title: A Selective Novel Peroxisome Proliferator-Activated Receptor (PPAR)-α Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo.
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.
authors.affiliation: Inception Sciences, San Diego, California, United States of America.
authors.forename: Davorka
authors.initials: D
authors.lastname: Messmer
authors.affiliation: Inception Sciences, San Diego, California, United States of America.
authors.forename: Kymmy
authors.initials: K
authors.lastname: Lorrain
authors.affiliation: Inception Sciences, San Diego, California, United States of America.
authors.forename: Karin
authors.initials: K
authors.lastname: Stebbins
authors.affiliation: Inception Sciences, San Diego, California, United States of America.
authors.forename: Yalda
authors.initials: Y
authors.lastname: Bravo
authors.affiliation: Inception Sciences, San Diego, California, United States of America.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stock
authors.affiliation: Inception Sciences, San Diego, California, United States of America.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Cabrera
authors.affiliation: Inception Sciences, San Diego, California, United States of America.
authors.forename: Lucia
authors.initials: L
authors.lastname: Correa
authors.affiliation: Inception Sciences, San Diego, California, United States of America.
authors.forename: Austin
authors.initials: A
authors.lastname: Chen
authors.affiliation: Inception Sciences, San Diego, California, United States of America.
authors.forename: Jason
authors.initials: J
authors.lastname: Jacintho
authors.affiliation: The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, United States of America.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.affiliation: The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, United States of America.
authors.forename: Xiao Jie
authors.initials: XJ
authors.lastname: Yan
authors.affiliation: Division of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Spaner
authors.affiliation: Inception Sciences, San Diego, California, United States of America.
authors.forename: Peppi
authors.initials: P
authors.lastname: Prasit
authors.affiliation: Inception Sciences, San Diego, California, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lorrain
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000235:genetics*; D013449:Sulfonamides / Q000008:administration & dosage*; D015533:Transcriptional Activation
chemical_list: D000631:Aminopyridines; D005227:Fatty Acids; C000608119:NXT629; D047493:PPAR alpha; D013449:Sulfonamides