Aminoguanidine impedes human pancreatic tumor growth and metastasis development in nude mice

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. C O N C L U S I O N :T h e a n t i t u m o r a l a c t i o n o f aminoguanidine is associated with decreased cell proliferation, reduced angiogenesis, and reduced expression of antioxidant enzymes.

Targeting eNOS in Pancreatic Cancer

“…Anecdotally, the one cell line not affected by L-NAME, PANC-1, was the only line with undetectable levels of activated eNOS (13). In agreement, N -nitro- l -arginine (L-NNA), an insoluble active metabolite of L-NAME, halved both subcutaneous and orthotopic xenograft tumor growth of the human PDAC cell line L3.6pl (41) and aminoguanidine, a broad NOS inhibitor with some specificity for iNOS, decreased tumor growth when given at high doses (42). …”

A multi-targeted approach to suppress tumor-promoting inflammation

“…It has been demonstrated that cancer-relevant mediators could include IL-1β [210], TNF-α [211], NF-κB [209] and STAT-1 [212], among others. In fact, NO blockage has reached promising results in experimental models, inhibiting tumor growth [213], prolonging survival [214], and reducing metastasis [215]. These data indicate that the pharmacological impairment of iNOS functioning may be useful in patients diagnosed with metastatic disease, since sustained high levels of systemic NO are reported in such patients [216–219].…”

COX-2 and survivin reduction may play a role in berberine-induced apoptosis in human ductal breast epithelial tumor cell line

“…To estimate the role of iNOS protein in berberineinduced apoptosis, the cells were treated with iNOS selective inhibitor, aminoguanidine (AG). Figure 3b showed that AG did not have a remarkable effect on T47D cell viability, whereas it has an inhibitory effect on some tumor cell growth [33]. Despite the no significant effect on cell vialbility, AG had a remarkable inhibitory effect on NO production (Fig.…”