Depletion of estrogen receptor in human breast tumor cells by a novel substituted indole that does not bind to the hormone binding domain

Bitonti, Alan J.; Dumont, Jennifer; Salituro, Francesco G.; McDonald, Ian A.; Jarvi, Esa T.; Frey, Lisa M.; Wright, Paul S.; Baumann, Russell J.

doi:10.1016/0960-0760(96)00006-4

Cited by 3 publications

(2 citation statements)

References 24 publications

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“…Allosteric modulation of ER function has previously been postulated to explain other receptor inhibitor interactions. [35][36][37] Not only does trilostane act noncompetitively, overall affinity of oestradiol binding is in fact significantly increased by trilostane in cytosol preparations of rat uteri (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

Non‐competitive steroid inhibition of oestrogen receptor functions

Puddefoot

Barker

Glover

et al. 2002

Intl Journal of Cancer

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Section: Discussionmentioning

confidence: 99%

Non‐competitive steroid inhibition of oestrogen receptor functions

Puddefoot

Barker

Glover

et al. 2002

Intl Journal of Cancer

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“…Moreover, some compounds which exhibit growth-inhibitory activity against MCF-7 cells without ER binding were reported. , One possible mechanism of their growth-inhibitory activity was thought to be the depletion of the ER or the ER−ERE complex, which probably resulted in the inhibition of the ER responsive gene expression. In preliminary results, compound 14d slightly suppressed the estradiol-stimulated ER transactivation in the (ERE) 2 −luciferase reporter gene assay (data not shown).…”

Section: Biological Activity and Discussionmentioning

confidence: 99%

Design and Synthesis of Potent Antitumor 5,4‘-Diaminoflavone Derivatives Based on Metabolic Considerations

et al. 1997

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Recently, we reported that 5,4'-diaminoflavone (1) exhibits potent and specific growth-inhibitory activity against the estrogen receptor (ER)-positive human breast cancer cell line MCF-7. However, when compound 1 was incubated with S-9 mix, its metabolites were observed. Moreover, addition of S-9 mix to the medium caused the drastic decrease in activity of compound 1. Since the 6-, 8-, and 3'-positions were considered to be metabolized oxidatively in vivo from MO calculations, a series of 5,4'-diaminoflavone derivatives substituted at such putative metabolic positions with various functional groups were synthesized aiming at the metabolically stable derivatives. Among them, 5,4'-diamino-6,8,3'-trifluoroflavone (14d) exhibited strong growth-inhibitory activity against MCF-7 cells even in the presence of S-9 mix. Moreover, orally administered compound 14d completely suppressed the growth of MCF-7 inoculated into nude mice, and the effect was more potent than that of compound 1. In addition to ER-positive breast cancer cells, compound 14d exhibited growth-inhibitory activity against a panel of human cancer cell lines including a part of ER-negative breast, endometrial, ovarian, and liver cancers. From these results, fluorine introduction to the putative metabolic positions of compound 1 was elucidated to be effective in the enhancement of the in vivo antitumor activity, probably due to the block of the metabolic deactivation.

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