Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth

James Kim; Jean Y. Tang; Ruoyu Gong; Jynho Kim; John J. Lee; Karl V. Clemons; Curtis R. Chong; Kris S. Chang; Mark Fereshteh; Dale Gardner; Tannishtha Reya; Jun O. Liu; Ervin H. Epstein; David A. Stevens; Philip A. Beachy

doi:10.1016/j.ccr.2010.02.027

Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth

James Kim, Jean Y. Tang, Ruoyu Gong, Jynho Kim, John J. Lee, Karl V. Clemons, Curtis R. Chong, Kris S. Chang, Mark Fereshteh, Dale Gardner, Tannishtha Reya, Jun O. Liu, Ervin H. Epstein, David A. Stevens, Philip A. Beachy

School of Medicine

Research output: Contribution to journal › Article › peer-review

350 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	388-399
Number of pages	12
Journal	Cancer cell
Volume	17
Issue number	4
DOIs	https://doi.org/10.1016/j.ccr.2010.02.027
State	Published - Apr 13 2010

Keywords

CELLCYCLE
CHEMBIO

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccr.2010.02.027

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Kim, J., Tang, J. Y., Gong, R., Kim, J., Lee, J. J., Clemons, K. V., Chong, C. R., Chang, K. S., Fereshteh, M., Gardner, D., Reya, T., Liu, J. O., Epstein, E. H., Stevens, D. A., & Beachy, P. A. (2010). Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth. Cancer cell, 17(4), 388-399. https://doi.org/10.1016/j.ccr.2010.02.027

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title = "Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth",

abstract = "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.",

keywords = "CELLCYCLE, CHEMBIO",

author = "James Kim and Tang, {Jean Y.} and Ruoyu Gong and Jynho Kim and Lee, {John J.} and Clemons, {Karl V.} and Chong, {Curtis R.} and Chang, {Kris S.} and Mark Fereshteh and Dale Gardner and Tannishtha Reya and Liu, {Jun O.} and Epstein, {Ervin H.} and Stevens, {David A.} and Beachy, {Philip A.}",

note = "Funding Information: We thank N. Sever for providing HEK 293S inducible SMO cell line, M. Martinez and A.J. Tong for technical assistance, P. Lovelace for assistance with FACS, A. Olson for assistance with confocal microscopy, and M. Scott for helpful comments and discussion of the manuscript. J.K. is a recipient of the American Society of Clinical Oncology Young Investigator Award. This research was supported in part by grants from the Prostate Cancer Foundation, from the Stanford University Center for Children's Brain Tumors, and from the National Institutes of Health. P.A.B is an investigator of the Howard Hughes Medical Institute. ",

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doi = "10.1016/j.ccr.2010.02.027",

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AU - Kim, James

AU - Tang, Jean Y.

AU - Gong, Ruoyu

AU - Kim, Jynho

AU - Lee, John J.

AU - Clemons, Karl V.

AU - Chong, Curtis R.

AU - Chang, Kris S.

AU - Fereshteh, Mark

AU - Gardner, Dale

AU - Reya, Tannishtha

AU - Liu, Jun O.

AU - Epstein, Ervin H.

AU - Stevens, David A.

AU - Beachy, Philip A.

N1 - Funding Information: We thank N. Sever for providing HEK 293S inducible SMO cell line, M. Martinez and A.J. Tong for technical assistance, P. Lovelace for assistance with FACS, A. Olson for assistance with confocal microscopy, and M. Scott for helpful comments and discussion of the manuscript. J.K. is a recipient of the American Society of Clinical Oncology Young Investigator Award. This research was supported in part by grants from the Prostate Cancer Foundation, from the Stanford University Center for Children's Brain Tumors, and from the National Institutes of Health. P.A.B is an investigator of the Howard Hughes Medical Institute.

PY - 2010/4/13

Y1 - 2010/4/13

N2 - 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.

AB - 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.

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Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth

Abstract

Keywords

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