Non-steroidal antiestrogens induce apoptosis in HL60 and MOLT3 leukemic cells; Involvement of reactive oxygen radicals and protein kinase C

The antitumoral activity of non-steroidal antiestrogens on promyelocytic le ukemia HL60 and T lymphoblastic MOLT3 cell lines was studied. Tamoxifen and its derivatives, clomiphene and nafoxidine, caused reduction of cell viabi lity in a dose-dependent manner. These drugs showed differences in their po tency following four days incubation, with nafoxidine being the most effici ent inhibitor and tamoxifen the least active. Apoptosis was induced as asse ssed by the DNA ladder pattern and formation of pre G(0)/G(1) population as detected by flow cytometry analysis of DNA. The effect of these drugs was abrogated by antioxidants: a-tocopherol was most effective in antagonizing the drugs' effect. N-acetyl L-cystein reversed mainly the decrease in cell viability caused by the drugs, but was less active on induction of apoptosi s. GF109203X, a protein kinase inhibitor, attenuated apoptosis induced by c lomiphene in MOLT3 cells. The results suggest that the antileukemic activit y of the antiestrogens is mediated by oxidative stress and protein kinase C (PKC) activation. Triphenylethylene antiestrogens and their derivatives ma y be used as antileukemic drugs which kill cells by apoptosis mediated by o xidative stress and activation of PKC.