Long-term treatment of farnesyltransferase inhibitor FTI-277 induces neurotoxicity of hippocampal neurons from rat embryo in a ROS-dependent manner.
Despite the well established anti-cancer effect of farnesyltransferase inhibitor FTI-277, the neurotoxic effects of the agent are not yet clearly defined at the molecular and cellular levels. Here, we report the neurotoxic effects of FTI-277 and the involvement of reactive oxygen species (ROS) in FTI-induced neurotoxicity. Although there is no significant effect of FTI-277 for 2 days, long-term treatment of FTI-277 for 4 days induced dramatic reduction in outgrowth, maturation and branching of neuritis and considerable cytoxicity in a dose- and time-dependent manner in primary cultured rat embryo hippocampal neurons. Interestingly, FTI-277 for 4 days dramatically decreased expression of synapsin I, a crucial molecule involved in the neuronal growth and plasticity, and increased a cytotoxic G-protein RhoB of which ectopic expression induced the neurotoxicity in hippocampal neurons. Moreover, treatment with FTI-277 dramatically increased intracellular levels of ROS, which was sustained for 4 days; while blockage of ROS rescued FTI-277-induced neurotoxicity as well as both decrease of synapsin I and increase of RhoB. Taken together, these results provide the molecular insights for the mechanisms which might be of use aiming for avoiding neurotoxic side effects by FTI agent for a drug development for a clinical use.
KI for BioCentury, Korea Advanced Institute of Science & Technology, Daejeon 305-701, Republic of Korea.
Dong-Myung
DM
Kim
Seung-Wook
SW
Ryu
Chulhee
C
Choi
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006624:Hippocampus / Q000187:drug effects*; D008715:Methionine / Q000031:analogs & derivatives* / Q000633:toxicity; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C096856:FTI 277; D017382:Reactive Oxygen Species; D008715:Methionine; D051231:Farnesyltranstransferase