2-Methoxyoestradiol (2-MeOE2) is an endogenous oestrogen metabolite which inhibits
tubulin polymerisation and has anti-tumour and anti-angiogenic activity. 2-MeOE2 induces apoptosis in a wide range of
cancer cell types and has recently been demonstrated to cooperate with TRAIL to induce apoptosis in
breast cancer cells.
2-Methoxyoestradiol-3,17-bis-O,O-sulphamate (2-MeOE2bisMATE) is a sulfamoylated derivative of 2-MeOE2 with enhanced activity and improved pharmacokinetic properties, and
2-MeOE2bisMATE is a promising candidate for early clinical trials. It is important, therefore, to understand the mechanisms by which
2-MeOE2bisMATE acts, and whether it retains the ability to cooperate with TRAIL. We demonstrate that 2-MeOE2bisMATE-induced apoptosis of CAL51
breast cancer cells was associated with rapid activation of
caspase 3 and 9, but not
caspase 8 (as measured by BID cleavage) and was completely prevented by the
caspase inhibitor zVADfmk. Interfering with Fas- or TRAIL-receptor function did not prevent 2-MeOE2bisMATE-induced apoptosis. Whereas CAL51 cells were resistant to TRAIL-induced apoptosis,
2-MeOE2bisMATE and TRAIL cooperated to induce cell death. This apoptosis was associated with enhanced activation of
caspases, but not increased expression of the DR5 TRAIL receptor, previously demonstrated to be induced by 2-MeOE2. Therefore, 2-MeOE2bisMATE-induced apoptosis is dependent on
caspases and like 2-MeOE2,
2-MeOE2bisMATE can overcome resistance to TRAIL by stimulating activation of downstream
caspases. Our results suggest that
2-MeOE2bisMATE and TRAIL might be a particularly effective combination of anti-
cancer agents.