title: Identification of specific pluripotent stem cell death--inducing small molecules by chemical screening.
abstract: A potential application of embryonic and inducible pluripotent stem cells for the therapy of degenerative diseases involves pure somatic cells, free of tumorigenic undifferentiated embryonic and inducible pluripotent stem cells. In complex collections of chemicals with pharmacological potential we expect to find molecules able to induce specific pluripotent stem cell death, which could be used in some cell therapy settings to eliminate undifferentiated cells. Therefore, we have screened a chemical library of 1120 small chemicals to identify compounds that induce specifically apoptotic cell death in undifferentiated mouse embryonic stem cells (ESCs). Interestingly, three compounds currently used as clinically approved drugs, nortriptyline, benzethonium chloride and methylbenzethonium chloride, induced differential effects in cell viability in ESCs versus mouse embryonic fibroblasts (MEFs). Nortriptyline induced apoptotic cell death in MEFs but not in ESCs, whereas benzethonium and methylbenzethonium chloride showed the opposite effect. Nortriptyline, a tricyclic antidepressant, has also been described as a potent inhibitor of mitochondrial permeability transition, one of two major mechanisms involved in mitochondrial membrane permeabilization during apoptosis. Benzethonium chloride and methylbenzethonium chloride are quaternary ammonium salts used as antimicrobial agents with broad spectrum and have also been described as anticancer agents. A similar effect of benzethonium chloride was observed in human induced pluripotent stem cells (hiPSCs) when compared to both primary human skin fibroblasts and an established human fibroblast cell line. Human fibroblasts and hiPSCs were similarly resistant to nortriptyline, although with a different behavior. Our results indicate differential sensitivity of ESCs, hiPSCs and fibroblasts to certain chemical compounds, which might have important applications in the stem cell-based therapy by eliminating undifferentiated pluripotent stem cells from stem cell-derived somatic cells to prevent tumor formation after transplantation for therapy of degenerative diseases.
authors: Aragon Health Sciences Institute (I+CS), Avda. Gómez Laguna, 25, 50009, Zaragoza, Spain.
authors: Celia
authors: C
authors: Conesa
authors: Michael Xavier
authors: MX
authors: Doss
authors: Charles
authors: C
authors: Antzelevitch
authors: Agapios
authors: A
authors: Sachinidis
authors: Javier
authors: J
authors: Sancho
authors: José Alberto
authors: JA
authors: Carrodeguas
references: Nature. 1981 Jul 9;292(5819):154-6
references: 7242681
references: Comb Chem High Throughput Screen. 2003 Nov;6(7):623-47
references: 14683491
references: J Clin Invest. 1996 Jul 1;98(1):216-24
references: 8690796
references: J Nerv Ment Dis. 1962 Jun;134:561-5
references: 13867307
references: Science. 1999 Jul 30;285(5428):754-6
references: 10427001
references: Differentiation. 1985;29(2):127-35
references: 2412924
references: Stem Cells. 2009 Jan;27(1):18-28
references: 19224508
references: J Pharmacol Exp Ther. 1983 Nov;227(2):538-44
references: 6195330
references: Nat Med. 1999 Dec;5(12):1410-2
references: 10581084
references: Genes Dev. 2002 Dec 1;16(23):2991-3003
references: 12464630
references: Comb Chem High Throughput Screen. 2008 Jan;11(1):70-82
references: 18220544
references: Science. 2001 Apr 27;292(5517):727-30
references: 11326099
references: Diabetes. 2000 Feb;49(2):157-62
references: 10868930
references: Dent Mater J. 2010 Jan;29(1):75-83
references: 20379016
references: Science. 1998 Nov 6;282(5391):1145-7
references: 9804556
references: Reprod Fertil Dev. 1994;6(5):543-52
references: 7569032
references: Eur J Neurosci. 2007 Aug;26(3):633-41
references: 17686041
references: J Appl Physiol (1985). 2002 Jan;92(1):288-96
references: 11744672
references: Apoptosis. 2007 May;12(5):841-55
references: 17453156
references: Differentiation. 1991 Nov;48(2):83-7
references: 1663468
references: Nat Rev Genet. 2000 Nov;1(2):116-25
references: 11253651
references: Cell Prolif. 2009 Dec;42(6):762-9
references: 19706044
references: Am J Trop Med Hyg. 1986 Nov;35(6):1110-6
references: 3789266
references: Gen Pharmacol. 1996 Jul;27(5):773-8
references: 8842678
references: Biophys J. 1999 Feb;76(2):725-34
references: 9929477
references: Genes Dev. 2005 May 15;19(10):1129-55
references: 15905405
references: Oncogene. 2004 Oct 21;23(49):8049-64
references: 15377997
references: Thromb Haemost. 2005 Oct;94(4):719-27
references: 16270623
references: J Exp Med. 2004 Jul 19;200(2):211-22
references: 15263028
references: Clin Cancer Res. 2006 Sep 15;12(18):5557-69
references: 17000693
references: Stroke. 2008 Feb;39(2):455-62
references: 18174477
references: Stem Cells. 2001;19(3):193-204
references: 11359944