homoharringtonine and bruceantin

Structures have been obtained for the complexes that tiamulin, homoharringtonine, and bruceantin form with the large ribosomal subunit of Haloarcula marismortui at resolutions ranging from 2.65 to 3.2 A. They show that all these inhibitors block protein synthesis by competing with the amino acid side chains of incoming aminoacyl-tRNAs for binding in the A-site cleft in the peptidyl-transferase center, which is universally conserved. In addition, these structures support the hypothesis that the species specificity exhibited by the A-site cleft inhibitors is determined by the interactions they make, or fail to make, with a single nucleotide, U2504 (Escherichia coli). In the ribosome, the position of U2504 is controlled by its interactions with neighboring nucleotides, whose identities vary among kingdoms.

Topics: Anti-Bacterial Agents; Crystallography, X-Ray; Diterpenes; Haloarcula marismortui; Harringtonines; Homoharringtonine; Models, Molecular; Protein Biosynthesis; Quassins; Ribosomes; Species Specificity; Static Electricity; Stereoisomerism; Uracil

The process of translation occurs at a nexus point downstream of a number of signal pathways and developmental processes. Modeling activation of the PTEN/AKT/mTOR pathway in the Emu-Myc mouse is a valuable tool to study tumor genotype/chemosensitivity relationships in vivo. In this model, blocking translation initiation with silvestrol, an inhibitor of the ribosome recruitment step has been showed to modulate the sensitivity of the tumors to the effect of standard chemotherapy. However, inhibitors of translation elongation have been tested as potential anti-cancer therapeutic agents in vitro, but have not been extensively tested in genetically well-defined mouse tumor models or for potential synergy with standard of care agents.. Here, we chose four structurally different chemical inhibitors of translation elongation: homoharringtonine, bruceantin, didemnin B and cycloheximide, and tested their ability to alter the chemoresistance of Emu-myc lymphomas harbouring lesions in Pten, Tsc2, Bcl-2, or eIF4E. We show that in some genetic settings, translation elongation inhibitors are able to synergize with doxorubicin by reinstating an apoptotic program in tumor cells. We attribute this effect to a reduction in levels of pro-oncogenic or pro-survival proteins having short half-lives, like Mcl-1, cyclin D1 or c-Myc. Using lymphomas cells grown ex vivo we reproduced the synergy observed in mice between chemotherapy and elongation inhibition and show that this is reversed by blocking protein degradation with a proteasome inhibitor.. Our results indicate that depleting short-lived pro-survival factors by inhibiting their synthesis could achieve a therapeutic response in tumors harboring PTEN/AKT/mTOR pathway mutations.

Topics: Animals; Base Sequence; Cell Line, Tumor; Cyclin D1; Cycloheximide; Depsipeptides; DNA Primers; Drug Resistance, Neoplasm; Eukaryotic Initiation Factor-4E; Female; Genes, bcl-2; Genes, myc; Harringtonines; Homoharringtonine; Lymphoma; Mice; Mice, Inbred C57BL; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Peptide Chain Elongation, Translational; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; PTEN Phosphohydrolase; Quassins; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins