RESUMO
Prostate cancer (PC) is the most diagnosed tumor in males and ranks as the second leading cause of male mortality in the western world. The CD39 and CD73 enzymes play a crucial role in cancer regulation by degrading nucleotides and forming nucleosides. This study aimed to investigate the expression of the CD39 and CD73 enzymes as potential therapeutic targets for PC. The initial part of this study retrospectively analyzed tissue samples from 23 PC patients. Using the TissueFAXSTM cytometry platform, we found significantly higher levels of CD39-labeling its intensity compared to CD73. Additionally, we observed a correlation between the Gleason score and the intensity of CD39 expression. In the prospective arm, blood samples were collected from 25 patients at the time of diagnosis and after six months of treatment to determine the expression of CD39 and CD73 in the serum extracellular vesicles (EVs) and to analyze nucleotide hydrolysis. Notably, the expression of CD39 in the EVs was significantly increased compared to the CD73 and/or combined CD39/CD73 expression levels at initial collection. Furthermore, our results demonstrated positive correlations between ADP hydrolysis and the transurethral resection and Gleason score. Understanding the role of ectonucleotidases is crucial for identifying new biomarkers in PC.
RESUMO
Depression is one of the most disabling diseases and causes a significant burden to both individual and society. Selective serotonin reuptake inhibitors and tricyclic antidepressants, such as fluoxetine and nortriptyline, respectively, are commonly used in treatment for depression. These antidepressants were tested on cerebral cortex and hippocampal synaptosomes after acute and chronic in vivo and in vitro treatments. In chronic treatment, fluoxetine and nortriptyline decreased ATP hydrolysis (17.8% and 16.3%, respectively) in hippocampus. In cerebral cortex, nortriptyline increased ATP (32.3%), ADP (51.8%), and AMP (59.5%) hydrolysis. However, fluoxetine decreased ATP (25.5%) hydrolysis and increased ADP (80.1%) and AMP (33.3%) hydrolysis. Significant activation of ADP hydrolysis was also observed in acute treatment with nortriptyline (49.8%) in cerebral cortex. However, in hippocampus, ATP (24.7%) and ADP (46.1%) hydrolysis were inhibited. Fluoxetine did not alter enzyme activities in acute treatment for both structures. In addition, there were significant changes in NTPDase activities when fluoxetine and nortriptyline (100, 250, and 500 microM) were tested in vitro. There was no inhibitory effect of fluoxetine and nortriptyline on AMP hydrolysis in cerebral cortex and hippocampus. The findings showed that these antidepressant drugs can affect the ecto-nucleotidase pathway, suggesting that the extracellular adenosine levels could be modulated by these drugs.
Assuntos
Adenosina Trifosfatases/metabolismo , Antidepressivos de Segunda Geração/farmacologia , Antidepressivos Tricíclicos/farmacologia , Fluoxetina/farmacologia , Nortriptilina/farmacologia , Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Isoenzimas/metabolismo , Masculino , Norepinefrina/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serotonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismoRESUMO
Depression is a serious condition associated with considerable morbidity and mortality. Selective serotonin reuptake inhibitors and tricyclic antidepressants, such as fluoxetine and nortriptyline, respectively, were commonly used in treatment for depression. Selective serotonin reuptake inhibitors have been associated with increased risk of bleeding complications, possibly as a result of inhibition of platelet aggregation. ATP, ADP and adenosine are signaling molecules in the vascular system and nucleotidases activities are considered an important thromboregulatory system which functions in the maintenance of blood fluidity. Therefore, here we investigate the effect of in vivo (acute and chronic) and in vitro treatments with the antidepressant drugs on nucleotidases activities in rat blood serum. In acute treatment, nortriptyline decreased ATP hydrolysis (41%), but not altered ADP and AMP hydrolysis. In contrast, fluoxetine did not alter NTPDase and ecto-5'-nucleotidase activities. A significant inhibition of ATP, ADP, and AMP hydrolysis were observed in chronic treatment with fluoxetine (60%, 32%, and 42% for ATP, ADP, and AMP hydrolysis, respectively). Similar effects were shown in chronic treatment with nortriptyline (37%, 41%, and 30% for ATP, ADP, and AMP hydrolysis, respectively). In addition, there were no significant changes in NTPDase and ecto-5'-nucleotidase activities when fluoxetine and nortriptyline (100, 250, and 500 microM) were tested in vitro. Our results have shown that fluoxetine and nortriptyline changed the nucleotide catabolism, suggesting that homeostasis of vascular system can be altered by antidepressant treatments.
Assuntos
5'-Nucleotidase/sangue , Antidepressivos/farmacologia , Fluoxetina/farmacologia , Nortriptilina/farmacologia , Nucleosídeo-Trifosfatase/sangue , 5'-Nucleotidase/metabolismo , Animais , Antidepressivos/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fluoxetina/administração & dosagem , Masculino , Nortriptilina/administração & dosagem , Nucleosídeo-Trifosfatase/metabolismo , Ratos , Ratos WistarRESUMO
The effects of sertraline, a selective serotonin reuptake inhibitor, and clomipramine, a tricyclic antidepressant, were tested on ecto-nucleotidases from synaptosomes of cerebral cortex and hippocampus of rats. Sertraline and clomipramine (100-500 microM) inhibited NTPDase, but not ecto-5'-nucleotidase activity in both cerebral cortex and hippocampus. In cortical synaptosomes, sertraline inhibited both ATP and ADP hydrolysis in the concentrations tested. The inhibitory effect varied from 21% to 83% for ATP hydrolysis and 48% to 75% for ADP hydrolysis. The inhibition promoted by sertraline in hippocampal synaptosomes varied from 38% to 89% for ATP hydrolysis and 45% to 77% for ADP hydrolysis. A significant inhibition of cortical NTPDase activity by clomipramine was observed in the all concentrations tested (35-72% and 36-87% for ATP and ADP hydrolysis, respectively). Similar effects were observed in hippocampus (29-91% and 48-83% for ATP and ADP hydrolysis, respectively). There was no inhibitory effect of sertraline and clomipramine on AMP hydrolysis in cerebral cortex and hippocampus. Our results have shown that classical antidepressants inhibit the extracellular catabolism of ATP. Therefore, it is possible to suggest that changes induced by antidepressants on bilayer membrane could affect NTPDase activities and consequently, modulating ATP and adenosine levels in the synaptic cleft.
Assuntos
Antidepressivos Tricíclicos/farmacologia , Antidepressivos/farmacologia , Clomipramina/farmacologia , Nucleosídeos/metabolismo , Sertralina/farmacologia , 5'-Nucleotidase/metabolismo , Difosfato de Adenosina/metabolismo , Monofosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/enzimologia , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Masculino , Proteínas do Tecido Nervoso/biossíntese , Ratos , Ratos Wistar , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/enzimologiaRESUMO
ATP and adenosine may play a role in the mechanisms of synaptic plasticity and memory formation. Previous studies have shown that ecto-nucleotidase activities are altered during memory consolidation of an aversive task named step-down inhibitory avoidance. Here we investigate ecto-nucleotidase activities in hippocampal synaptosomes of rats submitted to training and test sessions of habituation to open field, which is one of the most elementary forms of learning. There were no significant alterations on ATP, ADP and AMP hydrolysis immediately after the training session. However, immediately after the test session (0min), there was a significant increase of ATP hydrolysis (61%), but not of ADP and AMP hydrolysis. Sixty minutes after the test session, a significant increase of NTPDase (75% and 60.5% for ATP and ADP hydrolysis, respectively) and ecto-5'-nucleotidase (40%) activities was observed. This study reveals the involvement of ecto-nucleotidase activities in different learning paradigms during memory processing.