title: The anti-tumor effect of HDAC inhibition in a human pancreas cancer model is significantly improved by the simultaneous inhibition of cyclooxygenase 2.
abstract: Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer death worldwide, with no satisfactory treatment to date. In this study, we tested whether the combined inhibition of cyclooxygenase-2 (COX-2) and class I histone deacetylase (HDAC) may results in a better control of pancreatic ductal adenocarcinoma. The impact of the concomitant HDAC and COX-2 inhibition on cell growth, apoptosis and cell cycle was assessed first in vitro on human pancreas BxPC-3, PANC-1 or CFPAC-1 cells treated with chemical inhibitors (SAHA, MS-275 and celecoxib) or HDAC1/2/3/7 siRNA. To test the potential antitumoral activity of this combination in vivo, we have developed and characterized, a refined chick chorioallantoic membrane tumor model that histologically and proteomically mimics human pancreatic ductal adenocarcinoma. The combination of HDAC1/3 and COX-2 inhibition significantly impaired proliferation of BxPC-3 cells in vitro and stalled entirely the BxPC-3 cells tumor growth onto the chorioallantoic membrane in vivo. The combination was more effective than either drug used alone. Consistently, we showed that both HDAC1 and HDAC3 inhibition induced the expression of COX-2 via the NF-kB pathway. Our data demonstrate, for the first time in a Pancreatic Ductal Adenocarcinoma (PDAC) model, a significant action of HDAC and COX-2 inhibitors on cancer cell growth, which sets the basis for the development of potentially effective new combinatory therapies for pancreatic ductal adenocarcinoma patients.
authors.affiliation: Metastasis Research Laboratory, GIGA-Cancer, University of Liege, Liege, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Peulen
authors.forename: Arnaud
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Paul
authors.initials: P
authors.lastname: Peixoto
authors.forename: Andrei
authors.initials: A
authors.lastname: Turtoi
authors.forename: Denis
authors.initials: D
authors.lastname: Mottet
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
authors.forename: Vincent
authors.initials: V
authors.lastname: Castronovo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D049033:Chorioallantoic Membrane / Q000166:cytology / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000473:pathology*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D056572:Histone Deacetylase Inhibitors; D051546:Cyclooxygenase 2; D056284:Histone Deacetylase 1
references.citation: Int J Cancer. 2010 Apr 15;126(8):1797-1805
references.pmid: 19609945
references.citation: Cell Death Differ. 2012 Jul;19(7):1239-52
references.pmid: 22301920
references.citation: J Clin Pathol. 1986 Jun;39(6):610-4
references.pmid: 3522636
references.citation: Cancer Biol Ther. 2008 Apr;7(4):523-31
references.pmid: 18296916
references.citation: PLoS One. 2012;7(5):e36940
references.pmid: 22615851
references.citation: Proc Natl Acad Sci U S A. 1990 May;87(10):4012-6
references.pmid: 1692630
references.citation: BMC Cancer. 2009 Nov 13;9:395
references.pmid: 19912635
references.citation: Oncogene. 2009 Jan 15;28(2):243-56
references.pmid: 18850004
references.citation: Int J Cancer. 2007 Aug 1;121(3):656-65
references.pmid: 17417771
references.citation: J Immunol. 2009 Jan 1;182(1):216-24
references.pmid: 19109152
references.citation: Mod Pathol. 2003 May;16(5):403-10
references.pmid: 12748245
references.citation: Biochem Biophys Res Commun. 2006 Oct 6;348(4):1245-53
references.pmid: 16904634
references.citation: Cancer Biol Ther. 2011 Apr 1;11(7):659-70
references.pmid: 21301206
references.citation: Ann Oncol. 2006 Jul;17(7):1096-102
references.pmid: 16641168
references.citation: Bone. 2008 Feb;42(2):422-31
references.pmid: 18088579
references.citation: World J Clin Oncol. 2011 May 10;2(5):195-202
references.pmid: 21611096
references.citation: Immunol Cell Biol. 2012 Jan;90(1):85-94
references.pmid: 22124371
references.citation: Clin Cancer Res. 2008 Oct 15;14(20):6663-73
references.pmid: 18927309
references.citation: Pharmaceuticals (Basel). 2010 Aug 1;3(8):2411-2469
references.pmid: 21151768
references.citation: Pancreatology. 2012 Mar-Apr;12(2):146-55
references.pmid: 22487525
references.citation: Mol Carcinog. 2013 Mar;52(3):218-28
references.pmid: 22121107
references.citation: Pancreas. 2010 May;39(4):425-35
references.pmid: 20418756
references.citation: Curr Cancer Drug Targets. 2012 May;12(4):439-52
references.pmid: 22309455
references.citation: Int J Clin Oncol. 2011 Dec;16(6):671-8
references.pmid: 21556798
references.citation: Mol Cancer Ther. 2003 Feb;2(2):151-63
references.pmid: 12589032
references.citation: Science. 2001 Aug 31;293(5535):1653-7
references.pmid: 11533489
references.citation: Int J Mol Med. 2008 Sep;22(3):293-9
references.pmid: 18698487
references.citation: Ann Surg Oncol. 2008 Aug;15(8):2318-28
references.pmid: 18506539
references.citation: Cancer Invest. 1986;4(1):15-23
references.pmid: 3754176
references.citation: Expert Opin Ther Targets. 2012 Jul;16(7):707-18
references.pmid: 22621256
references.citation: World J Gastroenterol. 2005 Nov 21;11(43):6765-9
references.pmid: 16425381
references.citation: Br J Cancer. 2012 Jan 3;106(1):77-84
references.pmid: 22134508
references.citation: Circ Res. 2007 Dec 7;101(12):1237-46
references.pmid: 17947801
references.citation: Oncogene. 2007 Oct 18;26(48):6954-8
references.pmid: 17486059
references.citation: Cancer Biol Ther. 2009 Jul;8(14):1328-39
references.pmid: 19421011
references.citation: Lancet. 2011 Sep 17;378(9796):1050
references.pmid: 21924981
references.citation: CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
references.pmid: 20610543
references.citation: Pancreatology. 2012 May-Jun;12(3):219-26
references.pmid: 22687377
references.citation: Kurume Med J. 2006;53(3-4):59-62
references.pmid: 17317933
references.citation: Virchows Arch. 2006 Jun;448(6):797-804
references.pmid: 16568310
references.citation: Gastroenterology. 2010 Apr;138(4):1595-606, 1606.e1-8
references.pmid: 20080097
references.citation: Histochem Cell Biol. 2008 Dec;130(6):1119-30
references.pmid: 19005674
references.citation: Clin Cancer Res. 2008 Jul 15;14(14):4517-25
references.pmid: 18579665
references.citation: Mol Cell Biol. 2001 Oct;21(20):7065-77
references.pmid: 11564889
references.citation: J Med Invest. 2011 Feb;58(1-2):106-9
references.pmid: 21372494
references.citation: Neoplasia. 2008 Aug;10(8):782-96
references.pmid: 18670639
references.citation: Am J Transl Res. 2011 Feb;3(2):166-79
references.pmid: 21416059
references.citation: J Clin Invest. 2012 Apr;122(4):1519-28
references.pmid: 22406536
references.citation: J Surg Oncol. 2013 Jan;107(1):67-77
references.pmid: 22711682
references.citation: Cancer Res. 1999 Sep 1;59(17):4356-62
references.pmid: 10485483
references.citation: Gut. 2009 Oct;58(10):1399-409
references.pmid: 19528037
references.citation: Int J Cancer. 1975 May 15;15(5):741-7
references.pmid: 1140870
references.citation: J Med Chem. 1997 Apr 25;40(9):1347-65
references.pmid: 9135032
references.citation: Clin Cancer Res. 2009 Jun 15;15(12):3970-7
references.pmid: 19509171
references.citation: J Pineal Res. 2010 Oct;49(3):264-70
references.pmid: 20626589
references.citation: Oncogene. 2002 Jan 17;21(3):427-36
references.pmid: 11821955
references.citation: Mol Cancer Ther. 2012 Oct;11(10):2127-37
references.pmid: 22784710
references.citation: Cancer Lett. 2009 Mar 18;275(2):247-55
references.pmid: 19056168
references.citation: Pancreas. 2011 Apr;40(3):453-9
references.pmid: 21343834
references.citation: J Proteome Res. 2011 Sep 2;10(9):4302-13
references.pmid: 21755970
references.citation: Biochim Biophys Acta. 2007 Jul;1773(7):1095-106
references.pmid: 17555830
references.citation: Pancreas. 2008 Apr;36(3):e1-9
references.pmid: 18362831