Abstract
Aromatase inhibitors (AIs), which block the conversion of androgens to estrogens, are used for hormone-dependent breast cancer treatment. Exemestane, a steroidal that belongs to the third-generation of AIs, is a mechanism-based inhibitor that binds covalently and irreversibly, inactivating and destabilizing aromatase. Since the biological effects of exemestane in breast cancer cells are not totally understood, its effects on cell viability, cell proliferation and mechanisms of cell death were studied in an ER-positive aromatase-overexpressing breast cancer cell line (MCF-7aro). The effects of 3-methyladenine (3-MA), an inhibitor of autophagy and of ZVAD-FMK, an apoptotic inhibitor, in exemestane treated cells were also investigated. Our results indicate that exemestane induces a strong inhibition in MCF-7aro cell proliferation in a dose- and time-dependent manner, promoting a significant cell cycle arrest in G0/G1 or in G2/M phases after 3 and 6 days of treatment, respectively. This was accompanied by a decrease in cell viability due to activation of cell death by apoptosis, via mitochondrial pathway and the occurrence of autophagy. Inhibition of autophagy by the autophagic inhibitor, 3-MA, resulted in a reduction of cell viability and activation of caspases. All together the results obtained suggest that exemestane induced mitochondrial-mediated apoptosis and autophagy, which act as a pro-survival process regulating breast cancer cell apoptosis.
Highlights
Breast cancer is the most common cause of cancer death in women worldwide
Morphological studies To investigate the morphological alterations induced by exemestane, MCF-7aro cells, were cultured with or without exemestane during 3, 6 (Fig. 1) and 9 days and examined by phase contrast microscopy, Giemsa and Hoechst staining
This study explored the in vitro effects of exemestane on MCF7aro cell proliferation, cell cycle progression and induction of cell death
Summary
Breast cancer is the most common cause of cancer death in women worldwide. 60% of premenopausal and 70–80% of post-menopausal women have hormone-dependent (estrogen receptor positive [ER+]) tumors [1,2]. As estrogens play a crucial role in stimulating ER+ tumor growth, the suppression of their effects is considered an important therapeutic target for breast cancer treatment. Two main approaches have been successfully applied. One targets the ER directly through the use of selective estrogen receptor modulators (SERM), such as tamoxifen, or of selective estrogen receptor down-regulators (SERD), like fulvestrant. The other is achieved by the use of aromatase inhibitors (AIs) that inhibit aromatase, the enzyme responsible by the last step of estrogen synthesis, blocking the conversion of androgens to estrogens [1,3]
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