Apoptosis and Autophagy in Breast Cancer Cells following Exemestane Treatment

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.

Autophagy Inhibition Augments the Anticancer Effects of Epirubicin Treatment in Anthracycline-Sensitive and -Resistant Triple-Negative Breast Cancer

“…Autophagy inhibition in combination with pharmacologic aggravators of endoplasmic reticulum stress in TNBC (19,38) and in combination with various drugs in other types of breast cancer cells (12,17,30,39) is known to enhance cell death. These findings are consistent with our results where caspase activation and increased PARP cleavage were clearly observed in epirubicin-resistant R8 and R75 cells following knockdown of autophagy with ATGsiRNAs (see Fig.…”

Anthricin Isolated fromAnthriscus sylvestris(L.) Hoffm. Inhibits the Growth of Breast Cancer Cells by Inhibiting Akt/mTOR Signaling, and Its Apoptotic Effects Are Enhanced by Autophagy Inhibition

“…mTOR represses the ULK1/2 complex, which recruits other autophagy-related proteins (Atg) for the formation of the autophagosome [16]. A recent report has suggested that autophagy acts as a prosurvival process that regulates apoptosis in breast cancer cells [17]. Therefore, we hypothesized that anthricin regulates Akt/mTOR signaling and autophagy to modulate cell death or cell survival.…”

Synthesis and characterisation of morin reduced gold nanoparticles and its cytotoxicity in MCF-7 cells

“…56 A possible application of these AuNPs is in the treatment of 57 breast cancer. The incidence of breast cancer has increased in Asian 58 countries in the past few decades with over 90,000 cases diagnosed 59 annually in India [11,12], a large portion of which being hormone 60 dependent [13]. Hormonal or chemotherapy involves the 61 administration of both steroidal and non-steroidal drugs which 62 act as anti-estrogens suppressing proliferation [14][15][16].…”