Antiproliferative and antimetastatic activity of a novel vasopressin V2 receptor peptide agonist in a breast cancer model

GV RIPOLL; J GARONA; N IANNUCCI; U ORLANDO; O CASCONE; E PODESTA; DE GOMEZ; DF ALONSO

Congreso; Annual Meeting 2010 AACR; 2010

AACR

Desmopressin (1-deamino-8-D-arginine vasopressin) is a synthetic analog of the antidiuretic hormone vasopressin. The compound acts as a selective agonist for the vasopressin V2 membrane receptor, which is expressed in the kidney collecting duct, endothelium and also in some tumor cells, including breast cancer cells. It is known that desmopressin causes endogenous release of coagulation factor VIII, von Willebrand factor and tissue-type plasminogen activator, as a result of a V2 receptor-mediated mechanism. Peptide sequence of desmopressin includes 9 aminoacid residues, having a disulfide bridge between positions 1 and 6. Upon homocysteine deamination in position 1 the biological effect is prolonged and substitution of  L-arginine for D-arginine in position 8 decreases the pressor effect of the molecule. Previously, desmopressin has been used during surgery to prevent bleeding in patients with coagulation defects and, more recently, to minimize spread of residual malignant cells after cancer surgery. In the present work, desmopressin and novel analogs with substitutions in positions 4 and 5 were synthesized using the Fmoc chemistry in the solid phase peptide synthesis (SPSS) strategy. Our aim was to explore the angiostatic activity of peptide analogs in breast cancer cells. We investigated in vitro the effect of vasopressin analogs on the MCF-7 human breast carcinoma, a cell line that expresses the V2 receptor. Treatment of MCF-7 monolayers with desmopressin (100 nM) in the presence of plasminogen induced the formation of angiostatin. Interestingly, an enhanced production of angiostatin was obtained with two novel peptide analogs designated VQ (1-deamino-4-valine-5-glutamine-8-D-arginine vasopressin) and AQ (1-deamino-4-alanine-5-glutamine-8-D-arginine vasopressin). We have also examined peptide effects on angiogenesis using a syngeneic mouse model. Balb/c inbred mice were injected intradermally with F3II mammary carcinoma cells (2 x 105 viable cells per mouse), and 5 days later quantification of vascularization was done by measuring the vessel density. Daily intravenous administration of desmopressin (2 microg/kg) significantly reduced tumor-induced angiogenesis in the present model. These results suggest that peptide agonists of the vasopressin V2 receptor may display antitumor properties in breast cancer associated with angiostatic mechanisms.