Anti-tumor efficacy of new 7 alpha-substituted androstanes as aromatase inhibitors in hormone-sensitive and resistant breast cancer cells

作者：Amaral Cristina; Varela Carla L; Mauricio Joao; Sobral Ana Filipa; Costa Saul C; Roleira Fernanda M F; Tavares da Silva Elisiario J; Correia da Silva Georgina^*; Teixeira Natercia^*

来源：Journal of Steroid Biochemistry and Molecular Biology, 2017, 171: 218-228.

DOI：10.1016/j.jsbmb.2017.04.002

• Estrogen receptor-positive breast cancer
• Aromatase inhibitors
• Steroids
• 7 alpha-substituted androstanes
• Apoptosis
• Acquired-resistance

The majority of breast cancer cases are estrogen receptor positive (ER+). Although, third-generation aromatase inhibitors (Als) 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 7 alpha-substituted steroidal molecules, 7 alpha-(2 xi,3 xi-epoxypropypandrosta-1,4-diene-3,17-dione (3), 7 alpha-allylandrost-4-ene-3,17-dione (6), 7 alpha-allylandrost-4-en-17-one (9), 7 alpha-ally)-3-oxoandrosta-1,4-dien-17 beta-ol (10) and 7 alpha-allylandrostal,4-diene-3,17-dione (12) are potent Als in placental microsomes. In this work, it was investigated their antiaromatase 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 Als can inhibit breast cancer cell growth, by causing cell cycle arrest and apoptosis. The effects of Als 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 Als 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 Als. In addition, allowed the discovery of new potent 7 alpha-substituted androstane molecules to inhibit tumor growth and prevent endocrine resistance.

• 出版日期2017-7