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

Biochim Biophys Acta. 2013 Jan;1831(1):117-25. doi: 10.1016/j.bbalip.2012.08.020.

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 LPA(2) 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 24h after radiation exposure. Our findings suggest that by specifically activating LPA(2) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Radiation Syndrome / drug therapy
  • Acute Radiation Syndrome / pathology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Bystander Effect / drug effects
  • Bystander Effect / radiation effects
  • Caspase Inhibitors / pharmacology
  • Caspases / metabolism
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / radiation effects
  • Cytoprotection / drug effects
  • Cytoprotection / radiation effects
  • DNA Fragmentation / drug effects
  • DNA Fragmentation / radiation effects
  • Embryo, Mammalian / cytology
  • Enzyme Activation / drug effects
  • Enzyme Activation / radiation effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology
  • Fibroblasts / pathology
  • Fibroblasts / radiation effects
  • Gamma Rays
  • Lysophospholipids / chemistry
  • Lysophospholipids / metabolism
  • Lysophospholipids / pharmacology
  • Mice
  • Mice, Knockout
  • Organophosphorus Compounds / pharmacology
  • Phosphoric Diester Hydrolases / genetics
  • Phosphoric Diester Hydrolases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Radiation Injuries / metabolism*
  • Radiation Injuries / pathology
  • Radiation Injuries / prevention & control*
  • Receptors, Lysophosphatidic Acid / metabolism*
  • Survival Analysis

Substances

  • Caspase Inhibitors
  • Lysophospholipids
  • Organophosphorus Compounds
  • RNA, Messenger
  • Receptors, Lysophosphatidic Acid
  • octadecenyl thiophosphate
  • Extracellular Signal-Regulated MAP Kinases
  • Phosphoric Diester Hydrolases
  • alkylglycerophosphoethanolamine phosphodiesterase
  • Caspases
  • lysophosphatidic acid