New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death

Abstract

BackgroundAromatase, the cytochrome P-450 enzyme (CYP19) responsible for estrogen biosynthesis, is an important target for the treatment of estrogen-dependent breast cancer. In fact, the use of synthetic aromatase inhibitors (AI), which induce suppression of estrogen synthesis, has shown to be an effective alternative to the classical tamoxifen for the treatment of postmenopausal patients with ER-positive breast cancer. New AIs obtained, in our laboratory, by modification of the A and D-rings of the natural substrate of aromatase, compounds 3a and 4a, showed previously to efficiently suppress aromatase activity in placental microsomes. In the present study we have investigated the effects of these compounds on cell proliferation, cell cycle progression and induction of cell death using the estrogen-dependent human breast cancer cell line stably transfected with the aromatase gene, MCF-7 aro cells.ResultsThe new steroids inhibit hormone-dependent proliferation of MCF-7aro cells in a time and dose-dependent manner, causing cell cycle arrest in G0/G1 phase and inducing cell death with features of apoptosis and autophagic cell death.ConclusionOur in vitro studies showed that the two steroidal AIs, 3a and 4a, are potent inhibitors of breast cancer cell proliferation. Moreover, it was also shown that the antiproliferative effects of these two steroids on MCF-7aro cells are mediated by disrupting cell cycle progression, through cell cycle arrest in G0/G1 phase and induction of cell death, being the dominant mechanism autophagic cell death. Our results are important for the elucidation of the cellular effects of steroidal AIs on breast cancer.

Apoptosis and Autophagy in Breast Cancer Cells following Exemestane Treatment

“…It has also been reported that some AIs, like letrozole, anastrozole and formestane inhibit proliferation of breast cancer cells by inducing cell cycle arrest in G 0 /G 1 phase and cell death by apoptosis [13], [23]. Recently, we demonstrated that the steroidal AIs 5α-androst-3-en-17-one and 3α,4α-epoxy-5α-androstan-17-one, previously synthesized in our laboratory [24], inhibit cell proliferation in various tumour cell lines [25] and induce apoptosis and autophagy in MCF-7aro cell line [26]. Nevertheless, the effects of exemestane in breast cancer cells are not totally understood.…”

Colorectal Cancer-Specific Cytochrome P450 2W1: Intracellular Localization, Glycosylation, and Catalytic Activity

“…Protein glycosylation represents one of the most common but complex post-translational protein modifications (Walsh and Jefferis, 2006) and has hitherto only been described for CYP19A1 (Cepa et al, 2008) among the human P450 enzymes. Because microsomal forms of P450 are oriented toward the cytoplasm, it is evident that they cannot be exposed to the glycosylation machinery residing in the luminal compartment of the ER.…”

Inhibition of aromatase activity in MCF-7aro human breast cancer cells by the natural androgens testosterone and androstenedione

“…Thus, testosterone and its non-aromatizable metabolite 5a-dihydrotestosterone (DHT), the most potent natural ligand for the AR (K D 10 -11 mol/L compared with 10 -9 mol/L for testosterone and 2=10 -7 mol/L for androstenedione), inhibit MCF-7 growth and E 2 -mediated upregulation of PR protein expression, presumably via AR signaling (32)(33)(34). Because MCF-7aro breast cancer cell line expresses high aromatase activity, it was observed that testosterone (1 nmol/L) can also stimulate MCF-7aro cell growth and that anti-aromatases have the ability to inhibit this proliferative effect, which indicates that the aromatization of testosterone with production of E 2 was responsible for the androgen-mediated cell growth (35,36). Compared with testosterone, androstenedione only slightly stimulates MCF-7 cell growth.…”