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Epoxomicin is a potent anti-tumor agent isolated from Actinomycetes that is used as a selective and irreversible inhibitor of the 20S proteasome. It inhibits proteasome activity in cell growth assays with an IC50 value of 4 nM and demonstrates potent cytotoxicity against B16-F10, HCT116, and Moser solid tumor cells, as well as P388 and K562 leukemia cells with IC50 values ranging from 2-44 nM.1,2 By inhibiting osteoblast proteasome activity, epoxomicin stimulates bone formation at concentrations as low as 10 nM.3 Intraperitoneal injection of 1.5 mg/kg epoxomicin given daily for two weeks induces Parkinson’s-like symptoms in rats and addition of 100 nM epoxomicin to rat ventral midbrain cultures results in apoptosis specific to dopaminergic neurons.4,5 Epoxomicin-induced parkinsonism can be a useful model to examine mechanisms and therapies for the disease.
1
Kim, K.B., Myung, J., Sin, N., et al. Proteasome inhibition by the natural products epoxomicin and dihydroeponemycin: Insights into specificity and potency. Bioorg Med Chem Lett93335-3340(1999).
2
Hanada, M., Sugawara, K., Kaneta, K., et al. Epoxomicin, a new antitumor agent of microbial origin. J Antibiot45(11)1746-1752(1992).
3
Garrett, I.R., Chen, D., Gutierrez, G., et al. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. J Clin Invest111(11)1771-1782(2003).
4
McNaught, K.S.M., Perl, D.P., Brownell, A., et al. Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson’s disease. Ann Neurol56149-162(2004).
5
Rideout, H.J., Lang-Rollin, I.C.J., Savalle, M., et al. Dopaminergic neurons in rat ventral midbrain cultures undergo selective apoptosis and form inclusions, but do not up-regulate iHSP70, following proteasomal inhibition. J Neurochem931304-1313(2005).
Hanada, M., Sugawara, K., Kaneta, K., et al. Epoxomicin, a new antitumor agent of microbial origin. J Antibiot45(11)1746-1752(1992).
Kim, K.B., Myung, J., Sin, N., et al. Proteasome inhibition by the natural products epoxomicin and dihydroeponemycin: Insights into specificity and potency. Bioorg Med Chem Lett93335-3340(1999).
Rideout, H.J., Lang-Rollin, I.C.J., Savalle, M., et al. Dopaminergic neurons in rat ventral midbrain cultures undergo selective apoptosis and form inclusions, but do not up-regulate iHSP70, following proteasomal inhibition. J Neurochem931304-1313(2005).
McNaught, K.S.M., Perl, D.P., Brownell, A., et al. Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson’s disease. Ann Neurol56149-162(2004).
Garrett, I.R., Chen, D., Gutierrez, G., et al. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. J Clin Invest111(11)1771-1782(2003).