title: Differential Potential of Pharmacological PARP Inhibitors for Inhibiting Cell Proliferation and Inducing Apoptosis in Human Breast Cancer Cells.
abstract: BRCA1/2-mutant cells are hypersensitive to inactivation of poly(ADP-ribose) polymerase 1 (PARP-1). We recently showed that inhibition of PARP-1 by NU1025 is strongly cytotoxic for BRCA1-positive BT-20 cells, but not BRCA1-deficient SKBr-3 cells. These results raised the possibility that other PARP-1 inhibitors, particularly those tested in clinical trials, may be more efficacious against BRCA1-deficient SKBr-3 breast cancer cells than NU1025. Thus, in the presented study the cytotoxicity of four PARP inhibitors under clinical evaluation (olaparib, rucaparib, iniparib and AZD2461) was examined and compared to that of NU1025. The sensitivity of breast cancer cells to the PARP-1 inhibition strongly varied. Remarkably, BRCA-1-deficient SKBr-3 cells were almost completely insensitive to NU1025, olaparib and rucaparib, whereas BRCA1-expressing BT-20 cells were strongly affected by NU1025 even at low doses. In contrast, iniparib and AZD2461 were cytotoxic for both BT-20 and SKBr-3 cells. Of the four tested PARP-1 inhibitors only AZD2461 strongly affected cell cycle progression. Interestingly, the anti-proliferative and pro-apoptotic potential of the tested PARP-1 inhibitors clearly correlated with their capacity to damage DNA. Further analyses revealed that proteomic signatures of the two studied breast cancer cell lines strongly differ, and a set of 197 proteins was differentially expressed in NU1025-treated BT-20 cancer cells. These results indicate that BT-20 cells may harbor an unknown defect in DNA repair pathway(s) rendering them sensitive to PARP-1 inhibition. They also imply that therapeutic applicability of PARP-1 inhibitors is not limited to BRCA mutation carriers but can be extended to patients harboring deficiencies in other components of the pathway(s).
authors.affiliation: Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Cell Cycle Regulation Group, Vienna, Austria.
authors.forename: Józefa
authors.initials: J
authors.lastname: Węsierska-Gądek
authors.affiliation: Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Cell Cycle Regulation Group, Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mauritz
authors.affiliation: Clinical Department of Laboratory Medicine Proteomics Core Facility, Medical University of Vienna, Borschkegasse 8a, Vienna, 1090, Austria.
authors.forename: Goran
authors.initials: G
authors.lastname: Mitulovic
authors.affiliation: Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Cell Cycle Regulation Group, Vienna, Austria.
authors.forename: Maria
authors.initials: M
authors.lastname: Cupo
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D019313:BRCA1 Protein / Q000096:biosynthesis / Q000235:genetics*; D001549:Benzamides / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D010793:Phthalazines / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage*; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis* / Q000235:genetics; D011799:Quinazolines / Q000008:administration & dosage*
chemical_list: C000609611:AZD2461; D019313:BRCA1 Protein; D001549:Benzamides; D007211:Indoles; C115774:NU 1025; D010793:Phthalazines; D010879:Piperazines; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; C090712:iniparib; C531549:rucaparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib
keywords: APOPTOSIS; CASPASE-3 ACTIVATION; CELL CYCLE; DNA DAMAGE; DNA REPAIR; PARP-1 SYNTHETIC LETHALITY