Associação Portuguesa de Investigação em Cancro
Anti-tumor efficacy of new aromatase inhibitors in hormone-sensitive and resistant breast cancer cells
Anti-tumor efficacy of new aromatase inhibitors in hormone-sensitive and resistant breast cancer cells
Breast cancer is the most common cause of cancer death in women, being 70%-80% of the tumors estrogen-receptor positive. One of the main therapeutic approaches applied is the use of aromatase inhibitors (AIs), since they decrease the synthesis of estrogens, which are necessary for the growth of this type of tumors. Although, despite its therapeutic success, the AIs used in the clinic induce some adverse effects, namely the occurrence of endocrine resistance. In the last years, the authors have been focusing on the design/synthesis and anti-tumor activity of new steroidal molecules, as potential AIs. This recently published work allowed the discovery of novel AIs with high anti-tumor efficacy, since they inhibit the growth of sensitive and resistant breast cancer cells. Furthermore, this study contributes to the identification of the key chemical modifications in steroidal scaffold that improve the anti-aromatase and anti-tumor efficacy, which highlights essential information for the rational design/synthesis of more effective AIs to be applied in clinic.
Authors and Affiliations:
Cristina Amarala, Carla L. Varelab,c, João Maurícioa,d, Ana Filipa Sobrala,e, Saul C. Costab, Fernanda M.F. Roleirab,c, Elisiário J. Tavares-da-Silvab,c, Georgina Correia-da-Silvaa, Natércia Teixeiraa
a UCIBIO-REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal;
b Pharmaceutical Chemistry Group, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
c CIEPQPF Centre for Chemical Processes Engineering and Forest Products, University of Coimbra, 3030-790 Coimbra, Portugal
d Institute of Biomedical Sciences Abel Salazar, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal e Faculty of Science and Technology, University of Coimbra, 3001-401 Coimbra, Portugal
Abstract:
The majority of breast cancer cases are estrogen receptor positive (ER+). Although, third-generation aromatase inhibitors (AIs) are used as first-line treatment in post-menopausal women, they cause endocrine resistance and bone loss, which limits their success. Therefore, there is a demand to discover new potent molecules, with less toxicity that can circumvent these drawbacks. Our group has previously demonstrated that new 7α-substituted steroidal molecules, 7α-(2ξ,3ξ-epoxypropyl)androsta-1,4-diene-3,17-dione (3), 7α-allylandrost-4-ene-3,17-dione (6), 7α-allylandrost-4-en-17-one (9), 7α-allyl-3-oxoandrosta-1,4-dien-17β-ol (10) and 7α-allylandrosta-1,4-diene-3,17-dione (12) are potent AIs in placental microsomes. In this work, it was investigated their anti-aromatase activity and in vitro effects in sensitive and resistant breast cancer cells. All the steroids efficiently inhibit aromatase in breast cancer cells, allowing to establish new structure-activity relationships for this class of compounds. Moreover, the new AIs can inhibit breast cancer cell growth, by causing cell cycle arrest and apoptosis. The effects of AIs 3 and 12 on sensitive cells were dependent on aromatase inhibition and androgen receptor (AR), while for AI 9 and AI 10 were AR- and ER-dependent, respectively. In addition, it was shown that all the AIs can sensitize resistant cancer cells being their behavior similar to the sensitive cells. In summary, this study contributes to the understanding of the structural modifications in steroidal scaffold that are translated into better aromatase inhibition and anti-tumor properties, providing important information for the rational design/synthesis of more effective AIs. In addition, allowed the discovery of new potent 7α-substituted androstane molecules to inhibit tumor growth and prevent endocrine resistance.
Journal: Journal of Steroid Biochemistry and Molecular Biology; in press (Available online 7 April 2017)
Link: http://www.sciencedirect.com/science/article/pii/S0960076017301012
