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Divergence of anti-angiogenic activity and hepatotoxicity of different stereoisomers of itraconazole
Joong Sup Shim1,2; Ruo-Jing Li1; Namandje N. Bumpus1,3; Sarah A. Head1; Kalyan Kumar1; Eun Ju Yang2; Junfang Lv2; Wei Shi1,4; Jun O. Liu1,5
2016
Source PublicationClinical Cancer Research
ISSN1078-0432
Volume22Issue:11Pages:2709-2720
Abstract

Purpose: Itraconazole is a triazole antifungal drug that has recently been found to inhibit angiogenesis. Itraconazole is a relatively well-tolerated drug but shows hepatotoxicity in a small subset of patients. Itraconazole contains three chiral centers and the commercial itraconazole is composed of four cis-stereoisomers (named IT-A, IT-B, IT-C, and IT-D). We sought to determine whether the stereoisomers of itraconazole might differ in their antiangiogenic activity and hepatotoxicity. 
Experimental Design: We assessed in vitro antiangiogenic activity of itraconazole and each stereoisomer using human umbilical vein endothelial cell (HUVEC) proliferation and tube formation assays. We also determined their hepatotoxicity using primary human hepatocytes in vitro and a mouse model in vivo. Mouse Matrigel plug and tumor xenograft models were used to evaluate in vivo antiangiogenic and antitumor activities of the stereoisomers.
Results: Of the four stereoisomers contained in commercial itraconazole, we found that IT-A (2S,4R,2’R) and IT-C (2S,4R,2’S) were more potent for inhibition of angiogenesis than IT-B (2R,4S,2’R) and IT-D (2R,4S,2’S). Interestingly, IT-A and IT-B were more hepatotoxic than ITC and IT-D. In mouse models, IT-C showed more potent antiangiogenic/antitumor activity with lower hepatotoxicity compared to itraconazole and IT-A.
Conclusions: These results demonstrate the segregation of influence of stereochemistry at different positions of itraconazole on its antiangiogenic activity and hepatotoxicity, with the 2 and 4 positions affecting the former and the 2’ position affecting the latter. They also suggest that IT-C may be superior to the racemic mixture of itraconazole as an anticancer drug candidate due to its lower hepatotoxicity and improved antiangiogenic activity.

KeywordItraconazole Stereoisomers Drug Repositioning Angiogenesis Hepatotoxicity
DOIhttps://doi.org/10.1158/1078-0432.CCR-15-1888
Indexed BySCIE
Language英语
WOS Research AreaOncology
WOS SubjectOncology
WOS IDWOS:000378338200016
Fulltext Access
Citation statistics
Cited Times [WOS]:9   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
2.Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
3.Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
4.Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, USA
5.Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
First Author AffilicationFaculty of Health Sciences
Recommended Citation
GB/T 7714
Joong Sup Shim,Ruo-Jing Li,Namandje N. Bumpus,et al. Divergence of anti-angiogenic activity and hepatotoxicity of different stereoisomers of itraconazole[J]. Clinical Cancer Research,2016,22(11):2709-2720.
APA Joong Sup Shim,Ruo-Jing Li,Namandje N. Bumpus,Sarah A. Head,Kalyan Kumar,Eun Ju Yang,Junfang Lv,Wei Shi,&Jun O. Liu.(2016).Divergence of anti-angiogenic activity and hepatotoxicity of different stereoisomers of itraconazole.Clinical Cancer Research,22(11),2709-2720.
MLA Joong Sup Shim,et al."Divergence of anti-angiogenic activity and hepatotoxicity of different stereoisomers of itraconazole".Clinical Cancer Research 22.11(2016):2709-2720.
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