PROTEIN-TYROSINE-PHOSPHATASE ACTIVITIES ARE INVOLVED IN APOPTOTIC CANCER CELL-DEATH INDUCED BY GL331, A NEW HOMOLOG OF ETOPOSIDE

GL331 is a semisynthetic topoisomerase II inhibitor derived from a pla nt toxin podophyllotoxin. In 72-h exposure assays, LD(50) values of GL 331 range from 0.5 to 2 mu M, which are three- to ten-fold lower than those of its homologous compound etoposide (VP-16), depending on diffe rent cancer cell lines including nasopharyngeal, hepatocellular, gastr ic, cervical and colon cancer types. Apoptotic DNA ladders could be de tected when cancer cells were treated with GL331 for 24 h even if the Bcl-2 and Bar protein levels were not altered during the period. Besid es acting as topoisomerase II inhibitors, both GL331 and VP-16 decreas e the cellular protein tyrosine kinase (PTK) activities in cancer cell s. The activities of protein tyrosine phosphatase (PTP) are significan tly increased after GL331 treatment but are not affected by VP-16. GL3 31-induced internucleosomal cleavage can be efficiently prevented by t wo inhibitors of PTP, sodium orthovanadate and zinc chloride, but not by okadaic acid, which inhibits serine/threonine phosphatase activity. These results indicate that GL331 may induce apoptotic cell death, an d that activation of protein tyrosine phosphatases may be involved in this process.