A novel tetracyclic peptide, trapoxin, induces phenotypic change from transformed to normal in sis-oncogene-transformed NIH3T3 cells.

A novel tetracyclic peptide, trapoxin [cyclo(L-phenylalanyl-L-phenylalanyl-D-pipecolinyl-L-2-amino-8-oxo-9, 10-epoxy-decanoyl)], was found to induce the flat phenotype in v-sis-transformed NIH3T3 cells at a quite low concentration of 1 ng/ml. Actin stress fiber could be detected after trapoxin treatment. Almost complete reversion into the flat phenotype was observed at 6 h after the administration of the compound. The effect of trapoxin was reversible, when the cell culture was incubated for more than 24 h after its removal. The intracellular level of sis-mRNA did not decrease with trapoxin treatment at a concentration (50 ng/ml), sufficient to reverse the transformed morphology. Substitution of pipecolinic acid with proline in trapoxin did not change the activity. WF3161, in which leucine was substituted for a phenylalanine of trapoxin, showed only one-sixteenth of the activity of trapoxin. Reduction of the epoxide residue of trapoxin destroyed the activity.