title: BCRP expression does not result in resistance to STX140 in vivo, despite the increased expression of BCRP in A2780 cells in vitro after long-term STX140 exposure.
abstract: 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.
authors.affiliation: Department of Endocrinology and Metabolic Medicine and Sterix Ltd., Imperial College London, St Mary's Hospital, London W2 1NY, UK. joanna.day@imperial.ac.uk
authors.forename: J M
authors.initials: JM
authors.lastname: Day
authors.forename: P A
authors.initials: PA
authors.lastname: Foster
authors.forename: H J
authors.initials: HJ
authors.lastname: Tutill
authors.forename: S P
authors.initials: SP
authors.lastname: Newman
authors.forename: Y T
authors.initials: YT
authors.lastname: Ho
authors.forename: M P
authors.initials: MP
authors.lastname: Leese
authors.forename: B V L
authors.initials: BV
authors.lastname: Potter
authors.forename: M J
authors.initials: MJ
authors.lastname: Reed
authors.forename: A
authors.initials: A
authors.lastname: Purohit
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D017931:DNA Primers; D019008:Drug Resistance, Neoplasm; D004963:Estrenes / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C526438:2-methoxyestradiol-3,17-O,O-bis(sulfamate); C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers; D004963:Estrenes; D009363:Neoplasm Proteins