Format

Send to

Choose Destination
Chem Biol. 2015 Feb 19;22(2):206-16. doi: 10.1016/j.chembiol.2014.12.009. Epub 2015 Jan 22.

Combined mitigation of the gastrointestinal and hematopoietic acute radiation syndromes by an LPA2 receptor-specific nonlipid agonist.

Author information

1
Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
2
Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
3
Department of Pathology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
4
Department of Preventive Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
5
RxBio, Johnson City, TN 37604, USA.
6
The Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
7
Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA. Electronic address: gtigyi@uthsc.edu.

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.

PMID:
25619933
PMCID:
PMC4336611
DOI:
10.1016/j.chembiol.2014.12.009
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center