Histamine Regulates Pancreatic Carcinoma Cell Growth.Through H1, H2, H3 And H4 Receptors.

GRACIELA P CRICCO; NORA A MOHAMAD; LORENA A SAMBUCO; FERNANDA GENRE; MAXIMO CROCI; ALICIA S GUTIÉRREZ; VANINA A MEDINA; ROSA M BERGOC; ELENA S RIVERA E; GABRIELA A MARTÍN

Mayo 9-12, 2007, Florencia, Italia.

Congreso; European Histamine Research Society, XXXVI Annual Meeting.; 2007

HISTAMINE REGULATES PANCREATIC CARCINOMA CELL GROWTH.THROUGH H1, H2, H3 AND H4 RECEPTORS. Graciela P Cricco, Nora A Mohamad, Lorena A Sambuco, Fernanda Genre, Maximo Croci, Alicia S Gutiérrez, Vanina A Medina, Rosa M Bergoc, Elena S Rivera, Gabriela A Martín. Radioisotopes Laboratory, School of Pharmacy and Biochemistry, University of Buenos Aires. Buenos Aires, 1113, Argentina. Panc-1 is a cell line derived from a human ductal pancreatic carcinoma. We have previously reported that histamine (HA) H1 and H2 receptors are expressed in these cells. Nanomolar HA doses stimulate cell proliferation while micromolar concentrations inhibit clonogenic growth.This inhibition is mediated by H1 and H2 receptors. We have also found out that intracellular levels of nitric oxide (NO) modulates PANC-1 cells proliferation and that the antiproliferative effect exerted by HA may be mediated by NO levels. In the present work we evaluated the presence of H3 and H4 receptors in PANC-1 cells and the action of HA on the growth of pancreatic carcinoma xenografts in nude mice. The expression of H3 and H4 receptors was demonstrated by immunoblotting and immunocitochemistry. Both receptors showed to be involved in cell proliferation when the respective agonists/antagonists were tested, being cell growth increased through H3 receptors and diminished by H4 receptors. Nude mice were sc inoculated with 3x106 PANC-1 cells. When tumor volume reached 65 mm3, animals received the following treatments during 25 days: HA (1mg/kg day, sc), aminoguanidine, a NO synthase inhibitor, (AG, po 2 or 4 mg/ml daily in drinking water), ranitidine (50 mg/kg day, po) or loratadine (Lor, 2.5 mg/ kg day, po). Tumor growth was significantly increased in HA and Lor treated animals while it was decreased in AG treated mice. The tumor expression of Bcl-2 family members determined by immunohistochemistry showed that Bcl-2/Bax ratio is enhanced by HA, Lor, and AG. Tumor vascularization assessment by Masson trichromic stain was augmented by HA but decreased by AG. In addition, immunohistochemical evaluation indicated that intratumoral levels of HA were higher in faster growing tumors In summary, HA stimulates pancreatic tumor cell proliferation in vivo exerting a direct antiapoptotic action. This effect on tumor growth is associated to an increased tumor synthesis of HA and to an angiogenic action. POSTER PRESENTATION