title: Anti-tumor efficacy of new 7α-substituted androstanes as aromatase inhibitors in hormone-sensitive and resistant breast cancer cells.
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.
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Amaral
authors.affiliation: Pharmaceutical Chemistry Group, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; CIEPQPF Centre for Chemical Processes Engineering and Forest Products, University of Coimbra, 3030-790 Coimbra, Portugal.
authors.forename: Carla L
authors.initials: CL
authors.lastname: Varela
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; Institute of Biomedical Sciences Abel Salazar, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Maurício
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; Faculty of Science and Technology, University of Coimbra, 3001-401 Coimbra, Portugal.
authors.forename: Ana Filipa
authors.initials: AF
authors.lastname: Sobral
authors.affiliation: Pharmaceutical Chemistry Group, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: Saul C
authors.initials: SC
authors.lastname: Costa
authors.affiliation: Pharmaceutical Chemistry Group, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; CIEPQPF Centre for Chemical Processes Engineering and Forest Products, University of Coimbra, 3030-790 Coimbra, Portugal.
authors.forename: Fernanda M F
authors.initials: FMF
authors.lastname: Roleira
authors.affiliation: Pharmaceutical Chemistry Group, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; CIEPQPF Centre for Chemical Processes Engineering and Forest Products, University of Coimbra, 3030-790 Coimbra, Portugal.
authors.forename: Elisiário J
authors.initials: EJ
authors.lastname: Tavares-da-Silva
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. Electronic address: george@ff.up.pt.
authors.forename: Georgina
authors.initials: G
authors.lastname: Correia-da-Silva
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. Electronic address: natercia@ff.up.pt.
authors.forename: Natércia
authors.initials: N
authors.lastname: Teixeira
mesh_terms: D000731:Androstanes / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001141:Aromatase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C410798:AR protein, human; D000731:Androstanes; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D009363:Neoplasm Proteins; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D001141:Aromatase; C561410:CYP19A1 protein, human
keywords: 7α-substituted androstanes; Acquired-resistance; Apoptosis; Aromatase inhibitors; Estrogen receptor-positive breast cancer; Steroids