The Vasopressin Receptor Antagonist Tolvaptan Counteracts Tumor Growth in a Murine Xenograft Model of Small Cell Lung Cancer

Author:

Naldi Laura12,Fibbi Benedetta12,Polvani Simone3,Cirillo Chiara2,Pasella Francesca2,Bartolini Francesca2,Romano Francesca4,Fanelli Alessandra4,Peri Alessandro12ORCID,Marroncini Giada12ORCID

Affiliation:

1. Pituitary Diseases and Sodium Alterations Unit, AOU Careggi, 50139 Florence, Italy

2. Endocrinology, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, AOU Careggi, 50139 Florence, Italy

3. Gastroenterology Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy

4. Central Laboratory, Careggi University Hospital, 50139 Florence, Italy

Abstract

We have previously demonstrated that the vasopressin type 2 receptor (AVPR2) antagonist tolvaptan reduces cell proliferation and invasion and triggers apoptosis in different human cancer cell lines. To study this effect in vivo, a xenograft model of small cell lung cancer was developed in Fox1nu/nu nude mice through the subcutaneous inoculation of H69 cells, which express AVPR2. One group of mice (n = 5) was treated with tolvaptan for 60 days, whereas one group (n = 5) served as the control. A reduced growth was observed in the tolvaptan group in which the mean tumor volume was significantly smaller on day 60 compared to the control group. In the latter group, a significantly lower survival was observed. The analysis of excised tumors revealed that tolvaptan effectively inhibited the cAMP/PKA and PI3K/AKT signaling pathways. The expression of the proliferative marker proliferating cell nuclear antigen (PCNA) was significantly lower in tumors excised from tolvaptan-treated mice, whereas the expression levels of the apoptotic marker caspase-3 were higher than those in control animals. Furthermore, tumor vascularization was significantly lower in the tolvaptan group. Overall, these findings suggest that tolvaptan counteracts tumor progression in vivo and, if confirmed, might indicate a possible role of this molecule as an adjuvant in anticancer strategies.

Funder

Italian University and Research Ministry

Publisher

MDPI AG

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