title: Combined mitigation of the gastrointestinal and hematopoietic acute radiation syndromes by an LPA2 receptor-specific nonlipid agonist.
abstract: Pharmacological mitigation of injuries caused by high-dose ionizing radiation is an unsolved medical problem. A specific nonlipid agonist of the type 2 G protein coupled receptor for lysophosphatidic acid (LPA2) 2-[4-(1,3-dioxo-1H,3H-benzoisoquinolin-2-yl)butylsulfamoyl]benzoic acid (DBIBB) when administered with a postirradiation delay of up to 72 hr reduced mortality of C57BL/6 mice but not LPA2 knockout mice. DBIBB mitigated the gastrointestinal radiation syndrome, increased intestinal crypt survival and enterocyte proliferation, and reduced apoptosis. DBIBB enhanced DNA repair by augmenting the resolution of γ-H2AX foci, increased clonogenic survival of irradiated IEC-6 cells, attenuated the radiation-induced death of human CD34(+) hematopoietic progenitors and enhanced the survival of the granulocyte/macrophage lineage. DBIBB also increased the survival of mice suffering from the hematopoietic acute radiation syndrome after total-body irradiation. DBIBB represents a drug candidate capable of mitigating acute radiation syndrome caused by high-dose γ-radiation to the hematopoietic and gastrointestinal system.
authors.affiliation: Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Renukadevi
authors.initials: R
authors.lastname: Patil
authors.affiliation: Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Szabó
authors.affiliation: Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: James I
authors.initials: JI
authors.lastname: Fells
authors.affiliation: Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Balogh
authors.affiliation: Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Keng G
authors.initials: KG
authors.lastname: Lim
authors.affiliation: Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Derek D
authors.initials: DD
authors.lastname: Norman
authors.affiliation: Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Sue-Chin
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Department of Pathology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Louisa
authors.initials: L
authors.lastname: Balazs
authors.affiliation: Department of Preventive Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Fridtjof
authors.initials: F
authors.lastname: Thomas
authors.affiliation: Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Shivaputra
authors.initials: S
authors.lastname: Patil
authors.affiliation: RxBio, Johnson City, TN 37604, USA.
authors.forename: Karin
authors.initials: K
authors.lastname: Emmons-Thompson
authors.affiliation: RxBio, Johnson City, TN 37604, USA.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Boler
authors.affiliation: RxBio, Johnson City, TN 37604, USA.
authors.forename: Jur
authors.initials: J
authors.lastname: Strobos
authors.affiliation: RxBio, Johnson City, TN 37604, USA.
authors.forename: Shannon W
authors.initials: SW
authors.lastname: McCool
authors.affiliation: RxBio, Johnson City, TN 37604, USA.
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Yates
authors.affiliation: The Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stabenow
authors.affiliation: The Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Gerrald I
authors.initials: GI
authors.lastname: Byrne
authors.affiliation: Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.affiliation: Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA. Electronic address: gtigyi@uthsc.edu.
authors.forename: Gábor J
authors.initials: GJ
authors.lastname: Tigyi
mesh_terms: D054508:Acute Radiation Syndrome / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D001665:Binding Sites; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D053938:DNA Fragmentation / Q000187:drug effects / Q000528:radiation effects; D005720:Gamma Rays; D006657:Histones / Q000378:metabolism; D006801:Humans; D008246:Lysophospholipids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062105:Molecular Docking Simulation; D053644:Naphthalimides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C000602829:2-(4-(1,3-dioxo-1H,3H-benzoisoquinolin-2-yl)butylsulfamoyl)benzoic acid; D006657:Histones; D008246:Lysophospholipids; D053644:Naphthalimides; D049368:Receptors, Lysophosphatidic Acid; D013449:Sulfonamides; D053181:Caspase 8; C032881:lysophosphatidic acid