RESUMO
The role of mast cells in tumor growth is still controversial. In this study we analyzed the effects of both histamine and pre-formed mediators spontaneously released by mast cells on the growth of two human hepatocellular carcinoma cell lines, HA22T/VGH and HuH-6, with different characteristics of differentiation, biological behavior and genetic defects. We showed that total mast cell releasate, exocytosed granules (granule remnants) and histamine reduced cell viability and proliferation in HuH-6 cells. In contrast, in HA22T/VGH cells granule remnants and histamine induced a weak but significant increase in cell growth. We showed that both cell lines expressed histamine receptors H1 and H2 and that the selective H1 antagonist terfenadine reverted the histamine-induced inhibition of HuH-6 cell growth, whereas the selective H2 antagonist ranitidine inhibited the histamine-induced cell growth of HA22T/VGH cells. We demonstrated that histamine down-regulated the expression of beta-catenin, COX-2 and survivin in HuH-6 cells and that this was associated with caspase-3 activation and PARP cleavage. On the contrary, in HA22T/VGH cells expression of survivin and beta-catenin increased after treatment with granule remnants and histamine. Overall, our results suggest that mediators stored in mast cell granules and histamine may affect the growth of liver cancer cells. However, mast cells and histamine may play different roles depending on the tumor cell features. Finally, these data suggest that histamine and histamine receptor agonists/antagonists might be considered as "new therapeutic" drugs to inhibit liver tumor growth.
Assuntos
Animais , Feminino , Humanos , Ratos , Apoptose , Carcinoma Hepatocelular/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Ativação Enzimática , Exocitose , Histamina/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Neoplasias Hepáticas/metabolismo , Mastócitos/fisiologia , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Neoplasias/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Ranitidina/farmacologia , Ratos Wistar , Receptores Histamínicos/metabolismo , Terfenadina/farmacologia , beta Catenina/metabolismoAssuntos
Animais , Sistema Nervoso Central/metabolismo , Humanos , Mamíferos/metabolismo , Receptores Adrenérgicos/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores Colinérgicos/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de GABA-A/metabolismo , Receptores Histamínicos/metabolismo , Receptores Opioides/metabolismo , Receptores Purinérgicos/metabolismo , Receptores de Serotonina/metabolismoAssuntos
Animais , Função Atrial , Feminino , Cobaias , Coração/fisiologia , Átrios do Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Indóis/farmacologia , Masculino , Metiamida/farmacologia , Pirazinas/farmacologia , Receptores Histamínicos/metabolismo , Receptores Histamínicos H2/metabolismo , Relação Estrutura-AtividadeAssuntos
Animais , Pressão Sanguínea/efeitos dos fármacos , Gatos , Avaliação Pré-Clínica de Medicamentos , Feminino , Suco Gástrico/efeitos dos fármacos , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Indóis/farmacologia , Masculino , Pirazinas/farmacologia , Coelhos , Ratos , Receptores Histamínicos/metabolismo , Receptores Histamínicos H2/efeitos dos fármacos , Úlcera/tratamento farmacológicoRESUMO
Intracerebroventricular administration of adrenaline, noradrenaline phenylephrine, clonidine and histamine produced a significant rise in plasma cortisol concentration whereas isoprenaline had no effect. alpha-Adrenoceptor blockers (yohimbine or piperoxon) per se did not alter the plasma cortisol level. Central pretreatment with yohimbine or piperoxin, blocked the rise in plasma cortisol level induced by icv noradrenaline, phenylephrine and clonidine. In another set of experiments, both H1 and H2 receptor antagonists (mepyramine, and metiamide) per se had not significant effect on plasma cortisol concentration. Central histamine induced rise in plasma cortisol concentration was significantly blocked by icv pretreatment with both H1 and H2 receptor blockers. Furthermore, yohimbine also significantly prevented the rise of plasma cortisol level induced by icv histamine.