title: PARP and CHK inhibitors interact to cause DNA damage and cell death in mammary carcinoma cells.
abstract: The present studies examined viability and DNA damage levels in mammary carcinoma cells following PARP1 and CHK1 inhibitor drug combination exposure. PARP1 inhibitors [AZD2281 ; ABT888 ; NU1025 ; AG014699] interacted with CHK1 inhibitors [UCN-01 ; AZD7762 ; LY2603618] to kill mammary carcinoma cells. PARP1 and CHK1 inhibitors interacted to increase both single strand and double strand DNA breaks that correlated with increased γH2AX phosphorylation. Treatment of cells with CHK1 inhibitors increased the phosphorylation of CHK1 and ERK1/2. Knock down of ATM suppressed the drug-induced increases in CHK1 and ERK1/2 phosphorylation and enhanced tumor cell killing by PARP1 and CHK1 inhibitors. Expression of dominant negative MEK1 enhanced drug-induced DNA damage whereas expression of activated MEK1 suppressed both the DNA damage response and tumor cell killing. Collectively our data demonstrate that PARP1 and CHK1 inhibitors interact to kill mammary carcinoma cells and that increased DNA damage is a surrogate marker for the response of cells to this drug combination.
authors.affiliation: Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Booth
authors.forename: Nichola
authors.initials: N
authors.lastname: Cruickshanks
authors.forename: Thomas
authors.initials: T
authors.lastname: Ridder
authors.forename: Yun
authors.initials: Y
authors.lastname: Dai
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D061986:MCF-7 Cells; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: C468783:H2AX protein, human; D006657:Histones; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D047428:Protein Kinase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human
keywords: ATM; CHK1; DNA damage; PARP1; apoptosis; comet; kinase
references.citation: Nat Rev Cancer. 2010 Apr;10(4):293-301
references.pmid: 20200537
references.citation: Cancer Res. 2007 Feb 1;67(3):1046-53
references.pmid: 17283137
references.citation: Nat Biotechnol. 2011 May;29(5):373-4
references.pmid: 21552220
references.citation: Mol Pharmacol. 2010 Nov;78(5):909-17
references.pmid: 20696794
references.citation: Cancer Res. 1985 May;45(5):2123-7
references.pmid: 2985245
references.citation: Clin Cancer Res. 2000 Jul;6(7):2860-7
references.pmid: 10914735
references.citation: Blood. 2002 Nov 1;100(9):3333-43
references.pmid: 12384435
references.citation: Br J Cancer. 2001 Jan 5;84(1):106-12
references.pmid: 11139322
references.citation: Br J Cancer. 2011 Mar 1;104(5):750-5
references.pmid: 21326243
references.citation: Invest New Drugs. 2013 Feb;31(1):136-44
references.pmid: 22492020
references.citation: Clin Cancer Res. 2007 Apr 1;13(7):1955-60
references.pmid: 17404075
references.citation: Expert Opin Investig Drugs. 2009 Jan;18(1):31-43
references.pmid: 19053880
references.citation: Mol Interv. 2011 Apr;11(2):133-40
references.pmid: 21540473
references.citation: Clin Cancer Res. 2007 May 1;13(9):2728-37
references.pmid: 17473206
references.citation: Nucleic Acids Res. 2011 Apr;39(8):3166-75
references.pmid: 21183466
references.citation: Lancet. 2010 Jul 24;376(9737):235-44
references.pmid: 20609467
references.citation: Mol Pharmacol. 2012 Aug;82(2):322-32
references.pmid: 22596349
references.citation: Radiat Res. 1991 Jun;126(3):367-71
references.pmid: 1903547
references.citation: N Engl J Med. 2009 Jul 9;361(2):123-34
references.pmid: 19553641
references.citation: Recent Pat Anticancer Drug Discov. 2006 Jan;1(1):55-68
references.pmid: 18221026
references.citation: Cancer Res. 2006 Dec 15;66(24):11954-66
references.pmid: 17178894
references.citation: Cancer Res. 2001 Jul 1;61(13):5106-15
references.pmid: 11431348
references.citation: Pharmacol Res. 2005 Jul;52(1):109-18
references.pmid: 15911339
references.citation: Radiat Res. 2003 Apr;159(4):439-52
references.pmid: 12643788
references.citation: Mutagenesis. 2008 Sep;23(5):331-9
references.pmid: 18644834
references.citation: Nat Cell Biol. 2003 Mar;5(3):255-60
references.pmid: 12598907
references.citation: Cancer Res. 2010 Jun 15;70(12):4972-81
references.pmid: 20501833
references.citation: J Biol Chem. 1999 Jun 18;274(25):17860-8
references.pmid: 10364231
references.citation: Nat Med. 2008 Dec;14(12):1351-6
references.pmid: 19029981
references.citation: Blood. 2008 Sep 15;112(6):2439-49
references.pmid: 18614762
references.citation: Cancer Cell. 2003 May;3(5):421-9
references.pmid: 12781359
references.citation: J Biol Chem. 2002 Jun 21;277(25):23028-36
references.pmid: 11948190
references.citation: Curr Opin Oncol. 2001 Nov;13(6):453-62
references.pmid: 11673685
references.citation: Br J Cancer. 1998 Nov;78(10):1269-77
references.pmid: 9823965
references.citation: DNA Repair (Amst). 2004 Aug-Sep;3(8-9):959-67
references.pmid: 15279782
references.citation: Mol Cancer Ther. 2008 Mar;7(3):616-29
references.pmid: 18347148
references.citation: Pharmacol Res. 2002 Feb;45(2):73-85
references.pmid: 11846617
references.citation: Oncogene. 2007 Dec 10;26(56):7741-8
references.pmid: 18066086
references.citation: Br J Cancer. 1995 Oct;72(4):849-56
references.pmid: 7547230
references.citation: Annu Rev Biochem. 2004;73:39-85
references.pmid: 15189136