2-Methoxyoestrogens are emerging as a new class of anti-neoplastic agents. 2-Methoxyoestradiol (2-MeOE2), an endogenous oestrogen metabolite, has shown anti-proliferative effects in ER+ve and ER-ve breast cancer cell lines. In this study we have investigated the effects of sulphamoylated derivatives of 2-MeOE2, 2-methoxyoestradiol-3-O-monosulphamate (2-MeOE2MATE) and 2-methoxyoestradiol 3,17 bis sulphamate (2-MeOE2bisMATE) in ER-ve MDA-MB-231 cells. Both 2-MeOE2MATE and 2-MeOE2bisMATE were potent, irreversible growth inhibitors, with IC50 values of 0.8μM and 0.3μM respectively compared with 4.5μM for 2-MeOE2. These compounds also suppressed the long-term clonogenic potential of MDA-MB-231 cells at 1μM. Flow cytometric analysis revealed that the cells were arrested in the G2-M phase of the cell cycle with an increase in the sub-G1 (apoptotic) fraction. Induction of apoptosis was confirmed by the characteristic DNA laddering, a marker of apoptosis. In all the assays, sulphamoylated derivatives were significantly more potent than the parent compound 2-MeOE2. In addition, they also induced BCL-2 and BCL-XL phosphorylation. Preliminary experiments have shown that the sulphamoylated derivatives bind to the colchicine binding site of tubulin. These results suggest that 2-MeOE2MATE and 2-MeOE2bisMATE may be acting via microtubule disruption, which in turn activates kinases leading to the phosphorylation of BCL-2, finally resulting in the induction of apoptosis. Further studies are in progress to understand the mechanism of action of these compounds. However, the results clearly show that the sulphamoylation of 2-MeOE2 greatly enhances its anti-neoplastic effects and also that their function is independent of ER status.
08 - 11 Apr 2002
British Endocrine Societies