Journal article
Discovery and Evaluation of Inhibitors of Human Ceramidase
Molecular cancer therapeutics, Vol.10(11), pp.2052-2061
11/2011
Handle:
https://hdl.handle.net/2376/100629
PMCID: PMC3213284
PMID: 21885864
Abstract
The ceramide/sphingosine-1-phosphate (S1P) rheostat has been hypothesized to play a critical role in regulating tumor cell fate, with elevated levels of ceramide inducing death and elevated levels of S1P leading to survival and proliferation. Ceramidases are key enzymes that control this rheostat by hydrolyzing ceramide to produce sphingosine, and may also confer resistance to drugs and radiation. Therefore, ceramidase inhibitors have excellent potential for development as new anticancer drugs. In this study, we identify a novel ceramidase inhibitor (Ceranib-1) by screening a small molecule library and describe the synthesis of a more potent analog (Ceranib-2). In a cell-based assay, both compounds were found to inhibit cellular ceramidase activity toward an exogenous ceramide analog, induce the accumulation of multiple ceramide species, decrease levels of sphingosine and S1P, inhibit the proliferation of cells alone and in combination with paclitaxel, and induce cell cycle arrest and cell death.
In vivo,
Ceranib-2 was found to delay tumor growth in a syngeneic tumor model without hematologic suppression or overt signs of toxicity. These data support the selection of ceramidases as suitable targets for anticancer drug development, and provide the first non-lipid inhibitors of human ceramidase activity.
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Details
- Title
- Discovery and Evaluation of Inhibitors of Human Ceramidase
- Creators
- Jeremiah M Draper - Department of Pharmaceutical & Biomedical Sciences, Medical University of South Carolina, Charleston, SCZuping Xia - Department of Pharmaceutical & Biomedical Sciences, Medical University of South Carolina, Charleston, SCRyan A Smith - Apogee Biotechnology Corporation, Hummelstown, PAYan Zhuang - Apogee Biotechnology Corporation, Hummelstown, PAWenxue Wang - Department of Pharmaceutical & Biomedical Sciences, Medical University of South Carolina, Charleston, SCCharles D Smith - Department of Pharmaceutical & Biomedical Sciences, Medical University of South Carolina, Charleston, SC
- Publication Details
- Molecular cancer therapeutics, Vol.10(11), pp.2052-2061
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Grant note
- R01 CA122226-05 || CA / National Cancer Institute : NCI
- Identifiers
- 99900546508401842
- Language
- English
- Resource Type
- Journal article