Human fibroblast growth factor 20 (FGF-20; CG53135-05): a novel cytoprotectant with radioprotective potential.
The aim was to evaluate the radioprotective properties of recombinant human fibroblast growth factor 20 (FGF-20; CG53135-05) in vitro and in vivo and to examine its effects on known cellular pathways of radioprotection. Relative transcript levels of the cyclooxygenase 2 (COX2), Mn-super oxide dismutase (SOD), CuZn-SOD, extracellular (EC)-SOD, nuclear respiratory factor 2 (Nrf2), glutathione peroxidase 1 (GPX1) and intestinal trefoil factor 3 (ITF3) genes, which are involved in radiation response pathways, were assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) in NIH/3T3, IEC18, CCD-18Co, CCD-1070sk and human umbilical vein endothelial cells (HUVEC) cells exposed to FGF-20. Activation of the radioprotective signal transduction pathways initiating with the serine/threonine Akt kinase and the extracellular regulated kinase (ERK) were analysed. Levels of intracellular hydrogen peroxide and cytosolic redox potential were also measured in irradiated and unirradiated cells in the presence or absence of FGF-20. The effects of FGF-20 on cell survival in vitro following ionizing radiation were evaluated using clonogenic assays. To test the potential activity of FGF-20 as a radioprotectant in vivo, mice were administered a single dose of FGF-20 (4 mg kg(-1), intraperitoneally (i.p.) 1 day before lethal total-body irradiation and evaluated for survival. In vitro exposure to FGF-20 increased expression of the Nrf2 transcription factor and oxygen radical scavenging enzymes such as MnSOD, activated signal transduction pathways (ERK and Akt) and resulted in increased survival of irradiated cells in vitro. FGF-20 treatment also resulted in a concomitant reduction in intracellular levels of injurious reactive oxygen species (ROS) following acute ionizing irradiation. Finally, prophylactic administration of FGF-20 to mice before potentially lethal, whole-body X-irradiation led to significant increases in overall survival. FGF-20 reduced the lethal effects of acute ionizing radiation exposure in cells by up-regulating important signalling and free radical scavenging pathways. Survival-sparing effects of FGF-20 prophylaxis in acutely irradiated mice presumably are elicited by comparable mechanisms. These results indicate that FGF-20, has significant radioprotective attributes with potential applications in clinical and non-clinical exposure settings.
Maclachlan
T
T
Curagen Corporation, Branford, CT, USA.
Narayanan
B
B
Gerlach
V L
VL
Smithson
G
G
Gerwien
R W
RW
Folkerts
O
O
Fey
E G
EG
Watkins
B
B
Seed
T
T
Alvarez
E
E
D000818:Animals; D002470:Cell Survival; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism; D042783:Endothelial Cells; D005346:Fibroblast Growth Factors / Q000502:physiology*; D016166:Free Radical Scavengers; D020869:Gene Expression Profiling; D005979:Glutathione Peroxidase / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000032:analysis; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018384:Oxidative Stress; D010455:Peptides / Q000378:metabolism; D011832:Radiation Injuries / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000378:metabolism; D000071164:Trefoil Factor-2; D014916:Whole-Body Irradiation; D000094765:Glutathione Peroxidase GPX1
C416003:FGF20 protein, human; D016166:Free Radical Scavengers; D010455:Peptides; D011837:Radiation-Protective Agents; D000071164:Trefoil Factor-2; D005346:Fibroblast Growth Factors; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D051546:Cyclooxygenase 2; D013482:Superoxide Dismutase; D000094765:Glutathione Peroxidase GPX1