Successful remission can be achieved with chemotherapy in most cases butrefractory diseases and relapses remain a major obstacle. Tumormicroenvironment, and more specially hypoxia is one of the key factorsknown to favor tumor growth as well as resistance to treatment. TMEM45Ahas been identified as a protein whose expression is increased by hypoxia,which displays strong anti-apoptotic properties and which seems to beinvolved in the resistance of cancer cells to chemotherapeutic drugs. Inparticular, when TMEM45A expression was silenced, humanhepatocarcinoma cells (HepG2) and human breast cancer cells (MDA-MB-231) incubated in the presence of etoposide or taxol under hypoxia becamesensitive to cell death induced by this chemotherapeutic molecule. The aimof this project is to identify chemosensitizing compounds which are able toinhibit the resistance to etoposide or taxol induced by TMEM45A in HepG2and MDA-MB-231 cells under hypoxia. In order to achieve this goal, arepresentative group from the chemical library NAMEDIC containingtherapeutic compounds was selected and their toxicity, structural similarityand ADME properties studied. In order to screen the potentialchemosensitizing effect of these molecules, a functional viability test basedon propidium iodide DNA labelling was optimized. After a first screening,three compounds (including two with a high structural similarity) wereidentified and have shown a potential chemosentizing effect. Thesemolecules will be validated using apoptosis measurements and their actionmechanism will be investigated in vitro and in vivo.
|Effective start/end date||1/10/15 → 30/09/19|
Attachment to an Research Institute in UNAMUR