Effects of steroidal aromatase inhibitors on sensitive and resistant breast cancer cells: Aromatase inhibition and autophagy

• Type: Article in International Scientific Journal
• Date: 2013

Authors

Cristina Amaral (Author) Other; Carla Varela (Author) Other; Margarida Azevedo (Author) Other; Elisiario Tavares da Silva (Author) Other; Fernanda M F Roleira (Author) Other; Shiuan Chen (Author) Other; Georgina Correia da Silva (Author) FFUP; Natercia Teixeira (Author) FFUP

Journal

Title: Journal of Steroid Biochemistry and Molecular Biology

Vol. 135

Pages: 51-59

ISSN: 0960-0760

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 29 Citations

Scopus - 27 Citations

Pubmed / Medline

Scientific classification

FOS: Medical and Health sciences > Clinical medicine

Other information

Authenticus ID: P-005-1F1

DOI: 10.1016/j.jsbmb.2012.12.017

Abstract (EN): Several therapeutic approaches are used in estrogen receptor positive (ER) breast cancers, being one of them the use of aromatase inhibitors (AIs). Although AIs demonstrate higher efficacy than tamoxifen, they can also exhibit de novo or acquired resistance after prolonged treatment. Recently, we have described the synthesis and biochemical evaluation of four steroidal AIs, 3 beta-hydroxyandrost-4-en-17-one (1), androst-4-en-17-one (12), 4 alpha,5 alpha-epoxyandrostan-17-one (13a) and 5 alpha-androst-2-en-17-one (16), obtained from modifications in the A-ring of the aromatase substrate, androstenedione. In this study, it was investigated the biological effects of these AIs in different breast cancer cell lines, an ER+ aromatase-overexpressing human breast cancer cell line (MCF-7aro cells), an estrogen-receptor negative (ER-) human breast cancer cell line (SK-BR-3 cells), and a late stage of acquired resistance cell line (LTEDaro cells). The effects of an autophagic inhibitor (3-methyladenine) plus Als 1, 12, 13a or exemestane in LTEDaro cells were also studied to understand the involvement of autophagy in Al acquired resistance. Our results showed that these steroids inhibit aromatase of MCF-7aro cells and decrease cell viability in a dose- and time-dependent manner. The new AI 1 is the most potent inhibitor, although the AI 12 demonstrates to be the most effective in decreasing cell viability. Besides, and in advantage over exemestane, Ala 12 and 13a also reduced LTEDaro cells viability. The use of the autophagic inhibitor allowed AIs to diminish viability of LTEDaro cells, presenting a similar behavior to the sensitive cells. Thus, inhibition of autophagy may sensitize hormone-resistant cancer cells to anti-estrogen therapies.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 9