Effects of steroidal aromatase inhibitors on sensitive and resistant breast cancer cells

One of the therapeutic approaches for the treatment of hormone-dependent breast cancer is the inhibition of the enzyme aromatase, by the use of aromatase inhibitors (AIs). However, besides the success of the third-generation AIs, they induce some adverse effects, like the rapid increase of bone loss and the occurrence of endocrine resistance.

In this work, our group has determined key chemical features in newly synthesized steroidal compounds that improve aromatase inhibition in order to achieve potent and specific AIs that also induce cell death of breast cancer cells and sensitize AIs-resistant cancer cells. In addition, autophagy inhibition, by targeting PI3K pathway, reverted the acquired resistance to some of the new AIs and exemestane, the third-generation steroidal AI used in clinic. Thus, combining AIs and autophagic inhibitors that target PI3K pathway may be a potential therapeutic strategy in breast cancer treatment. We believe that this study contributes to the development of new more potent steroidal AIs and may help to understand some of the mechanisms involved in AI-acquired resistance.

Authors and Affiliations:

Cristina Amaral^1,2, Carla Varela³, Margarida Azevedo¹, Elisiário Tavares da Silva³, Fernanda Roleira³, Shiuan Chen⁴, Georgina Correia-da-Silva^1,2, Natércia Teixeira^1,2

¹ Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal;

² Institute for Molecular and Cell Biology (IBMC), University of Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal;

³ CEF, Center for Pharmaceutical Studies, Pharmaceutical Chemistry Group, Faculty of Pharmacy, University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal;

⁴ Department of Cancer Biology, Beckman Research Institute of the City of Hope, Institute of the City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA.

Abstract: 

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, 3β-hydroxyandrost-4-en-17-one (1), androst-4-en-17-one (12), 4α,5α-epoxyandrostan-17-one (13a) and 5α-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 AIs 1, 12, 13a or exemestane in LTEDaro cells were also studied to understand the involvement of autophagy in AI 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, AIs 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.

Journal:

Journal of Steroid Biochemistry and Molecular Biology, 2013; 135: 51–59.

Link:

http://www.sciencedirect.com/science/article/pii/S0960076013000034