Synthetic 19-nortestosterone derivatives as estrogen receptor alpha subtype-selective ligands induce similar receptor conformational changes and steroid receptor coactivator recruitment than natural estrogens

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase

“…It is not known whether this is due to weak activity intrinsic to the androgens or to their conversion to metabolites with estrogenic activity in T47Dco cells. Both synthetic 19-norandrogen derivatives [19,20] and non-phenolic metabolites formed in human breast cancer cells from androgenic substrates [21] have been shown to exhibit estrogenic activity. These compounds have reduced and hydroxylated A-rings; for example, T is metabolized to 5α-androstane-3α, 17β-diol and its 3β-enantiomer in MCF-7 cells [21].…”

“…Thus, in this study we examined the possible conversion of selected androgens to aromatic A-ring derivatives with estrogenic activity using recombinant human aromatase, a preparation devoid of other contaminating enzymatic activities such as would be found in intact cells or isolated microsomes. Another potential route for obtaining compounds with estrogenic activity from androgens or 19-norsteroids is through formation of non-phenolic androgen metabolites by 5α-reduction followed by hydroxylation of the A-ring [19][20][21].DMA and 11β-MNT are not likely to be converted to estrogens by this route either as they are not substrates for 5α-reductase [22]. The most decisive method to determine the metabolism of DMA and 11β-MNT in vivo would be to isolate and characterize all possible metabolites.…”

Ligand-induced large-scale chromatin dynamics as a biosensor for the detection of estrogen receptor subtype selective ligands

“…We have previously reported that 19-nortestosterone A-ring reduced derivatives stimulated ERα-but not ERβ-driven reporter activity, including recruitment of coactivators (Larrea et al, 2001;Garcia-Becerra et al, 2006). We hypothesized that this receptor-specific transcription response would correlate with differential chromatin modification at the PRL-array, i.e., treatment of GFP-ERβ-expressing cells with synthetic ligands would not result in decondensed arrays.…”

“…Regarding this, we have systematically characterized the estrogenic activity of a number of synthetic 19-nortestosterone derivatives that function as agonists with high potency and efficacy preferentially for ERα (Chavez et al, 1985;Larrea et al, 1987Larrea et al, , 2001Lemus et al, 1992Lemus et al, , 2000Garcia-Becerra et al, 2002. Among these compounds, the A-ring 3β,5α-reduced derivatives of norethisterone (NET), levonorgestrel (LNG) and gestodene (GSD) behave as complete ERα agonists but are inactive on ERβ in terms of receptor binding, recruitment of coactivators and transcriptional activation (Larrea et al, 2001;Garcia-Becerra et al, 2006). Although, the precise molecular basis for their ERα selectivity remains unclear, these compounds may be of interest in identifying or developing new ligands for ER subtypes.…”

Mechanism of Action of the Anti-cancer Agent, Triptolide

“…However, a combination of TRAIL and triptolide results in cell death of TRAIL-resistant pancreatic cancer, at low concentrations of both TRAIL and triptolide. Cell death is mediated via apoptosis, as evidenced by an increase in caspase activation (Garcia-Becerra et al 2006). In another study, Yang et al have shown that triptolide can be combined with hydrocamptothecin, a topoisomerase inhibitor derived from Camptotheca accuminata to inhibit proliferation and induce cell death in Panc-1 pancreatic cancer cells (Yang et al 2011).…”