Marina Pifano

Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies that express neuropeptides as synaptophysin, chromogranin A (CgA), and specific neuronal enolase (NSE), among others. Vasopressin (AVP) is a neuropeptide with an endocrine, paracrine, and autocrine effect in normal and pathological tissues. AVP receptors are present in human lung, breast, pancreatic, colorectal, and gastrointestinal tumors. While AVP V1 receptors are associated with stimulation of cellular proliferation, AVP V2 receptor (V2r) is related to antiproliferative effects. Desmopressin (dDAVP) is a synthetic analog of AVP that acts as a selective agonist for the V2r, which shows antitumor properties in breast and colorectal cancer models. Recently, we developed a derivative of dDAVP named [V 4 Q 5 ]dDAVP, which presents higher antitumor effects in a breast cancer model compared to the parental compound. The goal of present work was to explore the antitumor properties of the V2r agonist dDAVP and its novel analog [V 4 Q 5 ]dDAVP on aggressive human lung (NCI-H82) and prostate cancer (PC-3) cell lines with neuroen-docrine (NE) characteristics. We study the presence of specific NE markers (CgA and NSE) and V2r expression in NCI-H82 and PC-3. Both cell lines express high levels of NE markers NSE and CgA but then incubation with dDAVP diminished expression levels of both markers. DDAVP and [V 4 Q 5 ]dDAVP significantly reduced proliferation, doubling time, and migration in both tumor cell cultures. [V 4 Q 5 ]dDAVP analog showed a higher cytostatic effect than dDAVP, on cellular proliferation in the NCI-H82 cell line. Silencing of V2r using small interfering RNA significantly attenuated the inhibitory effects of [V 4 Q 5 ] dDAVP on NCI-H82 cell proliferation. We, preliminarily, explored the in vivo effect of dDAVP and [V 4 Q 5 ]dDAVP on NCI-H82 small cell lung cancer xenografts. Treated tumors (0.3 μg kg −1 , thrice a week) grew slower in comparison to vehicle-treated animals. In this work, we demonstrated that the specific agonists of V2r, dDAVP, and [V 4 Q 5 ]dDAVP displays antitumor capacity on different human models of lung and prostate cancers with NE features, showing their potential therapeutic benefits in the treatment of these aggressive tumors.

The synthetic nonapeptide 1‑desamino‑8‑D‑arginine vasopressin (dDAVP) can reduce tumor cell growth through agonist action on the vasopressin V2 receptor. A structure‑antiproliferative activity relationship analysis of dDAVP was performed using the alanine scanning technique on the aggressive MDA‑MB‑231 human breast carcinoma cell line. The results from this analysis demonstrated that the amino acids located at the loop of dDAVP are important for the antiproliferative activity of dDAVP, highlighting the key role of the N‑terminal region of the peptide in the interaction with the tumor cell surface receptor. The findings from this study present novel strategies for designing improved compounds with enhanced stability for cancer therapy.

Desmopressin (dDAVP) is a synthetic peptide analog of vasopressin with antidiuretic and hemostatic properties. Recent experimental evidence have suggested that dDAVP can inhibit metastasis formation by agonist action on V2 vasopressin receptors present in both tumor and endothelial cells. We have examined the kinetics of dDAVP effect during metastatic colonization and its potential association with hemostasis. The experimental metastasis assay was performed by injecting F3II mammary carcinoma cells into the lateral tail vein of syngeneic female BALB/c mice. Clinically relevant doses of dDAVP (0.3 to 2 μg/kg intravenously (i.v.)) produced a dose-dependent inhibition in the formation of lung nodules when administered during the first 24 hours after F3II tumor cell injection. The hemostatic agent tranexamic acid (10 mg/kg, i.v.) had no effect on metastasis formation in the same experimental conditions, while the anticoagulant enoxaparin (1 mg/kg, subcutaneously (s.c.)) did not modify t...