assayed. After afirst step of selection, based on biological/pharmacologicalproperties and chemical structure analysis, we identified three potential hits. Two hits are closely relatedamides/ureas and the third is a thiosemicarbazone. The compounds present no activity in cancer and normalcells when used alone but demonstrate chemosensitizing activity under hypoxia. Finally, by analyzing cell death,the indole thiosemicarbazone was shown to be able to significantly potentiate apoptosis induced by taxol andetoposide in two models of cancer cell lines. This new compound could lead to the development of an originalseries of chemosensitizers active under hypoxia

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KW - Cancer

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KW - Chemosensitizer

KW - Etoposide

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KW - Taxol

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