Comparison of 2-methoxyestradiol-induced, docetaxel-induced, and paclitaxel-induced apoptosis in hepatoma cells and its correlation with reactive oxygen species

BACKGROUND. Previously the authors observed that paclitaxel treatment of he patoma cells resulted in differential cytotoxicity. 'Whether other antimicr otubule agents (docetaxel and 2-methoxyestradiol) are more effective than p aclitaxel is not clear. Moreover, whether the modulation of reactive oxygen species (ROS) is involved in the drug-induced growth inhibition of hepatom a cells is not known. METHODS, The authors examined the effects of 2-methoxyestradiol, paclitaxel , and docetaxel on HepG2, Hep3B, HA22T/VGH, and Hepa1-6 hepatoma cell lines . The parameters examined included cell viability, cell membrane permeabili ty, cell cycle distribution, DNA fragmentation, and ROS generation. RESULTS. Docetaxel and paclitaxel inhibited the growth of hepatoma cells at submicromolar concentrations, whereas that of 2-methoxyestradiol was withi n a micromolar range. This drug-induced growth inhibition was cell cycle de pendent. 2-Methoxyestradiol-treated (10-50 mu M) cells resulted in G2/M blo ck prior to apoptosis. High dose (0.1 mu M) docetaxel- and paclitaxel-treat ed cells resulted in a G2/M arrest followed by generation of polyploidy or apoptosis; however, low dose (0.01 mu M) treatment induced apoptosis withou t G2/M arrest. The low dose effect was more significant in docetaxel-treate d cells than in paclitaxel-treated cells. Although these antimicrotubule ag ents increased the formation of ROS, antioxidant treatment did not block dr ug-induced cell cycle and growth inhibition effects. CONCLUSIONS. The current results suggest that the growth inhibition of hepa toma cells induced by 2-methoxyestradiol, paclitaxel, and docetaxel was med iated through G2/M-phase arrest, caspase activation, and DNA fragmentation. The drug-induced apoptosis was independent of ROS formation. Docetaxel was more effective than paclitaxel in killing hepatoma cells. The potential of using 2-methoxyestradiol and docetaxel for the treatment of patients with hepatoma is worthy of further study. (C) 2000 American Cancer Society.