Differential anti-proliferative activities of poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer cells
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Despite recent advances in the clinical evaluation of various poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer (TNBC) patients, data defining potential anti-tumor mechanisms beyond PARP inhibition for these agents are lacking. To address this issue, we investigated the effects of four different PARP inhibitors (AG-014699, AZD-2281, ABT-888, and BSI-201) in three genetically distinct TNBC cell lines (MDA-MB-468, MDA-MB-231, and Cal-51). Assays of cell viability and colony formation and flow cytometric analysis were used to determine effects on cell growth and cell cycle progression. PARP-dependent and -independent signaling mechanisms of each PARP inhibitor were investigated by western blotting and shRNA approaches. Potential synergistic interactions between PARP inhibitors and cisplatin in suppressing TNBC cell viability were assessed. These PARP inhibitors exhibited differential anti-tumor activities, with the relative potencies of AG-014699 > AZD-2281 > ABT-888 > BSI-201. The higher potencies of AG-014699 and AZD-2281 were associated with their effects on G2/M arrest and DNA damage as manifested by γ-H2AX formation and, for AG-014699, its unique ability to suppress Stat3 phosphorylation. Abilities of individual PARP inhibitors to sensitize TNBC cells to cisplatin varied to a great extent in a cell context- and cell line-specific manner. Differential activation of signaling pathways suggests that the PARP inhibitors currently in clinical trials have different anti-tumor mechanisms beyond PARP inhibition and these PARP-independent mechanisms warrant further investigation.
KeywordsPoly(ADP-ribose) polymerase PARP inhibitors Triple-negative breast cancer
Extracellular signal related kinases
Pathological complete response
PH domain leucine-rich repeat phosphatase
Triple-negative breast cancer
This study was supported by the Stefanie Spielman Fund for Breast Cancer Research and the Lucius A. Wing Endowed Chair Fund of The Ohio State University College of Medicine.
Conflict of interest
The authors declare no conflict of interest.
- 4.Gonzalez-Angulo AM, Timms KM, Liu S, Chen H, Litton JK, Potter J, Lanchbury JS, Stemke-Hale K, Hennessy BT, Arun BK, Hortobagyi GN, Do KA, Mills GB, Meric-Bernstam F (2011) Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 17(5):1082–1089PubMedCrossRefGoogle Scholar
- 7.Annunziata CM, Bates SE (2010) PARP inhibitors in BRCA1/BRCA2 germline mutation carriers with ovarian and breast cancer. F1000 Biol Rep. doi: 10.3410/B2-10
- 10.Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, Carmichael J (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376(9737):235–244PubMedCrossRefGoogle Scholar
- 14.O’Shaughnessy J, Schwartzberg LS, Danso MA, Rugo HS, Miller K, Yardley DA, Carlson RW, Finn RS, Charpentier E, Freese M, Gupta S, Blackwood-Chirchir A, Winer EP (2011) A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). J. J Clin Oncol 29:81s Abstract 1007CrossRefGoogle Scholar
- 15.Canan Koch SS, Thoresen LH, Tikhe JG, Maegley KA, Almassy RJ, Li J, Yu XH, Zook SE, Kumpf RA, Zhang C, Boritzki TJ, Mansour RN, Zhang KE, Ekker A, Calabrese CR, Curtin NJ, Kyle S, Thomas HD, Wang LZ, Calvert AH, Golding BT, Griffin RJ, Newell DR, Webber SE, Hostomsky Z (2002) Novel tricyclic poly(ADP-ribose) polymerase-1 inhibitors with potent anticancer chemopotentiating activity: design, synthesis, and X-ray cocrystal structure. J Med Chem 45(23):4961–4974PubMedCrossRefGoogle Scholar
- 16.Menear KA, Adcock C, Boulter R, Cockcroft XL, Copsey L, Cranston A, Dillon KJ, Drzewiecki J, Garman S, Gomez S, Javaid H, Kerrigan F, Knights C, Lau A, Loh VM Jr, Matthews IT, Moore S, O’Connor MJ, Smith GC, Martin NM (2008) 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phth alazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem 51(20):6581–6591PubMedCrossRefGoogle Scholar
- 17.Donawho CK, Luo Y, Penning TD, Bauch JL, Bouska JJ, Bontcheva-Diaz VD, Cox BF, DeWeese TL, Dillehay LE, Ferguson DC, Ghoreishi-Haack NS, Grimm DR, Guan R, Han EK, Holley-Shanks RR, Hristov B, Idler KB, Jarvis K, Johnson EF, Kleinberg LR, Klinghofer V, Lasko LM, Liu X, Marsh KC, McGonigal TP, Meulbroek JA, Olson AM, Palma JP, Rodriguez LE, Shi Y, Stavropoulos JA, Tsurutani AC, Zhu GD, Rosenberg SH, Giranda VL, Frost DJ (2007) ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res 13(9):2728–2737PubMedCrossRefGoogle Scholar
- 18.Bauer PI, Mendeleyeva J, Kirsten E, Comstock JA, Hakam A, Buki KG, Kun E (2002) Anti-cancer action of 4-iodo-3-nitrobenzamide in combination with buthionine sulfoximine: inactivation of poly(ADP-ribose) polymerase and tumor glycolysis and the appearance of a poly(ADP-ribose) polymerase protease. Biochem Pharmacol 63(3):455–462PubMedCrossRefGoogle Scholar
- 21.Lee KH, Hsu EC, Guh JH, Yang HC, Wang D, Kulp SK, Shapiro CL, Chen CS (2011) Targeting energy metabolic and oncogenic signaling pathways in triple-negative breast cancer by a novel adenosine monophosphate-activated protein kinase (AMPK) activator. J Biol Chem 286(45):39247–39258PubMedCrossRefGoogle Scholar
- 25.McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, Navolanic PM, Terrian DM, Franklin RA, D’Assoro AB, Salisbury JL, Mazzarino MC, Stivala F, Libra M (2006) Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul 46:249–279PubMedCrossRefGoogle Scholar
- 28.Evers B, Drost R, Schut E, de Bruin M, van der Burg E, Derksn PW, Holstege H, Liu X, van Drunen E, Beverloo HB, Smith GC, Martin NM, Lau A, O’Connor MJ, Jonkers J (2008) Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Clin Cancer Res 14(12):3916–3925PubMedCrossRefGoogle Scholar
- 29.Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, Derksen PW, de Bruin M, Zevenhoven J, Lau A, Boulter R, Cranston A, O’Connor MJ, Martin NM, Borst P, Jonkers J (2008) High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci USA 105(44):17079–17084PubMedCrossRefGoogle Scholar
- 32.Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M, Nam S, Eweis I, Diaz N, Sullivan D, Yoder S, Enkemann S, Eschrich S, Lee JH, Beam CA, Cheng J, Minton S, Muro-Cacho CA, Jove R (2006) Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 12(1):11–19PubMedCrossRefGoogle Scholar