Eficácia anti-tumoral de novos inibidores da aromatase em células de cancro da mama sensíveis e resistentes

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Eficácia anti-tumoral de novos inibidores da aromatase em células de cancro da mama sensíveis e resistentes

Quarta, 28.06.2017

O cancro de mama é a causa mais comum de morte por cancro em mulheres, sendo 70%-80% dos tumores recetor de estrogénio positivo. Uma das principais estratégias terapêuticas utilizadas é o uso de inibidores da aromatase (AIs), uma vez que diminuem a síntese de estrogénios necessários ao crescimento destes tumores. No entanto, apesar do seu sucesso terapêutico, os AIs utilizados na clínica induzem alguns efeitos adversos, nomeadamente o desenvolvimento de resistência endócrina. Nestes últimos anos, os autores têm-se dedicado ao design/síntese e estudo da atividadade anti-tumoral de novas moléculas esteróides, como potenciais AIs. Este estudo, recentemente publicado, permitiu a descoberta de novos AIs com elevada eficácia anti-tumoral em células tumorais sensíveis e resistentes aos AIs. Para além disso, contribuiu para a identificação das modificações estruturais nas moléculas esteróides que potenciam a eficácia anti-aromatásica e anti-tumoral, fornecendo, assim, informações essenciais para o desenho racional/síntese de novos AIs mais eficazes e com potencial uso clínico.

 

Autores e Afiliações:

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.

 

Revista: Journal of Steroid Biochemistry and Molecular Biology; in press (Available online 7 April 2017)

 

Link: http://www.sciencedirect.com/science/article/pii/S0960076017301012