Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth.
In a screen of drugs previously tested in humans we identified itraconazole, a systemic antifungal, as a potent antagonist of the Hedgehog (Hh) signaling pathway that acts by a mechanism distinct from its inhibitory effect on fungal sterol biosynthesis. Systemically administered itraconazole, like other Hh pathway antagonists, can suppress Hh pathway activity and the growth of medulloblastoma in a mouse allograft model and does so at serum levels comparable to those in patients undergoing antifungal therapy. Mechanistically, itraconazole appears to act on the essential Hh pathway component Smoothened (SMO) by a mechanism distinct from that of cyclopamine and other known SMO antagonists, and prevents the ciliary accumulation of SMO normally caused by Hh stimulation.
Kim
James
J
Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
Tang
Jean Y
JY
Gong
Ruoyu
R
Kim
Jynho
J
Lee
John J
JJ
Clemons
Karl V
KV
Chong
Curtis R
CR
Chang
Kris S
KS
Fereshteh
Mark
M
Gardner
Dale
D
Reya
Tannishtha
T
Liu
Jun O
JO
Epstein
Ervin H
EH
Stevens
David A
DA
Beachy
Philip A
PA
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002280:Basal Cell Carcinoma / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D003505:Cyclodextrins / Q000494:pharmacology; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology / Q000627:therapeutic use*; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000502:physiology; D051379:Mice; D008958:Models, Molecular; D015398:Signal Transduction / Q000187:drug effects*
D000935:Antifungal Agents; D000970:Antineoplastic Agents; D003505:Cyclodextrins; D053823:Hedgehog Proteins; D008077:Lipoproteins, LDL; D017964:Itraconazole
Science. 1998 Jun 5;280(5369):1603-7
9616123
Antimicrob Agents Chemother. 1992 Feb;36(2):477-80
1605615
Genes Dev. 2002 Nov 1;16(21):2743-8
12414725
J Urol. 2005 Jun;173(6):1947-52
15879788
Int J Clin Pharmacol Ther. 2007 Jul;45(7):377-84
17725244
Cancer Res. 2004 Jul 1;64(13):4385-9
15231643
Annu Rev Nutr. 1999;19:141-72
10448520
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14071-6
12391318
Nature. 1995 Mar 16;374(6519):272-6
7885448
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3196-201
19218434
J Biol. 2002 Nov 06;1(2):10
12437772
Leukemia. 2001 Oct;15(10):1670-1
11587231
Nature. 2000 Aug 31;406(6799):1005-9
10984056
Nat Chem Biol. 2006 Aug;2(8):415-6
16816845
N Engl J Med. 2009 Sep 17;361(12):1173-8
19726761
Proc Natl Acad Sci U S A. 1989 Oct;86(19):7321-5
2552439
Expert Opin Ther Pat. 2009 Aug;19(8):1039-56
19505195
Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17026-31
16282375
Cancer Cell. 2004 Sep;6(3):229-40
15380514
Clin Infect Dis. 1995 Dec;21(6):1485-7
8749640
Science. 1997 Aug 22;277(5329):1109-13
9262482
Cancer Res. 2007 Mar 1;67(5):2187-96
17332349
Cancer Cell. 2008 Sep 9;14(3):238-49
18772113
Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2623-8
19196978
FEBS Lett. 1979 Aug 15;104(2):236-40
225207
Antimicrob Agents Chemother. 1987 Dec;31(12):1874-8
3326525
Nature. 2001 May 17;411(6835):349-54
11357142
Nat Genet. 2001 Dec;29(4):418-25
11694875
Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):16970-5
18957545
Cancer Res. 1981 Aug;41(8):3179-85
6265078
Nature. 2004 Nov 18;432(7015):324-31
15549094
Yeast. 1999 Jun 30;15(9):755-63
10398344
Nature. 1998 Jan 1;391(6662):90-2
9422511
Antimicrob Agents Chemother. 2002 Aug;46(8):2420-6
12121913
Antimicrob Agents Chemother. 1993 Apr;37(4):778-84
8388198
Nat Genet. 2003 Apr;33(4):508-13
12652302
Antimicrob Agents Chemother. 1993 Oct;37(10):2224-7
8257148
Development. 1998 Sep;125(18):3553-62
9716521
Dev Biol. 2006 Aug 15;296(2):279-97
16828734
Toxicology. 2006 Nov 10;228(1):24-32
16989930
N Engl J Med. 2009 Sep 17;361(12):1202-5
19726764
Science. 2002 Aug 30;297(5586):1559-61
12202832
Nature. 2009 Apr 9;458(7239):776-9
19169242
J Health Econ. 2003 Mar;22(2):325-30
12606149
J Clin Oncol. 1989 Aug;7(8):1093-8
2474059
Antimicrob Agents Chemother. 1996 Feb;40(2):279-91
8834867
J Biol Chem. 2007 Mar 23;282(12):8959-68
17200122
Antimicrob Agents Chemother. 1991 May;35(5):846-50
1854166
Biochim Biophys Acta. 2007 Mar;1770(3):467-77
16963187
Nature. 2008 Sep 18;455(7211):406-10
18754008
J Health Econ. 2003 Mar;22(2):151-85
12606142
Science. 2007 Jul 20;317(5836):372-6
17641202
Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21666-71
19996169
Nature. 2005 Oct 13;437(7061):1018-21
16136078
J Antimicrob Chemother. 1999 Oct;44(4):429-37
10588302
J Med Chem. 2006 May 4;49(9):2677-80
16640327
Antimicrob Agents Chemother. 1991 Apr;35(4):707-13
1648887
J Biol Chem. 2002 Jul 12;277(28):25660-7
11964399
Genes Dev. 2008 Sep 15;22(18):2454-72
18794343
N Engl J Med. 2009 Sep 17;361(12):1164-72
19726763
Methods Mol Biol. 2005;289:329-40
15502196
Proc Natl Acad Sci U S A. 2006 May 30;103(22):8408-13
16707575
Cancer Res. 1979 Apr;39(4):1224-30
217532