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Molecular Medicine

, Volume 21, Issue 1, pp 410–419 | Cite as

A Selective Novel Peroxisome Proliferator-Activated Receptor (PPAR)-α Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo

  • Davorka Messmer
  • Kymmy Lorrain
  • Karin Stebbins
  • Yalda Bravo
  • Nicholas Stock
  • Geraldine Cabrera
  • Lucia Correa
  • Austin Chen
  • Jason Jacintho
  • Nicholas Chiorazzi
  • Xiao Jie Yan
  • David Spaner
  • Peppi Prasit
  • Daniel Lorrain
Research Article

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.

Notes

Acknowledgments

We would like to thank all employees of Inception Sciences for their support and contribution of this program.

Supplementary material

10020_2015_2101410_MOESM1_ESM.pdf (1.3 mb)
Supplementary material, approximately 1300 KB.

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Authors and Affiliations

  • Davorka Messmer
    • 1
  • Kymmy Lorrain
    • 1
  • Karin Stebbins
    • 1
  • Yalda Bravo
    • 1
  • Nicholas Stock
    • 1
  • Geraldine Cabrera
    • 1
  • Lucia Correa
    • 1
  • Austin Chen
    • 1
  • Jason Jacintho
    • 1
  • Nicholas Chiorazzi
    • 2
  • Xiao Jie Yan
    • 2
  • David Spaner
    • 3
    • 4
    • 5
  • Peppi Prasit
    • 1
  • Daniel Lorrain
    • 1
  1. 1.Inception SciencesSan DiegoUSA
  2. 2.The Feinstein Institute for Medical ResearchNorth Shore-LIJ Health SystemManhassetUSA
  3. 3.Division of Molecular and Cellular BiologySunnybrook Research InstituteTorontoCanada
  4. 4.Department of Medical BiophysicsUniversity of TorontoTorontoCanada
  5. 5.Department of ImmunologyUniversity of TorontoTorontoCanada

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