Reference Detail

Ref Type

Journal Article

PMID

(23428903)

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	Vol	Issue	Date	Pages	Journal Short Title
Cell cycle (Georgetown, Tex.)	12	6	2013 Mar 15	877-83	Cell Cycle

URL

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.

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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
CEP-8983	CEP-8983	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
CEP-8983			PARP Inhibitor (Pan) 31	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