RESUMO
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as an attractive cytokine that selectively targets cancer cells, however its efficacy has been challenged by a number of resistance mechanisms. Therefore, the current study investigated the potential of dipyridamole to enhance TRAIL efficacy and the probable underlying mechanisms. Dipyridamole dramatically sensitized p53-mutant human cancer cell lines: SW480, MG63 and DU145, to the antitumor activity of TRAIL, as evidenced by enabling TRAIL to efficiently cleave initiator and executioner caspases. Although dipyridamole upregulated both DR4 and DR5 and increased their cell surface expression, RNA interference revealed a preferential dependence on DR5. Moreover, dipyridamole inhibited survivin expression and its important consequences were confirmed by small interfering RNA. Mechanistically, dipyridamole induced transcriptional shutdown of survivin expression accompanying G(1) arrest that was characterized by downregulation of D-type cyclins and cdk6. In addition, a transcriptional mechanism powered by CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) induction was responsible for DR5 upregulation by dipyridamole. Importantly, dipyridamole-induced enhancement of TRAIL efficacy and alterations of protein expression were independent of either protein kinase A or protein kinase G. In conclusion, findings of the present study described novel mechanisms of dipyridamole action and highlighted its promising use as a potential enhancer of TRAIL efficacy.
Assuntos
Apoptose/efeitos dos fármacos , Dipiridamol/farmacologia , Fase G1/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Fosfodiesterase/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Apoptose/fisiologia , Northern Blotting , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Fase G1/fisiologia , Humanos , Immunoblotting , Proteínas Inibidoras de Apoptose , Luciferases/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/farmacologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/antagonistas & inibidores , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Survivina , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Hepatic hemangioma is the most common benign tumor of the liver, but there are a few reports on chronological changes in size of hepatic hemangioma. To elucidate natural history of hepatic hemangioma, we evaluated consecutive ultrasonograms of 27 hemangiomas in 23 patients. Underlying liver disease in these 23 patients included seven cases with chronic hepatitis, five cases with liver cirrhosis and three cases with fatty liver. The remaining eight cases showed no evidence of liver disease. Follow-up period ranged 12 to 114 months (average 44). During the follow-up, six (22.2%) hemangiomas changed in size on US, which included three lesions with increase in size, one lesion with decrease in size and two lesions with spontaneous regression. Of 12 patients with chronic liver disease, only one patient showed significant change in the hemangioma size, which regressed spontaneously. These results showed that there was no case showing increase in size of hemangioma in patients with chronic liver disease. Thus, if clinically diagnosed hemangioma which tends to increase in size is detected on US or other imaging modalities in patients with chronic liver disease, aimed aspiration biopsy should be preferably performed considering the possibility of hepatocellular carcinoma.
Assuntos
Hemangioma , Neoplasias Hepáticas , Adulto , Feminino , Seguimentos , Hemangioma/diagnóstico por imagem , Hemangioma/patologia , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , UltrassonografiaRESUMO
1. Pregnant rats were exposed to hydrocortisone in a dose of 10 mg/kg on days 9-11 or days 13-15 of gestation. The offsprings born to these mothers were observed for their behavioral development and the response to kainic acid during the infantile period. The response to kainic acid was assessed by the frequency of wet-dog shakes behavior and limbic seizures. 2. The growth rate in the infantile offspring of the 13-15dHc-F1 group showed a slight but significant decrease. 3. All the 13-15dHc-F1 rats exhibited the rearing activity in an open-field at 17 days of age, earlier than in the controls. 4. The ambulatory activity in the 9-11dHc-F1 rats showed a significant decrease at 15 and 17 days of age, whereas no change was shown in the 9-11dHc-F1 rats. 5. The frequency of the wet-dog shakes during the 60 minutes observation after the s.c. injection of 9 mg/kg kainic acid was significantly low in both the 9-11dHc-F1 and 13-15dHc-F1 groups as compared with that in the controls when tested at 25 days of age. The decrease in the response to kainic acid was slightly greater in the 9-11dHC-F1 rats. 6. The frequency of seizures with forelimb clonus and rearing during the 60 minutes observation in the 13-15dHc-F1 was less than that in the controls, whereas no significant difference in the frequency of seizures between the 9-11dHc-F1 and paired control groups was noted. 7. The second generation rats raised from the 9-11dHc-F1 rats by brother-sister mating showed a decrease in the frequency in the kainic acid-induced wet-dog shakes as shown in the F1 offspring. No change in the response to kainic acid was shown in the 13-15dHc-F2 rats.
