Evidence for involvement of tyrosine phosphorylation in taxol-induced apoptosis in a human ovarian tumor cell line.

Taxol is an antineoplastic agent with significant activity against ovarian as well as breast cancer. To investigate mechanisms by which taxol exerts its cytotoxic action, taxol-induced apoptosis, characterized by morphologic changes and internucleosomal DNA fragmentation, was examined in a human ovarian tumor cell line. Time-dependent morphologic changes, characteristic of apoptosis, were observed over the same time as the appearance of internucleosomal DNA fragmentation. The specific protein tyrosine kinase inhibitors genistein and herbimycin A, and the ATP depletion agent sodium azide, interfered with taxol-induced DNA fragmentation and clonal cell death. Based on a quantitative reverse transcription-polymerase chain reaction technique, bcl-2 alpha oncogene expression was decreased in conjunction with taxol-induced DNA fragmentation, and this decrease could be blocked by genistein. These results strongly implicate protein tyrosine phosphorylation as an event that mediates apoptosis and, thus, the antitumor activity of taxol in ovarian cancer.