RESUMEN
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.
Asunto(s)
Animales , Femenino , Humanos , Ratas , Apoptosis , Carcinoma Hepatocelular/metabolismo , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Ciclooxigenasa 2/metabolismo , Activación Enzimática , Exocitosis , Histamina/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Neoplasias Hepáticas/metabolismo , Mastocitos/fisiología , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas de Neoplasias/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Ranitidina/farmacología , Ratas Wistar , Receptores Histamínicos/metabolismo , Terfenadina/farmacología , beta Catenina/metabolismoAsunto(s)
Animales , Sistema Nervioso Central/metabolismo , Humanos , Mamíferos/metabolismo , Receptores Adrenérgicos/metabolismo , Receptores de Superficie 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/metabolismoAsunto(s)
Animales , Función Atrial , Femenino , Cobayas , Corazón/fisiología , Atrios Cardíacos/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Indoles/farmacología , Masculino , Metiamida/farmacología , Pirazinas/farmacología , Receptores Histamínicos/metabolismo , Receptores Histamínicos H2/metabolismo , Relación Estructura-ActividadAsunto(s)
Animales , Presión Sanguínea/efectos de los fármacos , Gatos , Evaluación Preclínica de Medicamentos , Femenino , Jugo Gástrico/efectos de los fármacos , Cobayas , Frecuencia Cardíaca/efectos de los fármacos , Indoles/farmacología , Masculino , Pirazinas/farmacología , Conejos , Ratas , Receptores Histamínicos/metabolismo , Receptores Histamínicos H2/efectos de los fármacos , Úlcera/tratamiento farmacológicoRESUMEN
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.