Combined Mitigation of the Gastrointestinal and Hematopoietic Acute Radiation Syndromes by an LPA2 Receptor-Specific Nonlipid Agonist

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 adm...

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Bibliographic Details
Published in:Chemistry & biology 2015-02, Vol.22 (2), p.206-216
Main Authors: Patil, Renukadevi, Szabó, Erzsébet, Fells, James I., Balogh, Andrea, Lim, Keng G., Fujiwara, Yuko, Norman, Derek D., Lee, Sue-Chin, Balazs, Louisa, Thomas, Fridtjof, Patil, Shivaputra, Emmons-Thompson, Karin, Boler, Alyssa, Strobos, Jur, McCool, Shannon W., Yates, C. Ryan, Stabenow, Jennifer, Byrne, Gerrald I., Miller, Duane D., Tigyi, Gábor J.
Format: Article
Language:English
Subjects:
Acute Radiation Syndrome - metabolism
Acute Radiation Syndrome - pathology
Acute Radiation Syndrome - prevention & control
Animals
Apoptosis - drug effects
Apoptosis - radiation effects
Binding Sites
Caspase 8 - metabolism
Cell Line
DNA Fragmentation - drug effects
DNA Fragmentation - radiation effects
Gamma Rays
Histones - metabolism
Humans
Lysophospholipids - chemistry
Lysophospholipids - pharmacology
Lysophospholipids - therapeutic use
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Docking Simulation
Naphthalimides - chemistry
Naphthalimides - pharmacology
Naphthalimides - therapeutic use
Protein Structure, Tertiary
Receptors, Lysophosphatidic Acid - agonists
Receptors, Lysophosphatidic Acid - genetics
Receptors, Lysophosphatidic Acid - metabolism
Sulfonamides - chemistry
Sulfonamides - pharmacology
Sulfonamides - therapeutic use
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Summary: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. [Display omitted] •DBIBB is an LPA2 GPCR-specific agonist butylsulfamoyl benzoic acid analog•DBIBB protects cells from radiation injury and enhances DNA repair via LPA2•DBIBB decreases mortality due to GI and HEM acute radiation syndromes•DBIBB is an effective radiomitigator with postirradiation administration up to 72 hr Patil et al. identify a specific agonist of the lysophosphatidic acid type 2 GPCR sulfamoyl, benzoic acid derivative, DBIBB. DBIBB mitigates cell and tissue injury in vitro and in vivo when applied even days after exposure to high levels of ionizing radiation and therefore represents an effective radiomitigator.
ISSN:1074-5521
1879-1301
DOI:10.1016/j.chembiol.2014.12.009