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      Long-term treatment of farnesyltransferase inhibitor FTI-277 induces neurotoxicity of hippocampal neurons from rat embryo in a ROS-dependent manner.

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          Abstract

          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.

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          Author and article information

          Journal
          Biochem. Biophys. Res. Commun.
          Biochemical and biophysical research communications
          Elsevier BV
          1090-2104
          0006-291X
          Dec 03 2010
          : 403
          : 1
          Affiliations
          [1 ] KI for BioCentury, Korea Advanced Institute of Science & Technology, Daejeon 305-701, Republic of Korea.
          Article
          S0006-291X(10)02012-7
          10.1016/j.bbrc.2010.10.123
          21040708
          50968cdb-b94e-4c0b-bd97-5914392674e5
          History

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