title: Synergistic growth inhibitory effect of deracoxib with doxorubicin against a canine mammary tumor cell line, CMT-U27.
abstract: Cyclooxygenase (COX) inhibitors have been shown to exert anti-angiogenic and anti-tumor activities on many types of malignant tumors. These anticancer properties make it worthwhile to examine the possible benefit of combining COX inhibitors with other anti-cancer agents. In the present study, we evaluated the potential of deracoxib (DER) in potentiating antitumor activity of doxorubicin (DOX) in canine mammary carcinoma cells (CMT-U27). DER (50-250 µM) enhanced the antiproliferative activity of DOX by reducing the IC50 (approximately 3- to 3.5 fold). Interaction analysis of the data showed that combinations of DOX at 0.9 µM with DER (100-250 µM) produced synergism in the CMT-U27 cell line, with a ratio index ranging from 1.98 to 2.33. In additional studies identifying the mechanism of observed synergistic effect, we found that DER strongly potentiated DOX-caused G0/G1 arrest in cell cycle progression. Also, DER (100-250 µM) augmented apoptosis induction with approximately 1.35- and 1.37- fold increases in apoptotic response caused by DOX in the cells. DER enhanced the antiproliferative effect of DOX in conjunction with induction of apoptosis by modulation of Bcl-2 expression and changes in the cell cycle of the CMT-U27 cell line. Although the exact molecular mechanism of the alterations in the cell cycle and apoptosis observed with DER and DOX combinations require further investigations, the results suggest that the synergistic effect of DOX and DER combinations in CMT therapy may be achieved at relatively lower doses of DOX with lesser side effects. Therefore, combining DER with DOX may prove beneficial in the clinical treatment of canine mammary cancer.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Istanbul University, Istanbul, 34320, Turkey.
authors.forename: Tülay
authors.initials: T
authors.lastname: Bakirel
authors.forename: Fulya Üstün
authors.initials: FÜ
authors.lastname: Alkan
authors.forename: Oya
authors.initials: O
authors.lastname: Üstüner
authors.forename: Suzan
authors.initials: S
authors.lastname: Çinar
authors.forename: Funda
authors.initials: F
authors.lastname: Yildirim
authors.forename: Gaye
authors.initials: G
authors.lastname: Erten
authors.forename: Utku
authors.initials: U
authors.lastname: Bakirel
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; 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*; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004317:Doxorubicin; D013449:Sulfonamides; C471996:deracoxib; D000096926:Benzenesulfonamides
references.citation: Cancer Res. 1999 Dec 15;59(24):6178-84
references.pmid: 10626810
references.citation: Oncol Rep. 2000 Nov-Dec;7(6):1377-81
references.pmid: 11032948
references.citation: Res Vet Sci. 2000 Dec;69(3):255-62
references.pmid: 11124097
references.citation: Am J Vet Res. 2001 Nov;62(11):1825-30
references.pmid: 11703031
references.citation: Biochem Pharmacol. 2002 Feb 1;63(3):343-7
references.pmid: 11853685
references.citation: Oncology (Williston Park). 2002 May;16(5 Suppl 4):30-6
references.pmid: 12102578
references.citation: Clin Tech Small Anim Pract. 2003 May;18(2):67-72
references.pmid: 12831063
references.citation: Vet Clin North Am Small Anim Pract. 2003 May;33(3):573-96
references.pmid: 12852237
references.citation: Pharm Res. 2003 Sep;20(9):1485-95
references.pmid: 14567645
references.citation: J Mammary Gland Biol Neoplasia. 2003 Jan;8(1):31-43
references.pmid: 14587862
references.citation: Vet Clin Pathol. 2004;33(1):23-8
references.pmid: 15048623
references.citation: Semin Oncol. 2004 Apr;31(2 Suppl 7):22-9
references.pmid: 15179621
references.citation: Pharmacol Res. 2004 Nov;50(5):487-98
references.pmid: 15458769
references.citation: Int J Cancer. 2005 Jun 20;115(3):484-92
references.pmid: 15688368
references.citation: Clin Cancer Res. 2005 Mar 1;11(5):1999-2007
references.pmid: 15756026
references.citation: J Vet Med Sci. 2005 Mar;67(3):345-7
references.pmid: 15805744
references.citation: Am J Vet Res. 2005 Nov;66(11):1961-7
references.pmid: 16334957
references.citation: Clin Cancer Res. 2006 Jan 1;12(1):298-304
references.pmid: 16397055
references.citation: J Small Anim Pract. 2006 Jan;47(1):14-20
references.pmid: 16417605
references.citation: J Vet Pharmacol Ther. 2006 Feb;29(1):15-23
references.pmid: 16420297
references.citation: Mol Cancer Ther. 2006 Apr;5(4):919-26
references.pmid: 16648562
references.citation: Exp Toxicol Pathol. 2006 Nov;58(2-3):163-73
references.pmid: 16859903
references.citation: Crit Rev Oncol Hematol. 2007 Jan;61(1):52-69
references.pmid: 16945549
references.citation: Mol Cancer. 2006 Sep 05;5:34
references.pmid: 16953886
references.citation: J Vet Intern Med. 2006 Sep-Oct;20(5):1184-90
references.pmid: 17063714
references.citation: Eur J Cancer. 2007 Jan;43(2):433-42
references.pmid: 17097285
references.citation: Biomed Pharmacother. 2007 Jul;61(6):338-46
references.pmid: 17395421
references.citation: Int J Cancer. 2007 Aug 15;121(4):878-83
references.pmid: 17450522
references.citation: Vet J. 2008 Oct;178(1):103-8
references.pmid: 17719812
references.citation: Nat Rev Cancer. 2008 Feb;8(2):147-56
references.pmid: 18202698
references.citation: Angiology. 2009 Apr-May;60(2):242-53
references.pmid: 18505747
references.citation: Res Vet Sci. 2009 Aug;87(1):91-6
references.pmid: 19185891
references.citation: J Pharm Pharm Sci. 2008 Sep 20;11(2):81s-110s
references.pmid: 19203472
references.citation: Mol Pharmacol. 2009 Jun;75(6):1364-73
references.pmid: 19264847
references.citation: J Physiol Pharmacol. 2009 May;60 Suppl 1:95-106
references.pmid: 19609018
references.citation: J Vet Pharmacol Ther. 2009 Aug;32(4):329-37
references.pmid: 19614837
references.citation: Vet Comp Oncol. 2006 Jun;4(2):104-13
references.pmid: 19754820
references.citation: Exp Oncol. 2009 Sep;31(3):140-3
references.pmid: 19783968
references.citation: Cancer Res. 2010 Jan 15;70(2):440-6
references.pmid: 20068163
references.citation: J Appl Genet. 2010;51(1):37-50
references.pmid: 20145299
references.citation: J Cancer Res Clin Oncol. 2011 Jan;137(1):9-17
references.pmid: 20229271
references.citation: Mol Cell Pharmacol. 2009;1(1):29-43
references.pmid: 20333321
references.citation: Vet Pathol. 2011 Jan;48(1):98-116
references.pmid: 21149845
references.citation: Acta Vet Scand. 2010 Dec 22;52:67
references.pmid: 21176231
references.citation: J Am Vet Med Assoc. 2011 Oct 15;239(8):1084-9
references.pmid: 21985349
references.citation: Cancer Lett. 2012 Aug 28;321(2):187-94
references.pmid: 22343320
references.citation: Biochim Biophys Acta. 2012 Jul;1821(7):994-1002
references.pmid: 22521764
references.citation: Neoplasia. 2012 Jul;14(7):624-33
references.pmid: 22904679
references.citation: Genomics. 2013 Apr;101(4):213-20
references.pmid: 23201559
references.citation: Cancer Cell Int. 2012 Dec 19;12(1):53
references.pmid: 23249419
references.citation: ScientificWorldJournal. 2012;2012:976740
references.pmid: 23251109
references.citation: ISRN Vet Sci. 2012 Jan 23;2011:593015
references.pmid: 23738113
references.citation: BMC Vet Res. 2013 Jun 17;9:119
references.pmid: 23773525
references.citation: Prog Lipid Res. 2013 Oct;52(4):571-84
references.pmid: 23981364
references.citation: Cancers (Basel). 2011 Mar 30;3(2):1744-62
references.pmid: 24212780
references.citation: Iran J Pharm Res. 2011 Fall;10(4):655-83
references.pmid: 24250402
references.citation: Cancer Res Treat. 2014 Jan;46(1):81-92
references.pmid: 24520227
references.citation: ScientificWorldJournal. 2014 Jan 19;2014:919570
references.pmid: 24563633
references.citation: Acta Vet Hung. 2014 Sep;62(3):372-85
references.pmid: 25038953
references.citation: Pharmaceuticals (Basel). 2010 May 19;3(5):1594-1613
references.pmid: 27713319
references.citation: Cancer Res. 1988 Jan 1;48(1):117-21
references.pmid: 3334986
references.citation: J Reprod Fertil Suppl. 1993;47:489-99
references.pmid: 8229968
references.citation: Cytometry. 1998 Jan 1;31(1):1-9
references.pmid: 9450519
references.citation: Cancer Chemother Pharmacol. 1998;41(5):385-90
references.pmid: 9523734
references.citation: Eur J Cancer. 1998 Jul;34(8):1250-9
references.pmid: 9849488