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

Abstract

Previously, the authors observed that paclitaxel treatment of hepatoma cells resulted in differential cytotoxicity. Whether other antimicrotubule agents (docetaxel and 2-methoxyestradiol) are more effective than paclitaxel is not clear. Moreover, whether the modulation of reactive oxygen species (ROS) is involved in the drug-induced growth inhibition of hepatoma cells is not known. 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 permeability, cell cycle distribution, DNA fragmentation, and ROS generation. Docetaxel and paclitaxel inhibited the growth of hepatoma cells at submicromolar concentrations, whereas that of 2-methoxyestradiol was within a micromolar range. This drug-induced growth inhibition was cell cycle dependent. 2-Methoxyestradiol-treated (10-50 microM) cells resulted in G2/M block prior to apoptosis. High dose (0.1 microM) docetaxel- and paclitaxel-treated cells resulted in a G2/M arrest followed by generation of polyploidy or apoptosis; however, low dose (0.01 microM) treatment induced apoptosis without G2/M arrest. The low dose effect was more significant in docetaxel-treated cells than in paclitaxel-treated cells. Although these antimicrotubule agents increased the formation of ROS, antioxidant treatment did not block drug-induced cell cycle and growth inhibition effects. The current results suggest that the growth inhibition of hepatoma cells induced by 2-methoxyestradiol, paclitaxel, and docetaxel was mediated 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.