title: Novel mTOR inhibitory activity of ciclopirox enhances parthenolide antileukemia activity.
abstract: Ciclopirox, an antifungal agent commonly used for the dermatologic treatment of mycoses, has been shown recently to have antitumor properties. Although the exact mechanism of ciclopirox is unclear, its antitumor activity has been attributed to iron chelation and inhibition of the translation initiation factor eIF5A. In this study, we identify a novel function of ciclopirox in the inhibition of mTOR. As with other mTOR inhibitors, we show that ciclopirox significantly enhances the ability of the established preclinical antileukemia compound, parthenolide, to target acute myeloid leukemia. The combination of parthenolide and ciclopirox demonstrates greater toxicity against acute myeloid leukemia than treatment with either compound alone. We also demonstrate that the ability of ciclopirox to inhibit mTOR is specific to ciclopirox because neither iron chelators nor other eIF5A inhibitors affect mTOR activity, even at high doses. We have thus identified a novel function of ciclopirox that might be important for its antileukemic activity.
authors: Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, New York, USA.
authors: Siddhartha
authors: S
authors: Sen
authors: Duane C
authors: DC
authors: Hassane
authors: Cheryl
authors: C
authors: Corbett
authors: Michael W
authors: MW
authors: Becker
authors: Craig T
authors: CT
authors: Jordan
authors: Monica L
authors: ML
authors: Guzman
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000819:agonists / Q000494:pharmacology*; D000935:Antifungal Agents / Q000819:agonists / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000077768:Ciclopirox; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D011728:Pyridones / Q000819:agonists / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000819:agonists / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000935:Antifungal Agents; D011728:Pyridones; D012717:Sesquiterpenes; D000077768:Ciclopirox; C002669:parthenolide; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
references: Leukemia. 2000 Oct;14(10):1777-84
references: 11021753
references: J Exp Med. 2010 Apr 12;207(4):731-50
references: 20368581
references: Blood. 2010 Dec 23;116(26):5983-90
references: 20889920
references: Blood. 2010 Jan 21;115(3):453-74
references: 19880497
references: Int J Cancer. 2002 Aug 1;100(4):491-8
references: 12115536
references: Curr Cancer Drug Targets. 2010 Nov;10(7):705-15
references: 20578985
references: Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11008-13
references: 17576927
references: Mol Cancer Ther. 2010 Jun;9(6):1574-82
references: 20515939
references: Blood. 2005 Jun 1;105(11):4163-9
references: 15687234
references: Mol Cell. 2002 Sep;10(3):457-68
references: 12408816
references: Cancer. 2007 Nov 1;110(9):1900-10
references: 17786921
references: Mol Cancer Ther. 2009 Apr;8(4):742-53
references: 19372546
references: Blood. 2005 Mar 1;105(5):1867-74
references: 15528311
references: J Biol Chem. 2001 Oct 12;276(41):38052-60
references: 11498541
references: Blood. 2009 Oct 1;114(14):3064-73
references: 19589922
references: Pancreas. 2008 Oct;37(3):e45-53
references: 18815538
references: Nat Med. 2006 Oct;12(10):1167-74
references: 16998484
references: Blood. 2007 Dec 15;110(13):4427-35
references: 17804695
references: Blood. 2007 Oct 1;110(7):2659-66
references: 17609428
references: J Biol Chem. 1994 Nov 11;269(45):27827-32
references: 7961711
references: Oncogene. 2007 Mar 22;26(13):1932-40
references: 17001314
references: Genes Dev. 2004 Aug 15;18(16):1926-45
references: 15314020
references: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16220-5
references: 12451177
references: J Biol Chem. 1989 Nov 5;264(31):18527-30
references: 2509460
references: In Vivo. 2011 Nov-Dec;25(6):887-93
references: 22021681
references: Clin Cancer Res. 2005 Sep 15;11(18):6520-7
references: 16166428
references: Br J Haematol. 2008 Dec;143(5):661-71
references: 19036014
references: Cell. 2002 Jul 26;110(2):163-75
references: 12150925
references: Free Radic Biol Med. 2011 Dec 15;51(12):2249-58
references: 22019440
references: Br J Dermatol. 1976 Jul;95(1):83-8
references: 782504
references: Drugs. 2010 Nov 12;70(16):2133-52
references: 20964457
references: Oncogene. 2011 May 5;30(18):2098-107
references: 21217783
references: Cancer Biol Ther. 2003 May-Jun;2(3):222-32
references: 12878853
references: Life Sci. 1996;58(5):373-95
references: 8594303
references: Mol Cell Biol. 1996 Nov;16(11):6242-51
references: 8887654
references: J Gastrointest Surg. 2012 Jul;16(7):1333-40
references: 22618517
references: Mol Cells. 2003 Feb 28;15(1):55-61
references: 12661761
references: Blood. 1991 May 1;77(9):2031-6
references: 2018839
references: Cell. 2009 Jul 23;138(2):286-99
references: 19632179
references: Pancreas. 2013 Jan;42(1):160-7
references: 22699205
references: Bioorg Med Chem Lett. 2009 Aug 1;19(15):4346-9
references: 19505822
references: Ann N Y Acad Sci. 2005 Jun;1044:1-5
references: 15958691
references: J Exp Med. 1992 Jun 1;175(6):1501-9
references: 1375263
references: Cancer. 2001 Sep 1;92(5):1059-73
references: 11571716
references: Science. 2005 Feb 18;307(5712):1098-101
references: 15718470
references: Mol Cell Biol. 1997 Sep;17(9):5426-36
references: 9271419
references: J Biol Chem. 1989 Nov 5;264(31):18531-5
references: 2509461
references: Int J Hematol. 2005 Dec;82(5):389-96
references: 16533740
references: Curr Biol. 2004 Jul 27;14(14):1296-302
references: 15268862
references: Blood. 2007 Feb 15;109(4):1701-11
references: 17008552
references: Cell Stem Cell. 2010 Dec 3;7(6):708-17
references: 21112565