Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase.
Trapoxin (cyclo-(L-phenylalanyl-L-phenylalanyl-D-pipecolinyl-L-2-amino-8- oxo-9,10-epoxy-decanoyl)) is a fungal product that induces morphological reversion from transformed to normal in sis-transformed NIH3T3 fibroblasts. Trapoxin was found to cause accumulation of highly acetylated core histones in a variety of mammalian cell lines. In vitro experiments using partially purified mouse histone deacetylase showed that a low concentration of trapoxin irreversibly inhibited deacetylation of acetylated histone molecules. Chemical reduction of an epoxide group in trapoxin completely abolished the inhibitory activity, suggesting that trapoxin binds covalently to the histone deacetylase via the epoxide. In contrast, inhibition by trichostatin A, a known potent inhibitor of histone deacetylase, was reversible. Despite the different mode of inhibition, trapoxin and trichostatin A induced almost the same biological effects on the cell cycle and differentiation. These results strongly suggest that the in vivo effects commonly induced by these agents can be attributed to histone hyperacetylation resulting from the inhibition of histone deacetylase.
Kijima
M
M
Department of Agricultural Chemistry, Faculty of Agriculture, University of Tokyo, Japan.
Yoshida
M
M
Sugita
K
K
Horinouchi
S
S
Beppu
T
T
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000935:Antifungal Agents / Q000633:toxicity; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000633:toxicity; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009857:Oncogenes; D010455:Peptides; D018243:Teratocarcinoma; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010455:Peptides; C067070:trapoxin A; C012589:trichostatin A