RESUMO
Sorafenib, a multi-tyrosine kinase inhibitor, kills more effectively the non-metastatic prostate cancer cell line 22Rv1 than the highly metastatic prostate cancer cell line PC3. In 22Rv1 cells, constitutively active STAT3 and ERK are targeted by sorafenib, contrasting with PC3 cells, in which these kinases are not active. Notably, overexpression of a constitutively active MEK construct in 22Rv1 cells stimulates the sustained phosphorylation of Bad and protects from sorafenib-induced cell death. In PC3 cells, Src and AKT are constitutively activated and targeted by sorafenib, leading to an increase in Bim protein levels. Overexpression of constitutively active AKT or knockdown of Bim protects PC3 cells from sorafenib-induced killing. In both PC3 and 22Rv1 cells, Mcl-1 depletion is required for the induction of cell death by sorafenib as transient overexpression of Mcl-1 is protective. Interestingly, co-culturing of primary cancer-associated fibroblasts (CAFs) with 22Rv1 or PC3 cells protected the cancer cells from sorafenib-induced cell death, and this protection was largely overcome by co-administration of the Bcl-2 antagonist, ABT737. In summary, the differential tyrosine kinase profile of prostate cancer cells defines the cytotoxic efficacy of sorafenib and this profile is modulated by CAFs to promote resistance. The combination of sorafenib with Bcl-2 antagonists, such as ABT737, may constitute a promising therapeutic strategy against prostate cancer.
Assuntos
Benzenossulfonatos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Cocultura , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Masculino , Terapia de Alvo Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides , Niacinamida/análogos & derivados , Compostos de Fenilureia , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Próstata , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas pp60(c-src)/genética , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Transdução de Sinais/genética , SorafenibeRESUMO
Excessive daytime sleepiness (EDS) is one of the most frequent symptoms in patients with obstructive sleep apnoea (OSA). EDS can lead to substantial impairments in quality of life and is a major cause of fatal accidents. However, not all patients with OSA develop EDS. The aim of this paper is to review the current literature to identify factors having an impact on sleepiness in patients with OSA. Interestingly, a substantial heterogeneity of the results was found. Summarising these results, causes of EDS in patients with OSA are multifactorial. Severity of obesity and breathing disorders (apnoea/hypopnoea index) seem to be the most important predictors. Continuous positive airway pressure therapy significantly reduces sleepiness in patients with OSA.
Assuntos
Distúrbios do Sono por Sonolência Excessiva/etiologia , Distúrbios do Sono por Sonolência Excessiva/fisiopatologia , Pulmão/fisiopatologia , Síndromes da Apneia do Sono/complicações , Síndromes da Apneia do Sono/fisiopatologia , HumanosRESUMO
Chronic opioid use has been known to cause disturbed sleep as well as excessive daytime sleepiness. During induction and maintenance of opioid use there is a reduction of REM- and slow wave sleep. Central sleep apnea (CSA) has been reported in about 30 % of patients with chronic opioid use. Ataxic breathing and CSA are more prominent in NREM- than REM-sleep. CSA does not seem the sole cause of excessive daytime sleepiness in these patients. Further studies are necessary regarding the effects and consequences of chronic opioid use during sleep.
Assuntos
Analgésicos Opioides/efeitos adversos , Dor/tratamento farmacológico , Apneia do Sono Tipo Central/induzido quimicamente , Analgésicos Opioides/administração & dosagem , Ritmo Circadiano/efeitos dos fármacos , Pressão Positiva Contínua nas Vias Aéreas , Distúrbios do Sono por Sonolência Excessiva/induzido quimicamente , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Humanos , Assistência de Longa Duração , Polissonografia , Apneia do Sono Tipo Central/diagnóstico , Apneia do Sono Tipo Central/terapiaRESUMO
An increasing proportion of the patients with chronic pain are being treated with opioids on a long-term basis. There are indications that the causes of hypersomnia in patients under chronic opioid therapy are primarily related to breathing disorders during sleep. Hence, we compared the polysomnographies of three hypersomnic patients receiving long-term opioid therapy before and during nocturnal non-invasive ventilatory therapy. Significant findings were a central breathing pattern accompanied by reduced deep and REM sleep. On applying non-invasive ventilatory therapy, there was a significant improvement of respiratory status with an increase of deep sleep as well as a moderate decrease in hypersomnia. In patients under chronic opioid therapy with hypersomnia, the presence of central breathing disorders should be considered.
