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Chemical Compound Review

AC1NRAZ8     (2S,3S)-2-[[(2S,3S)-2- (ethanoyl-methyl...

Synonyms: SMP2_000342, EPX
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Disease relevance of epoxomicin


High impact information on epoxomicin

  • When administered systemically to mice, the proteasome inhibitors epoxomicin and proteasome inhibitor-1 increased bone volume and bone formation rates over 70% after only 5 days of treatment [6].
  • Enzymatic analyses with purified bovine erythrocyte proteasome reveal that epoxomicin potently inhibits primarily the chymotrypsin-like activity [1].
  • Utilizing biotinylated-epoxomicin as a molecular probe, we demonstrate that epoxomicin covalently binds to the LMP7, X, MECL1, and Z catalytic subunits of the proteasome [1].
  • In contrast to peptide aldehyde proteasome inhibitors, epoxomicin does not inhibit nonproteasomal proteases such trypsin, chymotrypsin, papain, calpain, and cathepsin B at concentrations of up to 50 microM [1].
  • Protection was abrogated by the proteasome inhibitor epoxomicin and disease-causing variants, indicating that it was mediated by the E3 ubiquitin ligase activity of Parkin [7].

Biological context of epoxomicin

  • Treatment of cells with a MEK inhibitor (U0126) or proteasome inhibitor (epoxomicin) also up-regulated Bim accumulation and rendered cells more sensitive to anoikis [8].
  • Proteasome inhibition by epoxomicin was unable to prevent tubulin loss. siRNA-mediated reduction of PPARgamma and PPARdelta proteins did not replicate the effects of PPARgamma inhibitors or interfere with the inhibitors' effects on apoptosis, cell cycle or tubulin [9].
  • The p27Kip1 protein expression before and after LY294002, wortmannin, or epoxomicin treatment and phosphorylation status of AKT were measured in parental and NPM/ALK+ cells by Western analysis [10].
  • A comparative biochemical analysis, after employing three different human fibroblasts cell lines (IMR90, MRC5 and WI38 cells), as well as two proteasome inhibitors (epoxomicin and MG132), has shown that proteasome inhibition results in the appearance of a senescence-like phenotype in all cell lines used [11].
  • A hypothesis has been put forward that epoxomicin stops spermiogenesis during the period of preparation to further deep reorganisation of spermatids by blocking proteolysis of short-lived regulatory proteins which are responsible among others for triggering the exchange of nucleohistones into nucleoprotamines [12].

Anatomical context of epoxomicin


Associations of epoxomicin with other chemical compounds

  • In this study we have investigated how partial and selective inhibition of the chymotrypsin-like activity of the proteasome by the proteasome inhibitors lactacystin or epoxomicin would affect Ag presentation [2].
  • Here, we report that proteasome inhibitors MG132 and epoxomicin significantly prevented Picea wilsonii pollen tube development and markedly altered tube morphology in a dose- and time-dependent manner, while hardly similar effects were detected when cysteine-protease inhibitor E-64 was used [18].

Gene context of epoxomicin

  • The proteasome inhibitors, lactacystin and epoxomicin, attenuated MIP-1beta induced CCR5 down-modulation as detected by fluorescence-activated cell sorter analysis and confocal microscopy [19].
  • The internalization of GH and GHR was inhibited by CIS-R107K, a dominant-negative SH2 domain mutant of CIS, and by the proteasome inhibitors MG132 and epoxomicin, which prolong GHR signaling to STAT5b [20].
  • The proteasome inhibitor epoxomicin abolished the MyD88 degradation induced by TGF-beta1 [21].
  • Epoxomicin also increased the expression of Bax and decreased that of Bcl-2, which may cause mitochondrial dysfunction and release of free radicals [3].
  • RESULTS: p27Kip1 was found to be downregulated in NPM/ALK-transformed hematopoietic cells, but inhibition of proteasome-dependent degradation pathway by epoxomicin reversed this effect [10].

Analytical, diagnostic and therapeutic context of epoxomicin


  1. Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. Meng, L., Mohan, R., Kwok, B.H., Elofsson, M., Sin, N., Crews, C.M. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  2. The selective proteasome inhibitors lactacystin and epoxomicin can be used to either up- or down-regulate antigen presentation at nontoxic doses. Schwarz, K., de Giuli, R., Schmidtke, G., Kostka, S., van den Broek, M., Kim, K.B., Crews, C.M., Kraft, R., Groettrup, M. J. Immunol. (2000) [Pubmed]
  3. Effect of proteasome inhibitor on cultured mesencephalic dopaminergic neurons. Kikuchi, S., Shinpo, K., Tsuji, S., Takeuchi, M., Yamagishi, S., Makita, Z., Niino, M., Yabe, I., Tashiro, K. Brain Res. (2003) [Pubmed]
  4. Establishment and some characteristics of epoxomicin (a proteasome inhibitor) resistant variants of the human squamous cell carcinoma cell line, A431. Ohkawa, K., Asakura, T., Aoki, K., Shibata, S., Minami, J., Fujiwara, C., Sai, T., Marushima, H., Kuzuu, H. Int. J. Oncol. (2004) [Pubmed]
  5. Epoxomicin, a new antitumor agent of microbial origin. Hanada, M., Sugawara, K., Kaneta, K., Toda, S., Nishiyama, Y., Tomita, K., Yamamoto, H., Konishi, M., Oki, T. J. Antibiot. (1992) [Pubmed]
  6. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. Garrett, I.R., Chen, D., Gutierrez, G., Zhao, M., Escobedo, A., Rossini, G., Harris, S.E., Gallwitz, W., Kim, K.B., Hu, S., Crews, C.M., Mundy, G.R. J. Clin. Invest. (2003) [Pubmed]
  7. Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Darios, F., Corti, O., Lücking, C.B., Hampe, C., Muriel, M.P., Abbas, N., Gu, W.J., Hirsch, E.C., Rooney, T., Ruberg, M., Brice, A. Hum. Mol. Genet. (2003) [Pubmed]
  8. Extracellular matrix metalloproteinase inducer (CD147) confers resistance of breast cancer cells to Anoikis through inhibition of Bim. Yang, J.M., O'Neill, P., Jin, W., Foty, R., Medina, D.J., Xu, Z., Lomas, M., Arndt, G.M., Tang, Y., Nakada, M., Yan, L., Hait, W.N. J. Biol. Chem. (2006) [Pubmed]
  9. PPARgamma inhibitors reduce tubulin protein levels by a PPARgamma, PPARdelta and proteasome-independent mechanism, resulting in cell cycle arrest, apoptosis and reduced metastasis of colorectal carcinoma cells. Schaefer, K.L., Takahashi, H., Morales, V.M., Harris, G., Barton, S., Osawa, E., Nakajima, A., Saubermann, L.J. Int. J. Cancer (2007) [Pubmed]
  10. NPM/ALK downregulates p27Kip1 in a PI-3K-dependent manner. Slupianek, A., Skorski, T. Exp. Hematol. (2004) [Pubmed]
  11. Proteasome inhibition induces a senescence-like phenotype in primary human fibroblasts cultures. Chondrogianni, N., Gonos, E.S. Biogerontology. (2004) [Pubmed]
  12. The influence of epoxomicin, inhibitor of proteasomal proteolytic activity, on spermiogenesis in Chara vulgaris. Kwiatkowska, M., Wojtczak, A., Popłońska, K., Teodorczyk, M. Folia Histochem. Cytobiol. (2003) [Pubmed]
  13. Cytosolic prion protein is not toxic and protects against Bax-mediated cell death in human primary neurons. Roucou, X., Guo, Q., Zhang, Y., Goodyer, C.G., LeBlanc, A.C. J. Biol. Chem. (2003) [Pubmed]
  14. Cooperative cytotoxicity of proteasome inhibitors and tumor necrosis factor-related apoptosis-inducing ligand in chemoresistant Bcl-2-overexpressing cells. Nencioni, A., Wille, L., Dal Bello, G., Boy, D., Cirmena, G., Wesselborg, S., Belka, C., Brossart, P., Patrone, F., Ballestrero, A. Clin. Cancer Res. (2005) [Pubmed]
  15. Effect of geranylgeranylaceton on cellular damage induced by proteasome inhibition in cultured spinal neurons. Kikuchi, S., Shinpo, K., Takeuchi, M., Tsuji, S., Yabe, I., Niino, M., Tashiro, K. J. Neurosci. Res. (2002) [Pubmed]
  16. Cyclic AMP delays neutrophil apoptosis via stabilization of Mcl-1. Kato, T., Kutsuna, H., Oshitani, N., Kitagawa, S. FEBS Lett. (2006) [Pubmed]
  17. Major histocompatibility complex class I restricted T-cell autoreactivity in human peripheral blood mononuclear cells. Eleftheriadis, T., Voyatzi, S., Antoniadi, G., Kartsios, C., Liakopoulos, V., Paraskevopoulos, P., Galaktidou, G. Cell. Immunol. (2006) [Pubmed]
  18. Roles of the ubiquitin/proteasome pathway in pollen tube growth with emphasis on MG132-induced alterations in ultrastructure, cytoskeleton, and cell wall components. Sheng, X., Hu, Z., Lü, H., Wang, X., Baluska, F., Samaj, J., Lin, J. Plant Physiol. (2006) [Pubmed]
  19. CXCR4/CCR5 down-modulation and chemotaxis are regulated by the proteasome pathway. Fernandis, A.Z., Cherla, R.P., Chernock, R.D., Ganju, R.K. J. Biol. Chem. (2002) [Pubmed]
  20. Role of the cytokine-induced SH2 domain-containing protein CIS in growth hormone receptor internalization. Landsman, T., Waxman, D.J. J. Biol. Chem. (2005) [Pubmed]
  21. Transforming growth factor-beta differentially inhibits MyD88-dependent, but not TRAM- and TRIF-dependent, lipopolysaccharide-induced TLR4 signaling. Naiki, Y., Michelsen, K.S., Zhang, W., Chen, S., Doherty, T.M., Arditi, M. J. Biol. Chem. (2005) [Pubmed]
  22. HIV-1 reverse transcriptase targeted for proteasomal degradation as a prototype vaccine against drug-resistant HIV-1. Starodubova, E., Boberg, A., Kashuba, E.V., Wahren, B., Karpov, V., Isaguliants, M. Vaccine (2006) [Pubmed]
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