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1.
Nature ; 539(7630): 555-559, 2016 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-27828947

RESUMO

Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB1) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB1 receptors. Genetic exclusion of CB1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB1 receptors signal through intra-mitochondrial Gαi protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.


Assuntos
Canabinoides/efeitos adversos , Transtornos da Memória/induzido quimicamente , Memória/efeitos dos fármacos , Memória/fisiologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Adenilil Ciclases/metabolismo , Animais , Canabinoides/metabolismo , Respiração Celular/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Transporte de Elétrons/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Transtornos da Memória/enzimologia , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Camundongos , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/enzimologia , Membranas Mitocondriais/metabolismo , NADH Desidrogenase/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Receptor CB1 de Canabinoide/deficiência , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
2.
Cancer Biol Ther ; 17(8): 849-58, 2016 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-26392056

RESUMO

Some compounds of a series of novel pyrrolo-1,5-benzoxa(thia)zepine, a well-known group of tubulin targeting agents, display anti-tumor effects mainly inducing cell cycle arrest and apoptosis in several human cancer models. A member of this family, pyrrolo-1,5-benzoxazepine-15 (PBOX-15), has previously shown potent pro-apoptotic activity in a variety of human tumor cell types, with minimal toxicity toward normal blood and bone marrow cells. In this study, we evaluated the PBOX-15-mediated effects in human colorectal cancer cell (CRC) lines, DLD-1 and HT-29. The compound, used at concentrations equal to or greater than 1 µM, inhibited the proliferation of human CRC cells, inducing a significant cell cycle arrest in the G2/M phase. In DLD-1 cells, treatments prolonged over 48 h triggered a strong activation of the intrinsic apoptotic pathway as indicated by activation of caspase-9, caspase-3 and PARP cleavage. Moreover, nanomolar concentrations of PBOX-15, significantly improved the oxaliplatin and 5-fluouracil-induced anti-proliferative effects in DLD1 cell line. The observed synergistic interaction of both PBOX-15/Oxaliplatin and PBOX-15/5FU may involve activation of p38 MAPK and JNK pathway, which in turn significantly increased caspase-3 cleavage in DLD-1 cells, treated with PBOX-5/Oxaliplatin but not with PBOX-15/5FU. Moreover, PBOX-15/5FU-treated cells showed an increase in expression of the pro-apoptotic protein Bax. Taken together, these results show that PBOX-15 could represent a promising compound for the treatment of human CRC and a strong candidate for novel therapeutic options.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/farmacologia , Compostos Organoplatínicos/farmacologia , Oxazepinas/farmacologia , Pirróis/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/patologia , Sinergismo Farmacológico , Fluoruracila/administração & dosagem , Células HT29 , Humanos , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Oxazepinas/administração & dosagem , Pirróis/administração & dosagem
3.
Oncotarget ; 6(17): 15464-81, 2015 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-26008966

RESUMO

Herein we show that a majority of human brain tumor samples and cell lines over-expressed cannabinoid receptor CB1 as compared to normal human astrocytes (NHA), while uniformly expressed low levels of CB2. This finding prompted us to investigate the therapeutic exploitation of CB1 inactivation by SR141716 treatment, with regard to its direct and indirect cell-mediated effects against gliomas. Functional studies, using U251MG glioma cells and primary tumor cell lines derived from glioma patients expressing different levels of CB1, highlighted SR141716 efficacy in inducing apoptosis via G1 phase stasis and block of TGF-ß1 secretion through a mechanism that involves STAT3 inhibition. According to the multivariate role of STAT3 in the immune escape too, interestingly SR141716 lead also to the functional and selective expression of MICA/B on the surface of responsive malignant glioma cells, but not on NHA. This makes SR141716 treated-glioma cells potent targets for allogeneic NK cell-mediated recognition through a NKG2D restricted mechanism, thus priming them for NK cell antitumor reactivity. These results indicate that CB1 and STAT3 participate in a new oncogenic network in the complex biology of glioma and their expression levels in patients dictate the efficacy of the CB1 antagonist SR141716 in multimodal glioma destruction.


Assuntos
Apoptose/efeitos dos fármacos , Glioma/tratamento farmacológico , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Astrócitos/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Glioma/imunologia , Glioma/patologia , Antígenos de Histocompatibilidade Classe I/biossíntese , Humanos , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Nus , Interferência de RNA , RNA Interferente Pequeno , Receptor CB1 de Canabinoide/biossíntese , Receptor CB1 de Canabinoide/genética , Rimonabanto , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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