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[PMID]: | 28396197 |
[Au] Autor: | Amaral C; Varela CL; Maurício J; Sobral AF; Costa SC; Roleira FMF; Tavares-da-Silva EJ; Correia-da-Silva G; Teixeira N |
[Ad] Endereço: | UCIBIO-REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. |
[Ti] Título: | Anti-tumor efficacy of new 7α-substituted androstanes as aromatase inhibitors in hormone-sensitive and resistant breast cancer cells. |
[So] Source: | J Steroid Biochem Mol Biol;171:218-228, 2017 Jul. | [Is] ISSN: | 1879-1220 |
[Cp] País de publicação: | England |
[La] Idioma: | eng |
[Ab] Resumo: | 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-17ß-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. |
[Mh] Termos MeSH primário: |
Androstanos/farmacologia Antineoplásicos Hormonais/farmacologia Apoptose/efeitos dos fármacos Inibidores da Aromatase/farmacologia Neoplasias da Mama/tratamento farmacológico Resistência a Medicamentos Antineoplásicos
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[Mh] Termos MeSH secundário: |
Androstanos/efeitos adversos Androstanos/química Antineoplásicos Hormonais/efeitos adversos Antineoplásicos Hormonais/química Aromatase/química Aromatase/genética Aromatase/metabolismo Inibidores da Aromatase/efeitos adversos Inibidores da Aromatase/química Neoplasias da Mama/metabolismo Neoplasias da Mama/patologia Ciclo Celular/efeitos dos fármacos Linhagem Celular Proliferação Celular/efeitos dos fármacos Sobrevivência Celular/efeitos dos fármacos Feminino Seres Humanos Concentração Inibidora 50 Células MCF-7 Proteínas de Neoplasias/química Proteínas de Neoplasias/genética Proteínas de Neoplasias/metabolismo Receptores Androgênicos/metabolismo Receptores Estrogênicos/metabolismo Proteínas Recombinantes/química Proteínas Recombinantes/metabolismo Relação Estrutura-Atividade
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[Pt] Tipo de publicação: | COMPARATIVE STUDY; JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (AR protein, human); 0 (Androstanes); 0 (Antineoplastic Agents, Hormonal); 0 (Aromatase Inhibitors); 0 (Neoplasm Proteins); 0 (Receptors, Androgen); 0 (Receptors, Estrogen); 0 (Recombinant Proteins); EC 1.14.14.1 (Aromatase); EC 1.14.14.1 (CYP19A1 protein, human) |
[Em] Mês de entrada: | 1707 |
[Cu] Atualização por classe: | 170718 |
[Lr] Data última revisão:
| 170718 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170412 |
[St] Status: | MEDLINE |
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