Exemestane's 17-hydroxylated metabolite exerts biological effects as an androgen

Abstract

Aromatase inhibitors (AI) are being evaluated as longterm adjuvant therapies and chemopreventives in breast cancer. However, there are concerns about bone mineral density loss in an estrogen-free environment. Unlike nonsteroidal AIs, the steroidal AI exemestane may exert beneficial effects on bone through its primary metabolite 17-hydroexemestane. We investigated 17-hydroexemestane and observed it bound estrogen receptor A (ERA) very weakly and androgen receptor (AR) strongly. Next, we evaluated 17-hydroexemestane in MCF-7 and T47D breast cancer cells and attributed dependency of its effects on ER or AR using the antiestrogen fulvestrant or the antiandrogen bicalutamide. 17-Hydroexemestane induced proliferation, stimulated cell cycle progression and regulated transcription at high sub-micromolar and micromolar concentrations through ER in both cell lines, but through AR at low nanomolar concentrations selectively in T47D cells. Responses of each cell type to high and low concentrations of the nonaromatizable synthetic androgen R1881 paralleled those of 17-hydroexemestane. 17-Hydroexemestane downregulated ERA protein levels at high concentrations in a cell type -specific manner similarly as 17B-estradiol, and increased AR protein accumulation at low concentrations in both cell types similarly as R1881. Computer docking indicated that the 17B-OH group of 17-hydroexemestane relative to the 17-keto group of exemestane contributed significantly more intermolecular interaction energy toward binding AR than ERA. Molecular modeling also indicated that 17-hydroexemestane interacted with ERA and AR through selective recognition motifs employed by 17B-estradiol and R1881, respectively. We conclude that 17-hydroexemestane exerts biological effects as an androgen. These results may have important implications for long-term maintenance of patients with AIs.

An “Omics” Approach to Determine the Mechanisms of Acquired Aromatase Inhibitor Resistance

“…Characterization of these resistant lines showed that LTEDaro, TþLET R, and TþANA R cells contained a constitutively active ER that did not require estrogen for activation (Masri et al, 2008). Although EXE has previously been shown to act as an androgen (Ariazi et al, 2007), studies from our laboratory demonstrate the estrogenlike activity of EXE. Based on genome-wide microarray analysis, a high correlation was seen between EXE-Only (EXE O, hormone-free) and T-treated AI-resistant lines.…”

Impact of nonsynonymous single nucleotide polymorphisms on in-vitro metabolism of exemestane by hepatic cytosolic reductases

“…The limited literature available describes 17β-dihydroexemestane (17β-DHE) as a prominent phase I EXE metabolite possessing both anti-aromatase and androgen agonistic activities in vitro [22, 26–30]. One study concluded that 17β-DHE concentrations were approximately 35–40% those of the parent drug in the plasma of healthy individuals taking EXE while another smaller study found that the amount of 17β-DHE relative to EXE in human plasma varied five-fold in a pool of only three participants [27, 31].…”

Histologic and Cytologic Detection of Endocrine and Reproductive Tract Effects of Exemestane in Female Rats Treated for up to Twenty-eight Days

“…However, in the course of this study, we recognized several factors complicating the interpretation of our results. First, as noted earlier, exemestane and its principal metabolite have weak androgenic activity (Zaccheo et al 1991;Ariazi et al 2007). Furthermore, inhibition of aromatase has been shown to increase circulating levels of endogenous testosterone (Baravalle et al 2006).…”