2-methoxyestradiol-3-17-o-o-bis(sulfamate) and Ovarian-Neoplasms

The anti-proliferative and anti-angiogenic properties of the endogenous oestrogen metabolite, 2-methoxyoestradiol (2-MeOE2), are enhanced in a series of sulphamoylated derivatives of 2-MeOE2. To investigate possible mechanisms of resistance to these compounds, a cell line, A2780.140, eightfold less sensitive to the 3,17-O,O-bis-sulphamoylated derivative, STX140, was derived from the A2780 ovarian cancer cell line by dose escalation. Other cell lines tested did not develop STX140 resistance. RT-PCR and immunoblot analysis demonstrated that breast cancer resistance protein (BCRP) expression is dramatically increased in A2780.140 cells. The cells are cross-resistant to the most structurally similar bis-sulphamates, and to BCRP substrates, mitoxantrone and doxorubicin; but they remain sensitive to taxol, an MDR1 substrate, and to all other sulphamates tested. Sensitivity can be restored using a BCRP inhibitor, and this pattern of resistance is also seen in a BCRP-expressing MCF-7-derived cell line, MCF-7.MR. In mice bearing wild-type (wt) and BCRP-expressing tumours on either flank, both STX140 and mitoxantrone inhibited the growth of the MCF-7wt xenografts, but only STX140 inhibited growth of the MCF-7.MR tumours. In conclusion, STX140, a promising orally bioavailable anti-cancer agent in pre-clinical development, is highly efficacious in BCRP-expressing xenografts. This is despite an increase in BCRP expression in A2780 cells in vitro after chronic dosing with STX140.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Base Sequence; Blotting, Western; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; DNA Primers; Drug Resistance, Neoplasm; Estrenes; Female; Flow Cytometry; Humans; Mice; Neoplasm Proteins; Ovarian Neoplasms; Reverse Transcriptase Polymerase Chain Reaction

Many anticancer drugs target microtubules and induce apoptosis. However, improved microtubule-targeting drugs, such as STX140 and STX641, are being developed. These compounds induce cell cycle arrest and apoptosis in a variety of tumour cells. The mechanisms that induce apoptosis and the key mediators involved are elucidated in this study. Results demonstrate that STX140 and STX641 depolarise mitochondrial bioenergetics and activate caspase 3/7 in A2780, LNCaP and MCF-7 cancer cells. Furthermore, both compounds cause a significant reduction in the expression of survivin and XIAP. This work details the temporal organisation of apoptosis induced by two microtubule disruptors and highlights the role that the down-regulation of survivin and XIAP may play in this process.

Topics: Adenosine Triphosphate; Apoptosis; Caspase 3; Caspase 7; Cell Cycle Proteins; Cell Growth Processes; Cell Line, Tumor; Down-Regulation; Enzyme Activation; Estrenes; Female; Humans; Inhibitor of Apoptosis Proteins; Male; Membrane Potential, Mitochondrial; Microtubule-Associated Proteins; Mitochondria; Ovarian Neoplasms; Prostatic Neoplasms; Survivin; Tubulin Modulators