title: SMAC Mimetic BV6 Enables Sensitization of Resistant Tumor Cells but also Affects Cytokine-Induced Killer (CIK) Cells: A Potential Challenge for Combination Therapy.
abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment option for high-risk hematological malignancies, and may also be offered to patients with solid malignancies refractory to conventional therapies. In case of patients' relapse, refractory tumor cells may then be targeted by cellular therapy-based combination strategies. Here, we investigated the potential of small molecule IAP (SMAC mimetic) BV6 in increasing cytokine-induced killer (CIK) cell-mediated cytotoxicity against different tumor targets. Four-hour pre-incubation with 2.5 μMol BV6 moderately enhanced CIK cell-mediated lysis of hematological (H9, THP-1, and Tanoue) and solid malignancies (RH1, RH30, and TE671). However, BV6 also increased apoptosis of non-malignant cells like peripheral blood mononuclear cells and most notably had an inhibitory effect on immune cells potentially limiting their cytotoxic potential. Hence, cytotoxicity increased in a dose-dependent manner when BV6 was removed before CIK cells were added to tumor targets. However, cytotoxic potential was not further increasable by extending BV6 pre-incubation period of target cells from 4 to 12 h. Molecular studies revealed that BV6 sensitization of target cells involved activation of caspases. Here, we provide evidence that SMAC mimetic may sensitize targets cells for CIK cell-induced cell death. However, BV6 also increased apoptosis of non-malignant cells like CIK cells and peripheral mononuclear cells. These findings may therefore be important for cell- and small molecule IAP-based combination therapies of resistant cancers after allogeneic HSCT.
authors.affiliation: Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents Medicine, University Hospital Frankfurt, Goethe University Frankfurt am Main , Frankfurt , Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Rettinger
authors.affiliation: Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents Medicine, University Hospital Frankfurt, Goethe University Frankfurt am Main , Frankfurt , Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Glatthaar
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe University Frankfurt am Main , Frankfurt , Germany.
authors.forename: Behnaz Ahangarian
authors.initials: BA
authors.lastname: Abhari
authors.affiliation: Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents Medicine, University Hospital Frankfurt, Goethe University Frankfurt am Main , Frankfurt , Germany ; Georg-Speyer-Haus, Institute for Biomedical Research , Frankfurt , Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Oelsner
authors.affiliation: Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents Medicine, University Hospital Frankfurt, Goethe University Frankfurt am Main , Frankfurt , Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Pfirrmann
authors.affiliation: Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents Medicine, University Hospital Frankfurt, Goethe University Frankfurt am Main , Frankfurt , Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Huenecke
authors.affiliation: Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents Medicine, University Hospital Frankfurt, Goethe University Frankfurt am Main , Frankfurt , Germany.
authors.forename: Selim
authors.initials: S
authors.lastname: Kuçi
authors.affiliation: Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents Medicine, University Hospital Frankfurt, Goethe University Frankfurt am Main , Frankfurt , Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Kreyenberg
authors.affiliation: Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents Medicine, University Hospital Frankfurt, Goethe University Frankfurt am Main , Frankfurt , Germany.
authors.forename: Andre M
authors.initials: AM
authors.lastname: Willasch
authors.affiliation: Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents Medicine, University Hospital Frankfurt, Goethe University Frankfurt am Main , Frankfurt , Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klingebiel
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe University Frankfurt am Main , Frankfurt , Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
authors.affiliation: Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents Medicine, University Hospital Frankfurt, Goethe University Frankfurt am Main , Frankfurt , Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bader
keywords: BV6; CIK cells; cellular therapy; leukemia; tumors
references.citation: Ann Hematol. 1997 Feb;74(2):51-6
references.pmid: 9063373
references.citation: Haematologica. 2010 Sep;95(9):1579-86
references.pmid: 20378565
references.citation: Bone Marrow Transplant. 2013 Aug;48(8):1141-3
references.pmid: 23474803
references.citation: Cell Death Differ. 2010 Oct;17(10):1645-54
references.pmid: 20431601
references.citation: Mol Cancer Ther. 2011 Oct;10(10):1867-75
references.pmid: 21859841
references.citation: Cell. 2008 May 16;133(4):693-703
references.pmid: 18485876
references.citation: J Cancer. 2011;2:363-8
references.pmid: 21716717
references.citation: Cell. 2007 Nov 16;131(4):682-93
references.pmid: 18022363
references.citation: Oncogene. 2008 Oct 20;27(48):6252-75
references.pmid: 18931692
references.citation: Int J Cancer. 2009 Aug 1;125(3):649-55
references.pmid: 19444908
references.citation: Nat Immunol. 2008 Dec;9(12):1364-70
references.pmid: 18997792
references.citation: J Biol Chem. 2008 Sep 5;283(36):24295-9
references.pmid: 18621737
references.citation: Cytotherapy. 2012 Jan;14(1):91-103
references.pmid: 21973023
references.citation: J Clin Invest. 2011 May;121(5):1822-6
references.pmid: 21540550
references.citation: Cancer Lett. 2009 Aug 8;280(2):125-33
references.pmid: 19359091
references.citation: Nature. 2001 Mar 1;410(6824):112-6
references.pmid: 11242052
references.citation: Cancer Res. 2011 Dec 15;71(24):7640-8
references.pmid: 22049529
references.citation: Lancet. 2003 Oct 25;362(9393):1375-7
references.pmid: 14585640
references.citation: J Biomed Biotechnol. 2010;2010:435745
references.pmid: 20368995
references.citation: Blood. 2010 Feb 4;115(5):925-35
references.pmid: 19880495
references.citation: Nat Immunol. 2008 Dec;9(12):1371-8
references.pmid: 18997794
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11778-83
references.pmid: 18697935
references.citation: Expert Opin Biol Ther. 2009 Jul;9(7):831-40
references.pmid: 19463075
references.citation: Nat Rev Cancer. 2010 Aug;10(8):561-74
references.pmid: 20651737
references.citation: N Engl J Med. 2011 Aug 25;365(8):725-33
references.pmid: 21830940
references.citation: Oncologist. 2004;9(3):282-94
references.pmid: 15169983
references.citation: Blood. 2011 Nov 17;118(20):5681-8
references.pmid: 21948300
references.citation: Blood. 2008 Sep 15;112(6):2563-74
references.pmid: 18565854
references.citation: Biol Blood Marrow Transplant. 2011 Nov;17(11):1679-87
references.pmid: 21664472
references.citation: Genes Dev. 2001 Nov 15;15(22):2922-33
references.pmid: 11711427
references.citation: Science. 2011 Oct 21;334(6054):376-80
references.pmid: 22021857
references.citation: Haematologica. 2007 Jul;92(7):952-9
references.pmid: 17606446
references.citation: Nat Cell Biol. 2008 Nov;10(11):1309-17
references.pmid: 18931663
references.citation: Blood. 2011 Sep 22;118(12):3301-10
references.pmid: 21821703
references.citation: Cell. 2007 Nov 16;131(4):669-81
references.pmid: 18022362
references.citation: Nat Rev Cancer. 2004 May;4(5):361-70
references.pmid: 15122207
references.citation: Int Immunol. 2008 Jul;20(7):841-8
references.pmid: 18469328
references.citation: Mol Cell. 2009 Dec 11;36(5):831-44
references.pmid: 20005846
references.citation: Exp Hematol. 2009 May;37(5):616-628.e2
references.pmid: 19375652
references.citation: Blood. 2003 Mar 15;101(6):2377-80
references.pmid: 12424198
references.citation: Bone Marrow Transplant. 2012 Jul;47(7):957-66
references.pmid: 21986635
references.citation: Science. 2004 Sep 3;305(5689):1471-4
references.pmid: 15353805
references.citation: Anticancer Drugs. 2009 Sep;20(8):646-58
references.pmid: 19550293
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3503-8
references.pmid: 18292232
references.citation: J Biol Chem. 2002 Nov 15;277(46):44236-43
references.pmid: 12218061
references.citation: Science. 2006 Oct 6;314(5796):126-9
references.pmid: 16946036
references.citation: Cancer Lett. 2004 Nov 25;215(2):129-40
references.pmid: 15488631
references.citation: Mol Cancer Ther. 2014 Apr;13(4):867-79
references.pmid: 24563541
references.citation: PLoS One. 2011;6(6):e21556
references.pmid: 21738708
references.citation: Cancer Res. 2008 Nov 15;68(22):9384-93
references.pmid: 19010913
references.citation: Cancer Res. 1997 Sep 1;57(17):3823-9
references.pmid: 9288794
references.citation: Science. 1998 Sep 11;281(5383):1680-3
references.pmid: 9733516
references.citation: Cancer Cell. 2007 Nov;12(5):445-56
references.pmid: 17996648
references.citation: Nat Rev Drug Discov. 2012 Feb 01;11(2):109-24
references.pmid: 22293567
references.citation: Eur J Immunol. 1998 Mar;28(3):891-900
references.pmid: 9541584
references.citation: Immunology. 2009 Mar;126(3):423-35
references.pmid: 18778291
references.citation: Leukemia. 2009 Mar;23(3):467-76
references.pmid: 19039324