Original Articles
Copyright ©2009 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Mar 7, 2009; 15(9): 1065-1071
Published online Mar 7, 2009. doi: 10.3748/wjg.15.1065
Aminoguanidine impedes human pancreatic tumor growth and metastasis development in nude mice
Nora A Mohamad, Graciela P Cricco, Lorena A Sambuco, Máximo Croci, Vanina A Medina, Alicia S Gutiérrez, Rosa M Bergoc, Elena S Rivera, Gabriela A Martín
Nora A Mohamad, Graciela P Cricco, Lorena A Sambuco, Vanina A Medina, Alicia S Gutiérrez, Rosa M Bergoc, Elena S Rivera, Gabriela A Martín, Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 954 (C1113AAB), Buenos Aires, Argentina
Máximo Croci, Institute of Immunooncology Dr. Ernesto Crescenti, Av. Córdoba 3200 (C1187AAS), Buenos Aires, Argentina
Rosa M Bergoc, Gabriela A Martín, National Research Council (CONICET), Av. Rivadavia 1917 (C1033AAJ), Buenos Aires, Argentina
Author contributions: Mohamad NA and Gutiérrez AS performed the ex vivo experiments; Cricco GP and Sambuco LA performed the in vivo experiments; Bergoc RM and Croci M performed the microscopical observation; Cricco GP and Martín GA designed the study; Rivera ES and Medina VA were involved in editing the manuscript and in critical review; Martín GA and Rivera ES participated in acquisition of funding; Mohamad NA, Cricco GP and Martín GA analyzed the data and wrote the manuscript.
Correspondence to: Dr. Gabriela A Martín, Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 954 (C1113AAB), Buenos Aires, Argentina. gamartin@ffyb.uba.ar
Telephone: +54-11-49648277-34
Fax: +54-11-49648277-31
Received: September 20, 2008
Revised: January 17, 2009
Accepted: January 24, 2009
Published online: March 7, 2009
Abstract

AIM: To study the action of aminoguanidine on pancreatic cancer xenografts in relation to cell proliferation, apoptosis, redox status and vascularization.

METHODS: Xenografts of PANC-1 cells were developed in nude mice. The animals were separated into two groups: control and aminoguanidine treated. Tumor growth, survival and appearance of metastases were determined in vivo in both groups. Tumors were excised and ex vivo histochemical studies were performed. Cell growth was assessed by Ki-67 expression. Apoptosis was studied by intratumoral expression of B cell lymphoma-2 protein (Bcl-2) family proteins and Terminal deoxynucleotidyl transferase biotin-dUTP Nick End Labeling (Tunel). Redox status was evaluated by the expression of endothelial nitric oxide synthase (eNOS), catalase, copper-zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPx). Finally, vascularization was determined by Massons trichromic staining, and by VEGF and CD34 expression.

RESULTS: Tumor volumes after 32 d of treatment by aminoguanidine (AG) were significantly lower than in control mice (P < 0.01). Median survival of AG mice was significantly greater than control animals (P < 0.01). The appearance of both homolateral and contralateral palpable metastases was significantly delayed in AG group. Apoptotic cells, intratumoral vascularization (trichromic stain) and the expression of Ki-67, Bax, eNOS, CD34, VEGF, catalase, CuZnSOD and MnSOD were diminished in AG treated mice (P < 0.01), while the expression of Bcl-2 and GPx did not change.

CONCLUSION: The antitumoral action of aminoguanidine is associated with decreased cell proliferation, reduced angiogenesis, and reduced expression of antioxidant enzymes.

Keywords: Aminoguanidine; Pancreatic ductal carcinoma; Tumor growth; Metastasis; Apoptosis