title: Vorinostat-induced autophagy switches from a death-promoting to a cytoprotective signal to drive acquired resistance.
abstract: Histone deacetylase inhibitors (HDACi) have shown promising activity against hematological malignancies in clinical trials and have led to the approval of vorinostat for the treatment of cutaneous T-cell lymphoma. However, de novo or acquired resistance to HDACi therapy is inevitable, and their molecular mechanisms are still unclear. To gain insight into HDACi resistance, we developed vorinostat-resistant clones from the hematological cell lines U937 and SUDHL6. Although cross-resistant to some but not all HDACi, the resistant cell lines exhibit dramatically increased sensitivity toward chloroquine, an inhibitor of autophagy. Consistent with this, resistant cells growing in vorinostat show increased autophagy. Inhibition of autophagy in vorinostat-resistant U937 cells by knockdown of Beclin-1 or Lamp-2 (lysosome-associated membrane protein 2) restores sensitivity to vorinostat. Interestingly, autophagy is also activated in parental U937 cells by de novo treatment with vorinostat. However, in contrast to the resistant cells, inhibition of autophagy decreases sensitivity to vorinostat. These results indicate that autophagy can switch from a proapoptotic signal to a prosurvival function driving acquired resistance. Moreover, inducers of autophagy (such as mammalian target of rapamycin inhibitors) synergize with vorinostat to induce cell death in parental cells, whereas the resistant cells remain insensitive. These data highlight the complexity of the design of combination strategies using modulators of autophagy and HDACi for the treatment of hematological malignancies.
authors: Lady Davis Institute for Medical Research, Segal Cancer Center, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors: D
authors: D
authors: Dupéré-Richer
authors: M
authors: M
authors: Kinal
authors: V
authors: V
authors: Ménasché
authors: T H
authors: TH
authors: Nielsen
authors: S
authors: S
authors: Del Rincon
authors: F
authors: F
authors: Pettersson
authors: W H
authors: WH
authors: Miller
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000633:toxicity*; D006801:Humans; D006877:Hydroxamic Acids / Q000633:toxicity*; D052119:Lysosomal-Associated Membrane Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020298:U937 Cells; D000077337:Vorinostat
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D052119:Lysosomal-Associated Membrane Protein 2; D008565:Membrane Proteins; D020011:Protective Agents; D034741:RNA, Small Interfering; D000077337:Vorinostat; D002738:Chloroquine; D058570:TOR Serine-Threonine Kinases
references: Blood. 2003 May 15;101(10):4055-62
references: 12531799
references: J Cell Mol Med. 2010 Oct;14(10):2448-59
references: 19583815
references: Autophagy. 2010 Oct;6(7):891-900
references: 20724831
references: Proc Natl Acad Sci U S A. 1978 Jul;75(7):3327-31
references: 28524
references: Oncology. 2004;66(6):481-91
references: 15452378
references: Mol Cell Biol. 2005 Jul;25(13):5429-44
references: 15964800
references: Blood. 2008 Oct 1;112(7):2896-905
references: 18660379
references: PLoS One. 2011;6(6):e20987
references: 21695163
references: J Biomed Biotechnol. 2011;2011:475641
references: 21188171
references: Oncogene. 2007 Aug 13;26(37):5541-52
references: 17694093
references: Leuk Lymphoma. 2012 Feb;53(2):259-62
references: 21823829
references: Nat Rev Drug Discov. 2009 Aug;8(8):627-44
references: 19644473
references: Oncogene. 1999 Nov 25;18(50):7016-25
references: 10597302
references: Cell Res. 2012 Jan;22(1):43-61
references: 21912435
references: Blood. 2009 Jul 9;114(2):380-93
references: 19383971
references: Blood. 2008 Feb 1;111(3):1060-6
references: 17962510
references: EMBO J. 2007 Jan 24;26(2):313-24
references: 17245426
references: Cancer Res. 2010 May 1;70(9):3431-4
references: 20424122
references: Nat Med. 2010 Feb;16(2):205-13
references: 20072130
references: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10833-8
references: 11535817
references: Science. 2009 Aug 14;325(5942):834-40
references: 19608861
references: Cancer Res. 2004 Nov 1;64(21):7706-10
references: 15520174
references: Blood. 2010 Oct 14;116(15):2732-41
references: 20566897
references: Sci Signal. 2009 Aug 18;2(84):pe51
references: 19690328
references: Blood. 2007 Jul 1;110(1):313-22
references: 17363733
references: Anticancer Res. 2008 May-Jun;28(3A):1585-91
references: 18630516
references: Clin Cancer Res. 2007 Dec 15;13(24):7237-42
references: 18094401
references: Blood. 2009 Oct 1;114(14):2926-35
references: 19641186
references: Nat Rev Clin Oncol. 2011 May 17;8(9):528-39
references: 21587219
references: J Clin Oncol. 2007 Jul 20;25(21):3109-15
references: 17577020
references: Nat Rev Drug Discov. 2007 Apr;6(4):304-12
references: 17396135
references: Autophagy. 2011 Apr;7(4):440-1
references: 21224727
references: J Neurol Sci. 2011 May 15;304(1-2):1-8
references: 21377170
references: Cell. 2005 Jan 28;120(2):237-48
references: 15680329
references: Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18030-5
references: 15596714
references: Cancer Res. 2010 Oct 15;70(20):8097-107
references: 20876803
references: Mol Cell Biol. 2012 Jan;32(1):2-11
references: 22025673
references: Oncogene. 2005 Jul 7;24(29):4609-23
references: 15897906