Iniparib Nonselectively Modifies Cysteine-Containing Proteins in Tumor Cells and Is Not a Bona Fide PARP Inhibitor
| Autor: | Allison J. Xu, David Maag, Melanie J. Schroeder Patterson, Paul Ellis, Uri S. Ladror, Damien B. Ready, Eric F. Johnson, Bruce W. Surber, Niru B. Soni, Ramesh Iyer, Yan Shi, Joann P. Palma, Larry R. Solomon, John E. Harlan, Thomas D. Penning, Cherrie K. Donawho, Xuesong Liu, Alexander R. Shoemaker |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
DNA Repair Veliparib Poly ADP ribose polymerase Metabolite Poly (ADP-Ribose) Polymerase-1 Antineoplastic Agents Mice SCID Poly(ADP-ribose) Polymerase Inhibitors Biology Poly (ADP-Ribose) Polymerase Inhibitor Mice chemistry.chemical_compound Cell Line Tumor Temozolomide Animals Humans Cysteine BRCA2 Protein Drug Synergism Neoplasms Experimental Xenograft Model Antitumor Assays Molecular biology Dacarbazine Mice Inbred C57BL Cell killing Oncology chemistry Benzamides PARP inhibitor Benzimidazoles Female NAD+ kinase Poly(ADP-ribose) Polymerases Iniparib |
| Zdroj: | Clinical Cancer Research. 18:510-523 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-11-1973 |
| Popis: | Purpose: PARP inhibitors are being developed as therapeutic agents for cancer. More than six compounds have entered clinical trials. The majority of these compounds are β-nicotinamide adenine dinucleotide (NAD+)-competitive inhibitors. One exception is iniparib, which has been proposed to be a noncompetitive PARP inhibitor. In this study, we compare the biologic activities of two different structural classes of NAD+-competitive compounds with iniparib and its C-nitroso metabolite. Experimental Design: Two chemical series of NAD+-competitive PARP inhibitors, iniparib and its C-nitroso metabolite, were analyzed in enzymatic and cellular assays. Viability assays were carried out in MDA-MB-436 (BRCA1-deficient) and DLD1−/− (BRCA2-deficient) cells together with BRCA-proficient MDA-MB-231 and DLD1+/+ cells. Capan-1 and B16F10 xenograft models were used to compare iniparib and veliparib in vivo. Mass spectrometry and the 3H-labeling method were used to monitor the covalent modification of proteins. Results: All NAD+-competitive inhibitors show robust activity in a PARP cellular assay, strongly potentiate the activity of temozolomide, and elicit robust cell killing in BRCA-deficient tumor cells in vitro and in vivo. Cell killing was associated with an induction of DNA damage. In contrast, neither iniparib nor its C-nitroso metabolite inhibited PARP enzymatic or cellular activity, potentiated temozolomide, or showed activity in a BRCA-deficient setting. We find that the nitroso metabolite of iniparib forms adducts with many cysteine-containing proteins. Furthermore, both iniparib and its nitroso metabolite form protein adducts nonspecifically in tumor cells. Conclusions: Iniparib nonselectively modifies cysteine-containing proteins in tumor cells, and the primary mechanism of action for iniparib is likely not via inhibition of PARP activity. Clin Cancer Res; 18(2); 510–23. ©2011 AACR. |
| Databáze: | OpenAIRE |
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