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|Ref Type||Journal Article|
|Authors||Michels J, Vitale I, Senovilla L, Enot DP, Garcia P, Lissa D, Olaussen KA, Brenner C, Soria JC, Castedo M, Kroemer G|
|Title||Synergistic interaction between cisplatin and PARP inhibitors in non-small cell lung cancer.|
|Journal||Cell cycle (Georgetown, Tex.)|
|Date||2013 Mar 15|
|Abstract Text||The antineoplastic agent cis-diammineplatinum(II) dichloride (cisplatin, CDDP) is part of the poorly effective standard treatment of non-small cell lung carcinoma (NSCLC). Here, we report a novel strategy to improve the efficacy of CDDP. In conditions in which CDDP alone or either of two PARP inhibitors, PJ34 hydrochloride hydrate or CEP 8983, used as standalone treatments were inefficient in killing NSCLC cells, the combination of CDDP plus PJ34 or that of CDDP plus CEP 8983 were found to kill a substantial fraction of the cells. This cytotoxic synergy could be recapitulated by combining CDDP and the siRNA-mediated depletion of the principal PARP isoform, PARP1, indicating that it is mediated by on-target effects of PJ34 or CEP 8983. CDDP and PARP inhibitors synergized in inducing DNA damage foci, mitochondrial membrane permeabilization leading to cytochrome c release, and dissipation of the inner transmembrane potential, caspase activation, plasma membrane rupture and loss of clonogenic potential in NSCLC cells. Collectively, our results indicate that CDDP can be advantageously combined with PARP inhibitors to kill several NSCLC cell lines, independently from their p53 status. Combined treatment with CDDP and PARP inhibitors elicits the intrinsic pathway of apoptosis.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|CEP-8983||PARP Inhibitor (Pan) 26||CEP-8983 inhibits PARP1 and PARP2, potentially resulting in decreased tumor cell viability and increased sensitivity to DNA damaging agents (PMID: 24439051, PMID: 23428903).|
|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|
|TP53 wild-type||lung non-small cell carcinoma||sensitive||CEP-8983 + Cisplatin||Preclinical||Actionable||In a preclinical study, the combination of CEP-8983 and Platinol (cisplatin) worked synergistically to induce cell death in non-small cell lung cancer cell lines in culture, irrespective of TP53 status (PMID: 23428903).||23428903|
|TP53 mutant||lung non-small cell carcinoma||sensitive||CEP-8983 + Cisplatin||Preclinical||Actionable||In a preclinical study, the combination of CEP-8983 and Platinol (cisplatin) worked synergistically to induce cell death in non-small cell lung cancer cell lines in culture, irrespective of TP53 status (PMID: 23428903).||23428903|