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[PMID]:29431540
[Au] Autor:Hong JH
[Ad] Endereço:a Department of Urology , Dankook University College of Medicine , Cheonan , Republic of Korea.
[Ti] Título:Pharmacokinetic/pharmacodynamic drug evaluation of enzalutamide for treating prostate cancer.
[So] Source:Expert Opin Drug Metab Toxicol;14(3):361-369, 2018 Mar.
[Is] ISSN:1744-7607
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Enzalutamide is the first approved second-generation androgen receptor (AR) antagonist in the treatment of metastatic castration-resistant prostate cancer (mCRPC) with or without docetaxel-based chemotherapy. Over the past 5 years, a number of attempts were made to determine the efficacy of enzalutamide in the different clinical settings. Areas covered: A literature search was performed at the PubMed, Embase, and Web of Science database to collect the most relevant and impactful studies, including basic science investigations, clinical trials, and reviews. This article focuses on the pharmacology, efficacy, tolerability, and future perspective of enzalutamide. Expert opinion: The treatment paradigm of CRPC has been dramatically challenged of late. Enzalutamide are in wide use because of its favorable efficacy and safety, but primary or acquired resistance to the drug will eventually develop. Further studies are thus necessary to identify appropriate patients who can achieve apparent benefits from enzalutamide alone or in combination with other drugs.
[Mh] Termos MeSH primário: Antagonistas de Receptores de Andrógenos/administração & dosagem
Feniltioidantoína/análogos & derivados
Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico
[Mh] Termos MeSH secundário: Antagonistas de Receptores de Andrógenos/farmacocinética
Antagonistas de Receptores de Andrógenos/farmacologia
Animais
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Resistência a Medicamentos Antineoplásicos
Seres Humanos
Masculino
Metástase Neoplásica
Feniltioidantoína/administração & dosagem
Feniltioidantoína/farmacocinética
Feniltioidantoína/farmacologia
Neoplasias de Próstata Resistentes à Castração/patologia
Taxoides/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Androgen Receptor Antagonists); 0 (MDV 3100); 0 (Taxoids); 15H5577CQD (docetaxel); 2010-15-3 (Phenylthiohydantoin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180213
[St] Status:MEDLINE
[do] DOI:10.1080/17425255.2018.1440288


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[PMID]:29289696
[Au] Autor:Passoni MT; Kristensen MN; Morais RN; Woitkowiak C; Boareto AC; da Silva Amaral BA; Grechi N; Dalsenter PR; Munkboel CH; Styrishave B; Kristensen DM; Gomes C; van Ravenzwaay B; Martino-Andrade AJ
[Ad] Endereço:Department of Pharmacology, Reproductive Toxicology Laboratory, Federal University of Paraná (UFPR), Curitiba, PR, Brazil.
[Ti] Título:Assessment of the analgesic dipyrone as a possible (anti)androgenic endocrine disruptor.
[So] Source:Toxicol Lett;285:139-147, 2018 Mar 15.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Mild analgesics have been associated with antiandrogenic effects, but there are no such studies on dipyrone, despite its high prevalence of use in many countries. We examined the production of steroid hormones in human H295R cells after exposure to dipyrone and two metabolites, 4-Methylaminoantipyrine (MAA) and 4-Aminoantipyrine (AA), as well as fetal testicular testosterone production in rats following maternal dipyrone exposure. Androgen agonistic/antagonistic effects were examined in vitro for dipyrone and its metabolites in the Yeast Androgen Screen (YAS) assay and in vivo for dipyrone through the Hershberger assay. In vitro we tested dipyrone, MAA, and AA (0.1-1000 µM) while in vivo we used dipyrone (50, 100, 200 mg/kg/day). In the H295R assay, dipyrone, MAA and AA reduced the production of androgens and corticosteroids. Testosterone was reduced at concentrations 4-13 times higher than the maximum plasma concentrations reported in humans for MAA and AA. No effects were observed in the fetal testosterone production assay. In the YAS and Hershberger assays, no androgen agonistic/antagonistic activities were observed. These results indicate that dipyrone and its metabolites do not interact with the androgen receptor, but have the potential to inhibit steroidogenesis, however only at concentrations that are not relevant under normal medical use.
[Mh] Termos MeSH primário: Analgésicos/toxicidade
Antagonistas de Receptores de Andrógenos/toxicidade
Androgênios/toxicidade
Dipirona/toxicidade
Disruptores Endócrinos/toxicidade
[Mh] Termos MeSH secundário: Analgésicos/sangue
Antagonistas de Receptores de Andrógenos/sangue
Androgênios/sangue
Animais
Bioensaio
Linhagem Celular Tumoral
Dipirona/sangue
Disruptores Endócrinos/sangue
Feminino
Seres Humanos
Masculino
Gravidez
Efeitos Tardios da Exposição Pré-Natal/sangue
Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
Ratos
Ratos Wistar
Receptores Androgênicos/genética
Receptores Androgênicos/metabolismo
Testículo/efeitos dos fármacos
Testículo/embriologia
Testículo/metabolismo
Testosterona/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics); 0 (Androgen Receptor Antagonists); 0 (Androgens); 0 (Endocrine Disruptors); 0 (Receptors, Androgen); 3XMK78S47O (Testosterone); 6429L0L52Y (Dipyrone)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180219
[Lr] Data última revisão:
180219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180101
[St] Status:MEDLINE


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[PMID]:29202431
[Au] Autor:Lee A; Djamgoz MBA
[Ad] Endereço:Faculty of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
[Ti] Título:Triple negative breast cancer: Emerging therapeutic modalities and novel combination therapies.
[So] Source:Cancer Treat Rev;62:110-122, 2018 Jan.
[Is] ISSN:1532-1967
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Triple negative breast cancer (TNBC) is a complex and aggressive subtype of breast cancer which lacks oestrogen receptors, progesterone receptors and HER2 amplification, thereby making it difficult to target therapeutically. In addition, TNBC has the highest rates of metastatic disease and the poorest overall survival of all breast cancer subtypes. Resultantly, development of targeted therapies for TNBC is urgently needed. Recent efforts aimed at molecular characterisation of TNBCs have revealed various emerging therapeutic targets including PARP1, receptor and non-receptor tyrosine kinases, immune-checkpoints, androgen receptor and epigenetic proteins. Key successes include that of the PARP inhibitor, olaparib, which prolonged progression-free survival in a trial of BRCA-mutated breast cancer and for which clinical approval (in this setting) appears imminent. Nevertheless, the heterogeneity of TNBC has limited the clinical benefits of many trialled therapies in 'unselected' patients. Further, drug resistance develops following use of many targeted monotherapies due to upregulation of compensatory signalling pathways. In this review, we evaluate the current status of investigational targeted treatments and present evidence for the role of novel biomarkers and combination therapies in increasing response rates and circumventing drug-induced resistance. Additionally, we discuss promising novel targets in metastatic TNBC identified through preclinical and/or epidemiological studies.
[Mh] Termos MeSH primário: Antagonistas Adrenérgicos beta/uso terapêutico
Antagonistas de Receptores de Andrógenos/uso terapêutico
Inibidores da Angiogênese/uso terapêutico
Antineoplásicos Imunológicos/uso terapêutico
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Carcinoma/tratamento farmacológico
Inibidores de Histona Desacetilases/uso terapêutico
Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
Inibidores de Proteínas Quinases/uso terapêutico
Neoplasias de Mama Triplo Negativas/tratamento farmacológico
[Mh] Termos MeSH secundário: Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Adrenergic beta-Antagonists); 0 (Androgen Receptor Antagonists); 0 (Angiogenesis Inhibitors); 0 (Antineoplastic Agents, Immunological); 0 (Histone Deacetylase Inhibitors); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 0 (Protein Kinase Inhibitors)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180102
[Lr] Data última revisão:
180102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE


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[PMID]:29187427
[Au] Autor:Christopoulos PF; Vlachogiannis NI; Vogkou CT; Koutsilieris M
[Ad] Endereço:Department of Experimental Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
[Ti] Título:The Role of the Androgen Receptor Signaling in Breast Malignancies.
[So] Source:Anticancer Res;37(12):6533-6540, 2017 12.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:Breast cancer (BrCa) is the most common malignancy among women worldwide, and one of the leading causes of cancer-related deaths in females. Despite the development of novel therapeutic modalities, triple-negative breast cancer (TNBC) remains an incurable disease. Androgen receptor (AR) is widely expressed in BrCa and its role in the disease may differ depending on the molecular subtype and the stage. Interestingly, AR has been suggested as a potential target candidate in TNBC, while sex hormone levels may regulate the role of AR in BrCa subtypes. In the presence of estrogen receptor α (ERa), AR may antagonize the ERα-induced effects, whereas in the absence of estrogens, AR may act as an ERα-mimic, promoting tumor. Thus, depending on the BrCa micro-environment, both agonists and antagonists of the AR have been suggested as therapeutic approaches. Herein, we review the role of AR signaling in BrCa and the molecular cross-talk mechanisms with other molecules/pathways, as well as its therapeutic implications in the different subtypes of the disease.
[Mh] Termos MeSH primário: Neoplasias da Mama/metabolismo
Receptor alfa de Estrogênio/metabolismo
Receptores Androgênicos/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Antagonistas de Receptores de Andrógenos/uso terapêutico
Neoplasias da Mama/tratamento farmacológico
Estrogênios/uso terapêutico
Feminino
Seres Humanos
Terapia de Alvo Molecular
Neoplasias de Mama Triplo Negativas/tratamento farmacológico
Neoplasias de Mama Triplo Negativas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Androgen Receptor Antagonists); 0 (Estrogen Receptor alpha); 0 (Estrogens); 0 (Receptors, Androgen); 0 (estrogen receptor alpha, human)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171211
[Lr] Data última revisão:
171211
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171201
[St] Status:MEDLINE


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[PMID]:28977599
[Au] Autor:Masoodi KZ; Eisermann K; Yang Z; Dar JA; Pascal LE; Nguyen M; O'Malley K; Parrinello E; Feturi FG; Kenefake AN; Nelson JB; Johnston PA; Wipf P; Wang Z
[Ad] Endereço:Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15232.
[Ti] Título:Inhibition of Androgen Receptor Function and Level in Castration-Resistant Prostate Cancer Cells by 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone.
[So] Source:Endocrinology;158(10):3152-3161, 2017 Oct 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The androgen receptor (AR) plays a critical role in the development of castration-resistant prostate cancer (CRPC) as well as in the resistance to the second-generation AR antagonist enzalutamide and the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone. Novel agents targeting AR may inhibit the growth of prostate cancer cells resistant to enzalutamide and/or abiraterone. Through a high-throughput/high-content screening of a 220,000-member small molecule library, we have previously identified 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone (IMTPPE) (SID 3712502) as a novel small molecule capable of inhibiting AR transcriptional activity and protein level in C4-2 prostate cancer cells. In this study, we show that IMTPPE inhibits AR-target gene expression using real-time polymerase chain reaction, Western blot, and luciferase assays. IMTPPE inhibited proliferation of AR-positive, but not AR-negative, prostate cancer cells in culture. IMTPPE inhibited the transcriptional activity of a mutant AR lacking the ligand-binding domain (LBD), indicating that IMTPPE inhibition of AR is independent of the LBD. Furthermore, animal studies showed that IMTPPE inhibited the growth of 22Rv1 xenograft tumor, a model for enzalutamide-resistant prostate cancer. These findings suggest that IMTPPE is a potential lead compound for developing clinical candidates for the treatment of CRPC, including those resistant to enzalutamide.
[Mh] Termos MeSH primário: Antagonistas de Receptores de Andrógenos/farmacologia
Isoxazóis/farmacologia
Piperazinas/farmacologia
Neoplasias de Próstata Resistentes à Castração/química
Receptores Androgênicos/fisiologia
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação/genética
Sítios de Ligação/fisiologia
Linhagem Celular Tumoral
Resistência a Medicamentos Antineoplásicos
Expressão Gênica/efeitos dos fármacos
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Camundongos SCID
Feniltioidantoína/análogos & derivados
Regiões Promotoras Genéticas/efeitos dos fármacos
Isoformas de Proteínas/genética
Reação em Cadeia da Polimerase em Tempo Real
Receptores Androgênicos/análise
Receptores Androgênicos/genética
Tetra-Hidronaftalenos
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-((isoxazol-4-ylmethyl)thio)-1-(4-phenylpiperazin-1-yl)ethanone); 0 (Androgen Receptor Antagonists); 0 (Isoxazoles); 0 (MDV 3100); 0 (Piperazines); 0 (Protein Isoforms); 0 (Receptors, Androgen); 0 (Tetrahydronaphthalenes); 2010-15-3 (Phenylthiohydantoin); A61RXM4375 (bexarotene)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00408


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[PMID]:28971491
[Au] Autor:Abedinpour P; Baron VT; Chrastina A; Rondeau G; Pelayo J; Welsh J; Borgström P
[Ad] Endereço:Vaccine Research Institute of San Diego (VRISD), San Diego Science Center, San Diego, California.
[Ti] Título:Plumbagin improves the efficacy of androgen deprivation therapy in prostate cancer: A pre-clinical study.
[So] Source:Prostate;77(16):1550-1562, 2017 Dec.
[Is] ISSN:1097-0045
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Plumbagin is a candidate drug for the treatment of prostate cancer. Previous observations indicated that it may improve the efficacy of androgen deprivation therapy (ADT). This study evaluates the effectiveness of treatment with combinations of plumbagin and alternative strategies for ADT in mouse models of prostate cancer to support its clinical use. METHODS: Plumbagin was administered per oral in a new sesame oil formulation. Standard toxicology studies were performed in rats. For tumor growth studies, mouse prostate cancer cell spheroids were placed on top of grafted prostate tissue in a dorsal chamber and allowed to form tumors. Mice were separated in various treatment groups and tumor size was measured over time by intra-vital microscopy. Survival studies were done in mice after injection of prostate cancer cells in the prostate of male animals. Androgen receptor (AR) levels were analyzed by Western blot from prostate cancer cells treated with plumbagin. RESULTS: Plumbagin caused a decrease in AR levels in vitro. In mice, plumbagin at 1 mg/kg in sesame oil displayed low toxicity and caused a 50% tumor regression when combined with castration. The combination of plumbagin with various forms of chemical ADT including treatment with a GnRH receptor agonist, a GnRH receptor antagonist, or CYP17A1 inhibitors, outperformed ADT alone, increasing mouse survival compared to the standard regimen of castration alone. In contrast, the combination of plumbagin with AR antagonists, such as bicalutamide and enzalutamide, showed no improvement over AR antagonists alone. Thus, plumbagin is effective in combination with drugs that prevent the synthesis of testosterone or its conversion to dihydrotestosterone, but not with drugs that bind to AR. CONCLUSION: Plumbagin significantly improves the effect of ADT drugs currently used in the clinic, with few side effects in mice.
[Mh] Termos MeSH primário: Antagonistas de Receptores de Andrógenos/administração & dosagem
Antineoplásicos Fitogênicos/administração & dosagem
Naftoquinonas/administração & dosagem
Neoplasias da Próstata/tratamento farmacológico
Neoplasias da Próstata/patologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos Fitogênicos/química
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Relação Dose-Resposta a Droga
Avaliação Pré-Clínica de Medicamentos/métodos
Feminino
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Nus
Naftoquinonas/química
Neoplasias da Próstata/metabolismo
Ratos
Ratos Sprague-Dawley
Testes de Toxicidade/métodos
Resultado do Tratamento
Carga Tumoral/efeitos dos fármacos
Carga Tumoral/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androgen Receptor Antagonists); 0 (Antineoplastic Agents, Phytogenic); 0 (Naphthoquinones); YAS4TBQ4OQ (plumbagin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1002/pros.23428


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[PMID]:28888979
[Au] Autor:Lundqvist J; Tringali C; Oskarsson A
[Ad] Endereço:Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Box 7028, SE-750 07 Uppsala, Sweden. Electronic address: johan.lundqvist@slu.se.
[Ti] Título:Resveratrol, piceatannol and analogs inhibit activation of both wild-type and T877A mutant androgen receptor.
[So] Source:J Steroid Biochem Mol Biol;174:161-168, 2017 Nov.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Prostate cancer growth and progression are mainly dependent on androgens and many current prostate cancer treatment options target the synthesis or function of androgens. We have previously reported that resveratrol and synthetic analogs of resveratrol with a higher bioavailability inhibit the synthesis of androgens in human adrenocortical H295R cells. Now we have studied the antiandrogenic properties of resveratrol, piceatannol and analogs in two different prostate cell lines; LNCaP and RWPE. LNCaP carry a T877A mutation in the androgen receptor while RWPE has a wild-type androgen receptor. We found that resveratrol, piceatannol and all studied analogs were able to inhibit a dihydrotestosterone-induced activation of the androgen receptor, showing that they act as antiandrogens. In LNCaP cells, all studied compounds were able to statistically significantly decrease the androgenic signaling in concentrations ≥1µM and the synthetic analogs trimethylresveratrol (RSVTM) and tetramethylpiceatannol (PICTM) were the most potent compounds. RWPE cells were not as responsive to the studied compounds as the LNCaP cells. A statistically significant decrease in the androgenic signaling was observed at concentrations ≤5µM for most compounds and RSVTM was found to be the most potent compound. Further, we studied the effects of resveratrol, piceatannol and analogs on the levels of prostate-specific antigen (PSA) in LNCaP cells and found that all studied compounds decreased the level of PSA and that the synthetic analogs diacetylresveratrol (RSVDA), triacetylresveratrol (RSVTA) and RSVTM were the most potent compounds, decreasing the PSA level by approx. 50% at concentrations ≥10µM. In a cell-free receptor binding assay we were unable to show binding of resveratrol or analogs to the ligand binding domain of the androgen receptor, indicating that the observed effects are mediated via other mechanisms than direct ligand competition. We conclude that the resveratrol, piceatannol and analogs are highly interesting for chemoprevention of prostate cancer, since they have a high potency both as inhibitors of androgen synthesis and androgen receptor activation.
[Mh] Termos MeSH primário: Antagonistas de Receptores de Andrógenos/farmacologia
Receptores Androgênicos/metabolismo
Estilbenos/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Seres Humanos
Calicreínas/metabolismo
Antígeno Prostático Específico/metabolismo
Receptores Androgênicos/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AR protein, human); 0 (Androgen Receptor Antagonists); 0 (Receptors, Androgen); 0 (Stilbenes); 6KS3LS0D4F (3,3',4,5'-tetrahydroxystilbene); EC 3.4.21.- (Kallikreins); EC 3.4.21.- (kallikrein-related peptidase 3, human); EC 3.4.21.77 (Prostate-Specific Antigen); Q369O8926L (resveratrol)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170911
[St] Status:MEDLINE


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[PMID]:28757136
[Au] Autor:Divakar S; Saravanan K; Karthikeyan P; Elancheran R; Kabilan S; Balasubramanian KK; Devi R; Kotoky J; Ramanathan M
[Ad] Endereço:Department of Pharmacology, PSG College of Pharmacy, Coimbatore, Tamil Nadu, India.
[Ti] Título:Iminoenamine based novel androgen receptor antagonist exhibited anti-prostate cancer activity in androgen independent prostate cancer cells through inhibition of AKT pathway.
[So] Source:Chem Biol Interact;275:22-34, 2017 Sep 25.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Treatment by androgen receptor (AR) antagonists is one of the regimens for prostate cancer. The prolonged treatment with AR antagonist leads to the expression of point mutation in the ligand binding domain of the AR. This point mutation causes resistance to AR antagonist by converting them into an agonist. The T887A mutated AR was frequently expressed in androgen independent prostate cancer (AIPC) patients. Through literature survey and molecular modelling, we have identified a novel AR antagonist having a bulky ß-iminoenamine BF2 complex scaffold. The tested and standard ligands were screened in AR positive (LNCaP, MCF-7 and MDA-MB-453), AR negative (PC3), and non-cancerous (3T3) cell lines through anti-proliferation assay. The ligand, ARA3 was the most potent molecule among all the tested ligands and was 7.6 folds selective for AR positive cell lines. The mechanism of anti-prostate cancer activity of ARA3 was confirmed by western blot, qPCR, and apoptotic assays in LNCaP (T887A positive AR) cells. Structural activity relationship was derived by correlating the in-vitro and in-silico data. Consequently, we have identified the essential functional groups that could prevent the resistance concerning mutant AR. The ARA3 induces the apoptosis in AIPC cells by preventing the AR mediated activation of AKT pathway. The bicalutamide did not induce the apoptosis because it failed to prevent the AR mediated activation of AKT.
[Mh] Termos MeSH primário: Aminas/química
Aminas/farmacologia
Antagonistas de Receptores de Andrógenos/química
Neoplasias da Próstata/fisiopatologia
Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores
Receptores Androgênicos/metabolismo
[Mh] Termos MeSH secundário: Aminas/metabolismo
Antagonistas de Receptores de Andrógenos/metabolismo
Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Sítios de Ligação
Caspase 3/metabolismo
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Seres Humanos
Iminas/química
Masculino
Microscopia de Fluorescência
Simulação de Acoplamento Molecular
Mutação
Neoplasias da Próstata/enzimologia
Proteínas Proto-Oncogênicas c-akt/genética
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Receptores Androgênicos/genética
Proteína X Associada a bcl-2/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AR protein, human); 0 (Amines); 0 (Androgen Receptor Antagonists); 0 (Antineoplastic Agents); 0 (Imines); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Receptors, Androgen); 0 (bcl-2-Associated X Protein); EC 2.7.11.1 (AKT1 protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.4.22.- (Caspase 3)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE


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[PMID]:28757062
[Au] Autor:Lao K; Sun J; Wang C; Wang Y; You Q; Xiao H; Xiang H
[Ad] Endereço:Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
[Ti] Título:Design, synthesis and biological evaluation of novel 3-oxo-4-oxa-5α-androst-17ß-amide derivatives as dual 5α-reductase inhibitors and androgen receptor antagonists.
[So] Source:Bioorg Med Chem Lett;27(17):4212-4217, 2017 09 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Prostate cancer (PCa) is the second leading cause of death in men. Recently, some researches have showed that 5α-reductase inhibitors were beneficial in PCa treatment as well. In this study, a series of novel 3-oxo-4-oxa-5α-androst-17ß-amide derivatives have been designed and synthesized in a more simple and convenient method. Most of the synthesized compounds displayed good 5α-reductase inhibitory activities and androgen receptor binding affinities. Their anti-proliferation activities in PC-3 and LNCaP cell lines were also evaluated and the results indicated that most of the synthesized compounds exhibited potent anti-proliferative activities. It is obvious that the androgen-dependent cell line LNCaP was much more sensitive than the androgen-independent cell line PC-3. Among all the synthesized compounds, 11d and 11k displayed the best inhibition activity with 4-fold more sensitive toward LNCaP than PC-3, which was consistent with their high affinities observed in AR binding assay. Molecular modeling studies suggested that 11k could bind to AR in a manner similar to the binding of dihydrotestosterone to AR. Compared to the finasteride, 11k showed a longer plasma half-life (4h) and a better bioavailability. Overall, based on biological activities data, compound 11d and 11k can be identified as potential dual 5α-reductase inhibitors and AR antagonists which might be of therapeutic importance for prostate cancer treatment.
[Mh] Termos MeSH primário: Inibidores de 5-alfa Redutase/farmacologia
Amidas/farmacologia
Antagonistas de Receptores de Andrógenos/farmacologia
Antineoplásicos/farmacologia
Desenho de Drogas
[Mh] Termos MeSH secundário: 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo
Inibidores de 5-alfa Redutase/síntese química
Inibidores de 5-alfa Redutase/química
Amidas/síntese química
Amidas/química
Antagonistas de Receptores de Andrógenos/síntese química
Antagonistas de Receptores de Andrógenos/química
Antineoplásicos/síntese química
Antineoplásicos/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Estrutura Molecular
Receptores Androgênicos/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5-alpha Reductase Inhibitors); 0 (Amides); 0 (Androgen Receptor Antagonists); 0 (Antineoplastic Agents); 0 (Receptors, Androgen); EC 1.3.99.5 (3-Oxo-5-alpha-Steroid 4-Dehydrogenase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE


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[PMID]:28751550
[Au] Autor:Argilés JM; López-Soriano FJ; Stemmler B; Busquets S
[Ad] Endereço:Cancer Research Group, Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Diagonal 643, Barcelona 08028, Spain jargiles@ub.edu.
[Ti] Título:Novel targeted therapies for cancer cachexia.
[So] Source:Biochem J;474(16):2663-2678, 2017 Jul 27.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Anorexia and metabolic alterations are the main components of the cachectic syndrome. Glucose intolerance, fat depletion, muscle protein catabolism and other alterations are involved in the development of cancer cachexia, a multi-organ syndrome. Nutritional approach strategies are not satisfactory in reversing the cachectic syndrome. The aim of the present review is to deal with the recent therapeutic targeted approaches that have been designed to fight and counteract wasting in cancer patients. Indeed, some promising targeted therapeutic approaches include ghrelin agonists, selective androgen receptor agonists, ß-blockers and antimyostatin peptides. However, a multi-targeted approach seems absolutely essential to treat patients affected by cancer cachexia. This approach should not only involve combinations of drugs but also nutrition and an adequate program of physical exercise, factors that may lead to a synergy, essential to overcome the syndrome. This may efficiently reverse the metabolic changes described above and, at the same time, ameliorate the anorexia. Defining this therapeutic combination of drugs/nutrients/exercise is an exciting project that will stimulate many scientific efforts. Other aspects that will, no doubt, be very important for successful treatment of cancer wasting will be an optimized design of future clinical trials, together with a protocol for staging cancer patients in relation to their degree of cachexia. This will permit that nutritional/metabolic/pharmacological support can be started early in the course of the disease, before severe weight loss occurs. Indeed, timing is crucial and has to be taken very seriously when applying the therapeutic approach.
[Mh] Termos MeSH primário: Caquexia/terapia
Neoplasias/terapia
[Mh] Termos MeSH secundário: Antagonistas Adrenérgicos beta/uso terapêutico
Antagonistas de Receptores de Andrógenos/uso terapêutico
Anorexia/metabolismo
Anorexia/patologia
Anorexia/terapia
Caquexia/metabolismo
Caquexia/patologia
Dietoterapia/métodos
Terapia por Exercício/métodos
Grelina/agonistas
Seres Humanos
Miostatina/antagonistas & inibidores
Miostatina/metabolismo
Neoplasias/metabolismo
Neoplasias/patologia
Peptídeos/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Adrenergic beta-Antagonists); 0 (Androgen Receptor Antagonists); 0 (Ghrelin); 0 (MSTN protein, human); 0 (Myostatin); 0 (Peptides)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170803
[Lr] Data última revisão:
170803
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170729
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170032



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