Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
Cell ; 171(2): 273-285, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28985560

RESUMO

Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.


Assuntos
Morte Celular , Animais , Apoptose , Humanos , Ferro/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
3.
Oncotarget ; 7(51): 84675-84687, 2016 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-27835869

RESUMO

Inhibitors targeting epigenetic control points of oncogenes offer a potential mean of blocking tumor progression in small cell and non-small cell lung carcinomas (SCLC, NSCLC). OTX015 (MK-8628) is a BET inhibitor selectively blocking BRD2/3/4. OTX015 was evaluated in a panel of NSCLC or SCLC models harboring different oncogenic mutations. Cell proliferation inhibition and cell cycle arrest were seen in sensitive NSCLC cells. MYC and MYCN were downregulated at both the mRNA and protein levels. In addition, OTX015-treatment significantly downregulated various stemness cell markers, including NANOG, Musashi-1, CD113 and EpCAM in H3122-tumors in vivo. Conversely, in SCLC models, weak antitumor activity was observed with OTX015, both in vitro and in vivo. No predictive biomarkers of OTX015 activity were identified in a large panel of candidate genes known to be affected by BET inhibition. In NSCLC models, OTX015 was equally active in both EML4-ALK positive and negative cell lines, whereas in SCLC models the presence of functional RB1 protein, which controls cell progression at G1, may be related to the final biological outcome of OTX015. Gene expression profiling in NSCLC and SCLC cell lines showed that OTX015 affects important genes and pathways with a very high overlapping between both sensitive and resistant cell lines. These data support the rationale for the OTX015 Phase Ib (NCT02259114) in solid tumors, where NSCLC patients with rearranged ALK gene or KRAS-positive mutations are currently being treated.


Assuntos
Acetanilidas/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Quinase do Linfoma Anaplásico , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Camundongos , Camundongos Nus , Mutação/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Carcinoma de Pequenas Células do Pulmão/genética , Fatores de Transcrição , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Int J Cancer ; 139(9): 2047-55, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27388964

RESUMO

Bromodomain and extraterminal (BET) bromodomain (BRD) proteins are epigenetic readers that bind to acetylated lysine residues on chromatin, acting as co-activators or co-repressors of gene expression. BRD2 and BRD4, members of the BET family, are significantly increased in glioblastoma multiforme (GBM), the most common primary adult brain cancer. OTX015 (MK-8628), a novel BRD2/3/4 inhibitor, is under evaluation in dose-finding studies in solid tumors, including GBM. We investigated the pharmacologic characteristics of OTX015 as a single agent and combined with targeted therapy or conventional chemotherapies in glioblastoma cell lines. OTX015 displayed higher antiproliferative effects compared to its analog JQ1, with GI50 values of approximately 0.2 µM. In addition, C-MYC and CDKN1A mRNA levels increased transiently after 4 h-exposure to OTX015, while BRD2, SESN3, HEXIM-1, HIST2H2BE, and HIST1H2BK were rapidly upregulated and sustained after 24 h. Studies in three additional GBM cell lines supported the antiproliferative effects of OTX015. In U87MG cells, OTX015 showed synergistic to additive activity when administered concomitant to or before SN38, temozolomide or everolimus. Single agent oral OTX015 significantly increased survival in mice bearing orthotopic or heterotopic U87MG xenografts. OTX015 combined simultaneously with temozolomide improved mice survival over either single agent. The passage of OTX015 across the blood-brain barrier was demonstrated with OTX015 tumor levels 7 to 15-fold higher than in normal tissues, along with preferential binding of OTX015 to tumor tissue. The significant antitumor effects seen with OTX015 in GBM xenograft models highlight its therapeutic potential in GBM patients, alone or combined with conventional chemotherapies.


Assuntos
Acetanilidas/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Acetanilidas/farmacologia , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Sinergismo Farmacológico , Everolimo/administração & dosagem , Everolimo/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Irinotecano , Camundongos , Temozolomida , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cancer Chemother Pharmacol ; 72(4): 879-87, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23978989

RESUMO

PURPOSE: OTX008 is a galectin-1-targeting compound, currently undergoing a phase I clinical trial. This study aimed at investigating OTX008 pharmacokinetics (PK) and antineoplastic activity. METHODS: Pharmacokinetics and activity of OTX008 were analyzed in the human ovarian carcinoma A2780-1A9 and glioblastoma U87MG xenografted in nude mice. In vitro, OTX008 was tested on tumor and endothelial cells. RESULTS: After 5 mg/kg i.v., OTX008 achieved plasma Cmax of 14.39 µg/mL, distributed rapidly, and was eliminated with a half-life of 31.4 h. Tumor OTX008 Cmax (1.65 µg/g, 1.76 µM), achieved at 0.5 h, remained high at 24 h (0.516 µg/g, 0.55 µM) with AUC of 15.76 µg/g*h. OTX008 accumulated in the tumor after repeated administrations achieving a concentration of 2.3 µM, compatible with the concentrations active in vitro. OTX008 (5 mg/kg i.v., every other day for 3 weeks) inhibited the in vivo growth of A2780-1A9, whereas U87MG was not sensitive. In vitro, OTX008 affected endothelial cell proliferation, motility, invasiveness, and cord formation. Tumor cell proliferation was also inhibited, with differences in sensitivity among cell lines (IC50 from 1 to 190 µM). OTX008 potentiated the activity of the tyrosine kinase inhibitor sunitinib on A2780-1A9 in vivo and in vitro, where the combination showed synergistic (endothelial cells) and additive (A2780-1A9) antiproliferative activity, indicating that the combination targets both the tumor and vascular compartments. CONCLUSIONS: OTX008-alone or in combination with sunitinib-has a favorable PK and antineoplastic activity on selected tumor models through the effects on both endothelial and tumor cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Calixarenos/farmacologia , Galectina 1/metabolismo , Glioblastoma/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Calixarenos/administração & dosagem , Calixarenos/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Glioblastoma/patologia , Meia-Vida , Humanos , Indóis/administração & dosagem , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , Neoplasias Ovarianas/patologia , Pirróis/administração & dosagem , Sunitinibe , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Mol Genet Metab ; 92(1-2): 63-70, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17591452

RESUMO

Blood phenylalanine (Phe) levels provide a practical and reliable method for the diagnosis and monitoring of metabolic status in patients with phenylketonuria (PKU). To assess the reliability of blood Phe levels as a predictive biomarker of clinical outcomes in the development of treatments for PKU, a systematic literature review and meta-analysis of published trials of PKU, which included Phe level and neurological and dietary compliance outcome measures, was conducted. Within-study correlations between Phe level and intelligence quotient (IQ) were extracted from 40 studies. Significant, proportional correlations were found during critical periods (from 0 to 12 years of age) for early-treated patients with PKU (r=-0.35; 95% confidence interval [CI]: -0.44 to -0.27), where each 100 micromol/l increase in Phe predicted a 1.3- to 3.1-point reduction in IQ. Similar significant correlations were observed between IQ and mean lifetime Phe level for early-treated patients (r=0.34; 95% CI: -0.42 to -0.25), where each 100 micromol/l increase in Phe predicted a 1.9- to 4.1-point reduction in IQ. Moderate correlations were found between concurrent Phe level and IQ for early-treated patients. In conclusion, these results confirm a significant correlation between blood Phe level and IQ in patients with PKU, and support the use of Phe as a predictive biomarker for IQ in clinical trials.


Assuntos
Fenilalanina/sangue , Fenilcetonúrias/sangue , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...