Document Detail


Teriflunomide (leflunomide) promotes cytostatic, antioxidant, and apoptotic effects in transformed prostate epithelial cells: evidence supporting a role for teriflunomide in prostate cancer chemoprevention.
MedLine Citation:
PMID:  20563249     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Teriflunomide (TFN) is an inhibitor of de novo pyrimidine synthesis and the active metabolite of leflunomide. Leflunomide is prescribed to patients worldwide as an immunomodulatory and anti-inflammatory disease-modifying prodrug. Leflunomide inhibited the growth of human prostate cancer xenographs in mice, and leflunomide or TFN promoted cytostasis and/or apoptosis in cultured cells. These findings suggest that TFN could be useful in prostate cancer chemoprevention. We investigated the possible mechanistic aspects of this tenet by characterizing the effects of TFN using premalignant PWR-1E and malignant DU-145 human prostate epithelial cells. TFN promoted a dose- and time-dependent cytostasis or apoptosis induction in these cells. The cytostatic effects of TFN, which were reversible but not by the presence of excess uridine in the culture medium, included diminished cellular uridine levels, an inhibition in oxygen consumption, a suppression of reactive oxygen species (ROS) generation, S-phase cell cycle arrest, and a conspicuous reduction in the size and number of the nucleoli in the nuclei of these cells. Conversely, TFN's apoptogenic effects were characteristic of catastrophic mitochondrial disruption (i.e., a dissipation of mitochondrial inner transmembrane potential, enhanced ROS production, mitochondrial cytochrome c release, and cytoplasmic vacuolization) and followed by DNA fragmentation. The respiration-deficient derivatives of the DU-145 cells, which are also uridine auxotrophs, were markedly resistant to the cytostatic and apoptotic effects of TFN, implicating de novo pyrimidine synthesis and mitochondrial bioenergetics as the primary targets for TFN in the respiration competent cells. These mechanistic findings advocate a role for TFN and mitochondrial bioenergetics in prostate cancer chemoprevention.
Authors:
Numsen Hail; Ping Chen; Lane R Bushman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Neoplasia (New York, N.Y.)     Volume:  12     ISSN:  1476-5586     ISO Abbreviation:  Neoplasia     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-21     Completed Date:  2010-09-21     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  100886622     Medline TA:  Neoplasia     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  464-75     Citation Subset:  IM    
Affiliation:
Department of Pharmaceutical Sciences, University of Colorado Denver School of Pharmacy, 12700 E 19th Avenue, Aurora, CO 80045, USA. Numsen.Hail@UCDenver.edu
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Antioxidants / pharmacology*
Apoptosis / drug effects*
Caspases / metabolism
Cell Line, Transformed / drug effects
Cytochromes c / metabolism
Dose-Response Relationship, Drug
Epithelial Cells / drug effects*,  pathology
Flow Cytometry
Humans
Immunoblotting
Isoxazoles / pharmacology*
Male
Membrane Potential, Mitochondrial / drug effects
Mitochondria / drug effects,  metabolism
Oxygen Consumption / drug effects
Prostate / drug effects*,  pathology
Prostatic Neoplasms / metabolism,  pathology,  prevention & control*
Reactive Oxygen Species / metabolism
Time Factors
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
CA133901-01/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Antioxidants; 0/Isoxazoles; 0/Reactive Oxygen Species; 75706-12-6/leflunomide; 9007-43-6/Cytochromes c; EC 3.4.22.-/Caspases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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