1. A Selective Novel Peroxisome Proliferator-Activated Receptor (PPAR)-α Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo
- Author
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Jason D. Jacintho, Yalda Bravo, Lucia Correa, Xiao-Jie Yan, Davorka Messmer, Karin J. Stebbins, Geraldine Cabrera, Nicholas Simon Stock, Daniel S. Lorrain, Austin Chen, Nicholas Chiorazzi, Kymmy Lorrain, David Spaner, and Peppi Prasit
- Subjects
Transcriptional Activation ,Cell Survival ,Chronic lymphocytic leukemia ,Aminopyridines ,Peroxisome proliferator-activated receptor ,Apoptosis ,Biology ,Mice ,Downregulation and upregulation ,immune system diseases ,Cell Line, Tumor ,hemic and lymphatic diseases ,Genetics ,medicine ,Animals ,Humans ,PPAR alpha ,Receptor ,neoplasms ,Molecular Biology ,Genetics (clinical) ,Cell Proliferation ,chemistry.chemical_classification ,Sulfonamides ,Cell growth ,Fatty Acids ,Articles ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Cell biology ,Gene Expression Regulation, Neoplastic ,Leukemia ,chemistry ,Cell culture ,Molecular Medicine - 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)-α, a major transcriptional regulator of fatty acid oxidation, was recently shown to be upregulated in CLL. To evaluate PPARα as a potential therapeutic target, we developed a highly selective, potent small molecule antagonist of PPARα, NXT629. NXT629 inhibited agonist-induced transcription of PPARα-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 PPARα gene regulation could be a new therapeutic approach to treating CLL.
- Published
- 2015