Hypoxia is one of the most important biological phenomena that influences
cancer agressiveness and
chemotherapy resistance.
Cancer cells display dysregulated pathways notably resulting from oncogene expression.
Tumors also show modifications in extracellular pH, extracellular matrix remodeling, neo-angiogenesis,
hypoxia compared to normal tissues. Classically, the conventional anticancer
therapies are efficient in
cancer cells in normoxic conditions but under
hypoxia, chemoresistance may occur. The addition of compounds that potentiate their activity in low
oxygen environment could be a strategy to counteract this resistance. To identify new compounds active in
hypoxia, we screened one hundred molecules with different chemical structures from an internal chemolibrary. Their potential ability to increase the activity of
taxol and
etoposide independently of their mechanism of action has been assayed. After a first step of selection, based on
biological/pharmacological properties and chemical structure analysis, we identified three potential hits. Two hits are closely related
amides/ureas and the third is a
thiosemicarbazone. The compounds present no activity in
cancer and normal cells 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 and
etoposide in two models of
cancer cell lines. This new compound could lead to the development of an original series of chemosensitizers active under
hypoxia.