Potentialization of anticancer agents by identification of new chemosensitizers active under hypoxia

• Published in: Biochemical pharmacology 2019-04, Vol.162, p.224-236
• Main Authors: Marx, Sébastien, Van Gysel, Mégane, Breuer, Aurélie, Dal Maso, Thomas, Michiels, Carine, Wouters, Johan, Le Calvé, Benjamin
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - administration & dosage; Antineoplastic Agents - toxicity; Apoptosis - drug effects; Apoptosis - physiology; Cancer; Cell Hypoxia - drug effects; Cell Hypoxia - physiology; Chemosensitizer; DNA Fingerprinting - methods; Drug Synergism; Etoposide; Etoposide - administration & dosage; Etoposide - toxicity; Hep G2 Cells; Humans; Hypoxia; Paclitaxel - administration & dosage; Paclitaxel - toxicity; Taxol; Thiosemicarbazones - administration & dosage; Thiosemicarbazones - toxicity
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2019.01.004

[Display omitted] 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.