Differential effects of estrone and estrone-3-O-sulfamate derivatives on mitotic arrest, apoptosis, and microtubule assembly in human breast cancer cells

There is considerable interest in the potential use of estrogen derivatives for the treatment and prevention of breast cancer. We demonstrated previou sly that the sulfamoylated estrone derivative 2-methoxyestrone-3-O-sulfamat e (2-MeOEMATE) induced G(2)-M cell cycle arrest and modest levels of apopto sis in breast cancer cells in vitro, whereas the parent estrone derivative, 2-methoxyestrone, did not. 2-MeOEMATE also induced breast tumor regression in vivo in intact rats. To further explore the significance of sulfamoylat ion on the anticancer activity of estrone derivatives and to elucidate thei r mechanism of action, we synthesized two additional agents, 2-ethylestrone and 2-ethylestrone-3-O-sulfamate (2-EtEMATE), 2-MeOEMATE and 2-EtEMATE inh ibited the growth of a panel of estrogen receptor-negative and -positive br east cancer cell lines in vitro, induced mitotic arrest and apoptosis, and suppressed the long-term clonogenic potential of MCF7 and CAL51 breast canc er cells, In each assay, the sulfamoylated estrone derivatives were >10-fol d more potent than their parent compounds. The sulfamoylated estrone deriva tives were also significantly more potent inhibitors of cell growth than th e previously studied endogenous estradiol metabolite 2-methoxyestradiol, 2- MeOEMATE and 2-EtEMATE functioned as antimicrotubule agents and inhibited t he ability of paclitaxel to promote tubulin assembly in vitro. Like other a ntimicrotubule agents, the sulfamoylated estrone derivatives induced BCL-2 and BCL-X-L phosphorylation and increased p53 expression. 2-MeOEMATE and 2- EtEMATE are novel antimicrotubule agents that have potent anticancer activi ty in breast cancer cells in vitro and may be beneficial as anticancer agen ts in vivo.