Novel mTOR inhibitory activity of ciclopirox enhances parthenolide antileukemia activity

Siddhartha Sen, Duane C. Hassane, Cheryl Corbett, Michael W. Becker, Craig T. Jordan, Monica L. Guzman

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)799-807.e4
JournalExperimental Hematology
Volume41
Issue number9
DOIs
StatePublished - Sep 2013
Externally publishedYes

Bibliographical note

Funding Information:
M.L.G. was supported by the U.S. National Institutes of Health (NIH) through the NIH Director's New Innovator Award Program ( 1 DP2 OD007399-01 ), the National Cancer Institute ( R21 CA158728-01A1 ), and the Leukemia and Lymphoma Society ( LLS 6330-11 and LLS 6427-13 ); M.L.G is a V Foundation Scholar; D.C.H. is funded through the LLS ( LLS 6453-13 ); CTJ was supported by LLS grant 6230-11 .

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