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1.
Proc Natl Acad Sci U S A ; 109(8): 2724-9, 2012 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-22003129

RESUMO

Breast cancers are comprised of molecularly distinct subtypes that may respond differently to pathway-targeted therapies now under development. Collections of breast cancer cell lines mirror many of the molecular subtypes and pathways found in tumors, suggesting that treatment of cell lines with candidate therapeutic compounds can guide identification of associations between molecular subtypes, pathways, and drug response. In a test of 77 therapeutic compounds, nearly all drugs showed differential responses across these cell lines, and approximately one third showed subtype-, pathway-, and/or genomic aberration-specific responses. These observations suggest mechanisms of response and resistance and may inform efforts to develop molecular assays that predict clinical response.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/classificação , Neoplasias da Mama/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Dosagem de Genes/genética , Humanos , Modelos Biológicos , Transdução de Sinais/genética , Transcrição Gênica/efeitos dos fármacos
2.
PLoS One ; 10(8): e0135704, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26285134

RESUMO

Tumor cells adapt via metabolic reprogramming to meet elevated energy demands due to continuous proliferation, for example by switching to alternative energy sources. Nutrients such as glucose, fatty acids, ketone bodies and amino acids may be utilized as preferred substrates to fulfill increased energy requirements. In this study we investigated the metabolic characteristics of benign and cancer cells of the prostate with respect to their utilization of medium chain (MCTs) and long chain triglycerides (LCTs) under standard and glucose-starved culture conditions by assessing cell viability, glycolytic activity, mitochondrial respiration, the expression of genes encoding key metabolic enzymes as well as mitochondrial mass and mtDNA content. We report that BE prostate cells (RWPE-1) have a higher competence to utilize fatty acids as energy source than PCa cells (LNCaP, ABL, PC3) as shown not only by increased cell viability upon fatty acid supplementation but also by an increased ß-oxidation of fatty acids, although the base-line respiration was 2-fold higher in prostate cancer cells. Moreover, BE RWPE-1 cells were found to compensate for glucose starvation in the presence of fatty acids. Of notice, these findings were confirmed in vivo by showing that PCa tissue has a lower capacity in oxidizing fatty acids than benign prostate. Collectively, these metabolic differences between benign and prostate cancer cells and especially their differential utilization of fatty acids could be exploited to establish novel diagnostic and therapeutic strategies.


Assuntos
Gorduras na Dieta/metabolismo , Ácidos Graxos/metabolismo , Próstata/citologia , Próstata/patologia , Neoplasias da Próstata/patologia , Idoso , Linhagem Celular Tumoral , Respiração Celular , Sobrevivência Celular , DNA Mitocondrial/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Ácidos Graxos/química , Dosagem de Genes , Genoma Mitocondrial/genética , Glicólise , Humanos , Corpos Cetônicos/metabolismo , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Tamanho Mitocondrial , Fosforilação Oxidativa , Próstata/metabolismo , Triglicerídeos/metabolismo
3.
Nutrients ; 6(10): 4491-519, 2014 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-25338271

RESUMO

Prostate cancer (PCa), the most commonly diagnosed cancer and second leading cause of male cancer death in Western societies, is typically androgen-dependent, a characteristic that underlies the rationale of androgen deprivation therapy (ADT). Approximately 90% of patients initially respond to ADT strategies, however many experience side effects including hot flashes, cardiotoxicity, metabolic and musculoskeletal alterations. This review summarizes pre-clinical and clinical studies investigating the ability of dietary supplements to alleviate adverse effects arising from ADT. In particular, we focus on herbal compounds, phytoestrogens, selenium (Se), fatty acids (FA), calcium, and Vitamins D and E. Indeed, there is some evidence that calcium and Vitamin D can prevent the development of osteoporosis during ADT. On the other hand, caution should be taken with the antioxidants Se and Vitamin E until the basis underlying their respective association with type 2 diabetes mellitus and PCa tumor development has been clarified. However, many other promising supplements have not yet been subjected large-scale clinical trials making it difficult to assess their efficacy. Given the demographic trend of increased PCa diagnoses and dependence on ADT as a major therapeutic strategy, further studies are required to objectively evaluate these supplements as adjuvant for PCa patients receiving ADT.


Assuntos
Antagonistas de Androgênios/efeitos adversos , Diabetes Mellitus Tipo 2/dietoterapia , Suplementos Nutricionais , Osteoporose/dietoterapia , Neoplasias da Próstata/tratamento farmacológico , Antagonistas de Androgênios/uso terapêutico , Cálcio da Dieta/administração & dosagem , Cálcio da Dieta/farmacologia , Diabetes Mellitus Tipo 2/induzido quimicamente , Ácidos Graxos/administração & dosagem , Ácidos Graxos/farmacologia , Humanos , Masculino , Osteoporose/induzido quimicamente , Fitoestrógenos/administração & dosagem , Fitoestrógenos/farmacologia , Selênio/administração & dosagem , Selênio/farmacologia , Resultado do Tratamento , Vitamina D/administração & dosagem , Vitamina D/farmacologia , Vitamina E/administração & dosagem , Vitamina E/farmacologia
4.
Phytomedicine ; 20(14): 1306-14, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-23972793

RESUMO

This study aimed to investigate the mechanisms underlying the anti-proliferative effects of the ethanolic Cimicifuga racemosa extract BNO-1055 on prostate cells and evaluate its therapeutic potential. BNO-1055 dose-dependently attenuated cellular uptake and incorporation of thymidine and BrdU and significantly inhibited cell growth after long-time exposure. Similar results were obtained using saponin-enriched sub-fractions of BNO-1055. These inhibitory effects of BNO-1055 could be mimicked using pharmacological inhibitors and isoform-specific siRNAs targeting the equilibrative nucleoside transporters ENT1 and ENT2. Moreover, BNO-1055 attenuated the uptake of clinically relevant nucleoside analogs, e.g. the anti-cancer drugs gemcitabine and fludarabine. Consistent with inhibition of the salvage nucleoside uptake pathway BNO-1055 potentiated the cytotoxicity of the de novo nucleotide synthesis inhibitor 5-FU without significantly altering its uptake. Collectively, these data show for the first time that the anti-proliferative effects of BNO-1055 result from hindered nucleoside uptake due to impaired ENT activity and demonstrate the potential therapeutic use of BNO-1055 for modulation of nucleoside transport.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Proteínas de Transporte de Nucleosídeo Equilibrativas/metabolismo , Nucleosídeos/metabolismo , Fitoterapia , Extratos Vegetais/uso terapêutico , Próstata/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/farmacologia , Bromodesoxiuridina/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cimicifuga , Desoxicitidina/análogos & derivados , Desoxicitidina/metabolismo , Relação Dose-Resposta a Droga , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Masculino , Extratos Vegetais/farmacologia , Neoplasias da Próstata/metabolismo , RNA Interferente Pequeno/farmacologia , Saponinas/farmacologia , Saponinas/uso terapêutico , Timidina/metabolismo , Vidarabina/análogos & derivados , Vidarabina/metabolismo , Gencitabina
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