Publication Date
2015
Journal Title
Mol Med
Abstract
Tumor-specific metabolic changes can reveal new therapeutic targets. Our findings implicate a supporting role for fatty acid metabolism in chronic lymphocytic leukemia (CLL) cell survival. Peroxisome proliferator-activated receptor (PPAR)-alpha, a major transcriptional regulator of fatty acid oxidation, was recently shown to be upregulated in CLL. To evaluate PPAR alpha as a potential therapeutic target, we developed a highly selective, potent small molecule antagonist of PPAR alpha, NXT629. NXT629 inhibited agonist-induced transcription of PPAR alpha-regulated genes, demonstrating target engagement in CLL cells. Furthermore, NXT629 induced apoptosis of CLL cells even in the presence of a protective microenvironment. To mimic the proliferative lymphoid compartment of CLL, we examined the activity of NXT629 on CLL cells that were stimulated to proliferate in vitro. NXT629 reduced the number of leukemia cells undergoing cell division. In addition, in two xenograft mouse models of CLL (one a model for nondividing and one for dividing CLL), NXT629 reduced the number of viable CLL cells in vivo. Overall, these results suggest that fatty acid metabolism promotes survival and proliferation of primary CLL cells and that inhibiting PPAR alpha gene regulation could be a new therapeutic approach to treating CLL.
Volume Number
21
Pages
410-419
Document Type
Article
EPub Date
2015/06/13
Status
Faculty; Northwell Researcher
Facility
School of Medicine; Northwell Health
Primary Department
Molecular Medicine
Additional Departments
General Internal Medicine
PMID
DOI
10.2119/molmed.2015.00139