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1.
Acta Pharmacol Sin ; 40(7): 938-948, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30560903

RESUMO

L-Carnosine (ß-alanyl-L-histidine) is a naturally occurring dipeptide distributed in various organs of mammalians. We previously showed that carnosine inhibited proliferation of human gastric cancer cells through targeting both mitochondrial bioenergetics and glycolysis pathway. But the mechanism underlying carnosine action on mitochondrial bioenergetics of tumor cells remains unclear. In the current study we investigated the effect of carnosine on the growth of human gastric cancer SGC-7901 cells in vitro and in vivo. We firstly showed that hydrolysis of carnosine was not a prerequisite for its anti-gastric cancer effect. Treatment of SGC-7901 cells with carnosine (20 mmol/L) significantly decreased the activities of mitochondrial respiratory chain complexes I-IV and mitochondrial ATP production, and downregulated 13 proteins involved in mitochondrial bioenergetics. Furthermore, carnosine treatment significantly suppressed the phosphorylation of Akt, while inhibition of Akt activation with GSK690693 significantly reduced the localization of prohibitin-1 (PHB-1) in the mitochondria of SGC-7901 and BGC-823 cells. In addition, we showed that silencing of PHB-1 gene with shRNA markedly reduced the mitochondrial PHB-1 in SGC-7901 cells, and significantly decreased the colony formation capacity and growth rate of the cells. In SGC-7901 cell xenograft nude mice, administration of carnosine (250 mg kg/d, ip, for 3 weeks) significantly inhibited the tumor growth and decreased the expression of mitochondrial PHB-1 in tumor tissue. Taken together, these results suggest that carnosine may act on multiple mitochondrial proteins to down-regulate mitochondrial bioenergetics and then to inhibit the growth and proliferation of SGC-7901 and BGC-823 cells.


Assuntos
Antineoplásicos/uso terapêutico , Carnosina/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Carnosina/farmacologia , Linhagem Celular Tumoral , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Humanos , Camundongos Nus , Proteínas Mitocondriais/metabolismo , Proibitinas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Repressoras/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Integr Cancer Ther ; 17(1): 80-91, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28008780

RESUMO

Carnosine has been demonstrated to play an antitumorigenic role in certain types of cancer. However, its underlying mechanism is unclear. In this study, the roles of carnosine in cell proliferation and its underlying mechanism were investigated in the cultured human cervical gland carcinoma cells HeLa and cervical squamous carcinoma cells SiHa. The results showed that carnosine exerted a significant inhibitory effect on the proliferation of HeLa cells, whereas its inhibitory action on the proliferation of SiHa cells was much weaker. Carnosine decreased the ATP content through inhibiting both mitochondrial respiration and glycolysis pathways in cultured HeLa cells but not SiHa cells. Carnosine reduced the activities of isocitrate dehydrogenase and malate dehydrogenase in TCA (tricarboxylic acid) cycle and the activities of mitochondrial electron transport chain complex I, II, III, and IV in HeLa cells but not SiHa cells. Carnosine also decreased the mRNA and protein expression levels of ClpP, which plays a key role in maintaining the mitochondrial function in HeLa cells. In addition, carnosine induced G1 arrest by inhibiting the G1-S phase transition in both HeLa and SiHa cells. Taken together, these findings suggest that carnosine has a strong inhibitory action on the proliferation of human cervical gland carcinoma cells rather than cervical squamous carcinoma cells. Mitochondrial bioenergetics and glycolysis pathways and cell cycle may be involved in the carnosine action on the cell proliferation in cultured human cervical gland carcinoma cells HeLa.


Assuntos
Antineoplásicos/farmacologia , Carnosina/farmacologia , Ciclo Celular/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias do Colo do Útero/metabolismo , Apoptose/efeitos dos fármacos , Ciclo Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Feminino , Glicólise/efeitos dos fármacos , Glicólise/fisiologia , Células HeLa/efeitos dos fármacos , Células HeLa/metabolismo , Células HeLa/patologia , Células HeLa/fisiologia , Humanos , Mitocôndrias/efeitos dos fármacos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/fisiopatologia
3.
Brain Res Bull ; 124: 76-84, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27040711

RESUMO

Previously, we showed that carnosine upregulated the expression level of glutamate transporter 1 (GLT-1), which has been recognized as an important participant in the astrocyte-neuron lactate shuttle (ANLS), with ischemic model in vitro and in vivo. This study was designed to investigate the protective effect of carnosine on neuron/astrocyte co-cultures exposed to OGD/recovery, and to explore whether the ANLS or any other mechanism contributes to carnosine-induced neuroprotection on neuron/astrocyte. Co-cultures were treated with carnosine and exposed to OGD/recovery. Cell death and the extracellular levels of glutamate and GABA were measured. The mitochondrial respiration and glycolysis were detected by Seahorse Bioscience XF96 Extracellular Flux Analyzer. Results showed that carnosine decreased neuronal cell death, increased extracellular GABA level, and abolished the increase in extracellular glutamate and reversed the mitochondrial energy metabolism disorder induced by OGD/recovery. Carnosine also upregulated the mRNA level of neuronal glutamate transporter EAAC1 at 2h after OGD. Dihydrokainate, a specific inhibitor of GLT-1, decreased glycolysis but it did not affect mitochondrial respiration of the cells, and it could not reverse the increase in mitochondrial OXPHOS induced by carnosine in the co-cultures. The levels of mRNAs for monocarboxylate transporter1, 4 (MCT1, 4), which were expressed in astrocytes, and MCT2, the main neuronal MCT, were significantly increased at the early stage of recovery. Carnosine only partly reversed the increased expression of astrocytic MCT1 and MCT4. These results suggest that regulating astrocytic energy metabolism and extracellular glutamate and GABA levels but not the ANLS are involved in the carnosine-induced neuroprotection.


Assuntos
Astrócitos/efeitos dos fármacos , Carnosina/farmacologia , Hipóxia Celular/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Morte Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Técnicas de Cocultura , Glucose/deficiência , Ácido Glutâmico/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/fisiologia , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
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