PARP inhibitors sensitize Ewing sarcoma cells to Temozolomide-induced apoptosis via the mitochondrial pathway
Menée sur des lignées cellulaires de sarcome d'Ewing, cette étude évalue l'activité antitumorale de divers inhibiteurs de PARP (talazoparib, niraparib, olaparib, véliparib) en combinaison avec le témozolomide et d'autres agents de chimiothérapie
Ewing sarcoma (ES) has recently been reported to be sensitive to poly(ADP)-ribose polymerase (PARP) inhibitors. Searching for synergistic drug combinations, we tested several PARP inhibitors (talazoparib, niraparib, olaparib, veliparib) together with chemotherapeutics. Here, we report that PARP inhibitors synergize with temozolomide (TMZ) or SN-38 to induce apoptosis and also somewhat enhance the cytotoxicity of doxorubicin, etoposide or ifosfamide, whereas actinomycin D and vincristine show little synergism. Furthermore, triple therapy of olaparib, TMZ and SN-38 is significantly more effective compared to double or monotherapy. Mechanistic studies revealed that the mitochondrial pathway of apoptosis plays a critical role in mediating the synergy of PARP inhibition and TMZ. We show that subsequent to DNA damage-imposed checkpoint activation and G2 cell cycle arrest, olaparib/TMZ co-treatment causes downregulation of the antiapoptotic protein MCL-1, followed by activation of the proapoptotic proteins BAX and BAK, mitochondrial outer membrane permeabilization, activation of caspases and caspase-dependent cell death. Overexpression of a non-degradable MCL-1 mutant or BCL-2, knockdown of NOXA or BAX and BAK, or the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) all significantly reduce olaparib/TMZ-mediated apoptosis. These findings emphasize the role of PARP inhibitors for chemosensitization of ES with important implications for further (pre)clinical studies.
http://mct.aacrjournals.org/content/early/2015/10/02/1535-7163.MCT-15-0587.abstract 2015