Ethyl pyruvate, a potentially effective mitigator of damage after total-body irradiation.
Ethyl pyruvate (EP), a simple aliphatic ester of pyruvic acid, has been shown to improve survival and ameliorate organ damage in animal models of sepsis, ischemia/reperfusion injury and hemorrhagic shock. Incubating IL3-dependent mouse hematopoietic progenitor cell 32Dcl3 cells before or after irradiation with 10 mM EP increased resistance to radiation as assessed by clonogenic radiation survival curves, decreased release of mitochondrial cytochrome C into the cytoplasm, and decreased apoptosis. EP inhibited radiation-induced caspase 3 activation and poly(ADP-ribose) polymerase (PARP) cleavage in 32Dcl3 cells in a concentration-dependent fashion. EP was given i.p. to C57BL/6NHsd mice irradiated with 9.75 Gy total-body irradiation (TBI). This treatment significantly improved survival. The survival benefit was apparent irrespective of whether treatment with EP was started 1 h before TBI and continued for 5 consecutive days after TBI or the compound was injected only 1 h before or only for 5 days after TBI. In all of the in vitro and in vivo experiments, ethyl lactate, an inactive analogue of EP, had no detectable radioprotective or mitigating effects. EP may be an effective radioprotector and mitigator of the hematopoietic syndrome induced by TBI.
Epperly
Michael
M
Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Jin
Shunqian
S
Nie
Suhua
S
Cao
Shaonan
S
Zhang
Xichen
X
Franicola
Darcy
D
Wang
Hong
H
Fink
Mitchell P
MP
Greenberger
Joel S
JS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011773:Pyruvates / Q000008:administration & dosage*; D011837:Radiation-Protective Agents / Q000008:administration & dosage*; D016019:Survival Analysis; D015996:Survival Rate; D014916:Whole-Body Irradiation
D011773:Pyruvates; D011837:Radiation-Protective Agents; C046522:ethyl pyruvate