Induction of cellular differentiation and apoptosis by signal transduction inhibitors.

We have isolated signal transduction inhibitors of low molecular weight from microorganisms and plants. Since inducers of differentiation and apoptosis may be developed as new anticancer agents, we have studied induction of differentiation and apoptosis in neoplastic cells by our signal transduction inhibitors. Aristeromycin isolated as an Abl function inhibitor induced erythroid differentiation in human CML K562 cells. Aristeromycin may induce differentiation by inhibition of methylating reactions in the cell. We isolated dephostatin from Streptomyces as a tyrosine phosphatase inhibitor, and synthesized its stable analogue, 3,4-dephostatin. The stable analogue, 3,4-dephostatin, potentiated NGF-induced morphological differentiation in rat pheochromocytoma PC12h cells, possibly by inhibition of tyrosine dephosphorylation of MAPK. Erbstatin, a tyrosine kinase inhibitor, induced morphological apoptosis and internucleosomal DNA fragmentation in mouse leukemia L1210 and human SCLC cells. Erbstatin was shown to induce apoptosis by hydrogen peroxide formation. Thus, these signal transduction inhibitors appear to be useful tools for the mechanistic study of cellular differentiation and apoptosis.