Mitigation of radiation injury by selective stimulation of the LPA 2 receptor

Gyöngyi N. Kiss, Sue Chin Lee, James I. Fells, Jianxiong Liu, William J. Valentine, Yuko Fujiwara, Karin Emmons Thompson, Charles R. Yates, Balázs Sümegi, Gabor Tigyi

Research output: Contribution to journalReview article

21 Citations (Scopus)

Abstract

Due to its antiapoptotic action, derivatives of the lipid mediator lysophosphatidic acid (LPA) provide potential therapeutic utility in diseases associated with programmed cell death. Apoptosis is one of the major pathophysiological processes elicited by radiation injury to the organism. Consequently, therapeutic explorations applying compounds that mimic the antiapoptotic action of LPA have begun. Here we present a brief account of our decade-long drug discovery effort aimed at developing LPA mimics with a special focus on specific agonists of the LPA2 receptor subtype, which was found to be highly effective in protecting cells from apoptosis. We describe new evidence that 2-((3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)propyl)thio) benzoic acid (GRI977143), a prototypic nonlipid agonist specific to the LPA 2 receptor subtype, rescues apoptotically condemned cells in vitro and in vivo from injury caused by high-dose γ-irradiation. GRI977143 shows the features of a radiomitigator because it is effective in rescuing the lives of mice from deadly levels of radiation when administered 24 h after radiation exposure. Our findings suggest that by specifically activating LPA2 receptors GRI977143 activates the ERK1/2 prosurvival pathway, effectively reduces Bax translocation to the mitochondrion, attenuates the activation of initiator and effector caspases, reduces DNA fragmentation, and inhibits PARP-1 cleavage associated with γ-irradiation-induced apoptosis. GRI977143 also inhibits bystander apoptosis elicited by soluble proapoptotic mediators produced by irradiated cells. Thus, GRI977143 can serve as a prototype scaffold for lead optimization paving the way to more potent analogs amenable for therapeutic exploration. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.

Original languageEnglish
Pages (from-to)117-125
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1831
Issue number1
DOIs
Publication statusPublished - Jan 1 2013

Keywords

  • Apoptosis
  • Bystander-apoptosis
  • Distant effects of radiation exposure
  • LPA
  • Radiomitigator
  • Radioprotection

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Kiss, G. N., Lee, S. C., Fells, J. I., Liu, J., Valentine, W. J., Fujiwara, Y., Thompson, K. E., Yates, C. R., Sümegi, B., & Tigyi, G. (2013). Mitigation of radiation injury by selective stimulation of the LPA 2 receptor. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 1831(1), 117-125. https://doi.org/10.1016/j.bbalip.2012.08.020