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Ref Type Journal Article
PMID (26438158)
Authors Engert F, Schneider C, Weibeta LM, Probst M, Fulda S
Title PARP Inhibitors Sensitize Ewing Sarcoma Cells to Temozolomide-Induced Apoptosis via the Mitochondrial Pathway.
Journal Molecular cancer therapeutics
Vol 14
Issue 12
Date 2015 Dec
URL
Abstract Text Ewing sarcoma 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 with 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 cotreatment causes downregulation of the antiapoptotic protein MCL-1, followed by activation of the proapoptotic proteins BAX and BAK, mitochondrial outer membrane permeabilization (MOMP), activation of caspases, and caspase-dependent cell death. Overexpression of a nondegradable 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 Ewing sarcoma with important implications for further (pre)clinical studies.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Ewing sarcoma not applicable Olaparib + SN-38 Preclinical - Cell culture Actionable In a preclinical study, Ewing sarcoma cells treated with SN-38 combined with Lynparza (olaparib) resulted in synergism, demonstrating reduced cell viability in culture (PMID: 26438158). 26438158
Unknown unknown Ewing sarcoma not applicable Temozolomide + Veliparib Preclinical Actionable In a preclinical study, Ewing sarcoma cells treated with Temodar (temozolomide) combined with Veliparib (ABT-888) resulted in strong synergism, demonstrating reduced cell viability in culture (PMID: 26438158). 26438158
Unknown unknown Ewing sarcoma not applicable Niraparib + Temozolomide Preclinical - Cell culture Actionable In a preclinical study, treatment with Temodar (temozolomide) combined with Zejula (niraparib) demonstrated strong synergism in Ewing sarcoma cells in culture, resulting in decreased cell viability (PMID: 26438158). 26438158
Unknown unknown Ewing sarcoma not applicable Olaparib + Temozolomide Preclinical - Cell culture Actionable In a preclinical study, Ewing sarcoma cells treated with Temodar (temozolomide) combined with Lynparza (olaparib) resulted in very strong synergism, inducing apoptosis and reducing cell viability in culture (PMID: 26438158). 26438158
Unknown unknown Ewing sarcoma not applicable SN-38 + Veliparib Preclinical Actionable In a preclinical study, Ewing sarcoma cells treated with SN-38 combined with Veliparib (ABT-888) resulted in synergism, demonstrating reduced cell viability in culture (PMID: 26438158). 26438158
Unknown unknown Ewing sarcoma not applicable Talazoparib + Temozolomide Preclinical - Cell culture Actionable In a preclinical study, Ewing sarcoma cells treated with Temodar (temozolomide) combined with Talazoparib (BMN-673) resulted in strong synergism, demonstrating decreased cell viability in culture (PMID: 26438158). 26438158
Unknown unknown Ewing sarcoma not applicable SN-38 + Talazoparib Preclinical - Cell culture Actionable In a preclinical study, Ewing sarcoma cells treated with SN-38 combined with Talazoparib (BMN-673) resulted in synergism, demonstrating reduced cell viability in culture (PMID: 26438158). 26438158
Unknown unknown Ewing sarcoma not applicable Olaparib + SN-38 + Temozolomide Preclinical - Cell culture Actionable In a preclinical study, Ewing sarcoma cells treated with the combination of Temodar (temozolomide), SN-38, and Lynparza (olaparib) had a much greater effect on decreasing cell viability and inducing apoptosis when compared to each treatment administered as a single agent or as dual agents in culture (PMID: 26438158). 26438158
Unknown unknown Ewing sarcoma not applicable Niraparib + SN-38 Preclinical - Cell culture Actionable In a preclinical study, treatment with SN-38 combined with Zejula (niraparib) demonstrated synergism in Ewing sarcoma cells in culture, resulting in reduced cell viability (PMID: 26438158). 26438158