{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T11:52:26Z","timestamp":1783597946639,"version":"3.55.0"},"reference-count":48,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T00:00:00Z","timestamp":1722470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian University and Research Ministry","award":["PRIN 2017R5ZE2C"],"award-info":[{"award-number":["PRIN 2017R5ZE2C"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms25158402","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T12:38:20Z","timestamp":1722515900000},"page":"8402","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Vasopressin Receptor Antagonist Tolvaptan Counteracts Tumor Growth in a Murine Xenograft Model of Small Cell Lung Cancer"],"prefix":"10.3390","volume":"25","author":[{"given":"Laura","family":"Naldi","sequence":"first","affiliation":[{"name":"Pituitary Diseases and Sodium Alterations Unit, AOU Careggi, 50139 Florence, Italy"},{"name":"Endocrinology, Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, AOU Careggi, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Fibbi","sequence":"additional","affiliation":[{"name":"Pituitary Diseases and Sodium Alterations Unit, AOU Careggi, 50139 Florence, Italy"},{"name":"Endocrinology, Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, AOU Careggi, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Polvani","sequence":"additional","affiliation":[{"name":"Gastroenterology Unit, Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Cirillo","sequence":"additional","affiliation":[{"name":"Endocrinology, Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, AOU Careggi, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Pasella","sequence":"additional","affiliation":[{"name":"Endocrinology, Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, AOU Careggi, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Bartolini","sequence":"additional","affiliation":[{"name":"Endocrinology, Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, AOU Careggi, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Romano","sequence":"additional","affiliation":[{"name":"Central Laboratory, Careggi University Hospital, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Fanelli","sequence":"additional","affiliation":[{"name":"Central Laboratory, Careggi University Hospital, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6417-434X","authenticated-orcid":false,"given":"Alessandro","family":"Peri","sequence":"additional","affiliation":[{"name":"Pituitary Diseases and Sodium Alterations Unit, AOU Careggi, 50139 Florence, Italy"},{"name":"Endocrinology, Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, AOU Careggi, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6611-8103","authenticated-orcid":false,"given":"Giada","family":"Marroncini","sequence":"additional","affiliation":[{"name":"Pituitary Diseases and Sodium Alterations Unit, AOU Careggi, 50139 Florence, Italy"},{"name":"Endocrinology, Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, AOU Careggi, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1053\/j.ajkd.2011.08.029","article-title":"Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes","volume":"59","author":"Doshi","year":"2012","journal-title":"Am. J. Kidney Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.critrevonc.2016.03.010","article-title":"Hyponatremia in cancer patients: Time for a new approach","volume":"102","author":"Berardi","year":"2016","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/j.1365-2796.1995.tb00907.x","article-title":"Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in malignant disease","volume":"238","author":"Andersen","year":"1995","journal-title":"J. Intern. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1007\/s00280-017-3392-8","article-title":"Electrolyte disorders with platinum-based chemotherapy: Mechanisms, manifestations and management","volume":"80","author":"Oronsky","year":"2017","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Berardi, R., Santoni, M., Rinaldi, S., Nunzi, E., Smerilli, A., Caramanti, M., Morgese, F., Torniai, M., Savini, A., and Fiordoliva, I. (2016). Risk of Hyponatraemia in Cancer Patients Treated with Targeted Therapies: A Systematic Review and Meta-Analysis of Clinical Trials. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0152079"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1159\/000455014","article-title":"Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review","volume":"45","author":"Wanchoo","year":"2017","journal-title":"Am. J. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1159\/000493245","article-title":"Hyponatremia in Oncology Patients","volume":"52","year":"2019","journal-title":"Front. Horm. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1007\/s00520-007-0309-9","article-title":"Diagnosis and management of hyponatremia in cancer patients","volume":"15","author":"Raftopoulos","year":"2007","journal-title":"Support. Care Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1097\/SMJ.0b013e3181e63682","article-title":"Cisplatin-induced renal salt wasting syndrome","volume":"103","author":"Hamdi","year":"2010","journal-title":"South. Med. J."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kim, G.H. (2022). Pathophysiology of Drug-Induced Hyponatremia. J. Clin. Med., 11.","DOI":"10.3390\/jcm11195810"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Fibbi, B., Marroncini, G., Naldi, L., Anceschi, C., Errico, A., Norello, D., and Peri, A. (2023). Hyponatremia and Cancer: From Bedside to Benchside. Cancers, 15.","DOI":"10.3390\/cancers15041197"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"111419","DOI":"10.1016\/j.mce.2021.111419","article-title":"Low sodium and tolvaptan have opposite effects in human small cell lung cancer cells","volume":"537","author":"Marroncini","year":"2021","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Marroncini, G., Naldi, L., Fibbi, B., Errico, A., Polvani, S., Brogi, M., Fanelli, A., Maggi, M., and Peri, A. (2023). Hyponatremia Promotes Cancer Growth in a Murine Xenograft Model of Neuroblastoma. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202310.0905.v1"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1681\/ASN.2009080857","article-title":"Oral tolvaptan is safe and effective in chronic hyponatremia","volume":"21","author":"Berl","year":"2010","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1210\/jc.2012-4082","article-title":"Clinical review: The use of vaptans in clinical endocrinology","volume":"98","author":"Peri","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/ki.2015.4","article-title":"Current treatment practice and outcomes. Report of the hyponatremia registry","volume":"88","author":"Greenberg","year":"2015","journal-title":"Kidney Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1111\/cen.13315","article-title":"A systematic review of known interventions for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia and a meta-analysis of the vaptans","volume":"86","author":"Bhandari","year":"2017","journal-title":"Clin. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1634\/theoncologist.2011-0400","article-title":"Diagnosis and management of hyponatremia in cancer patients","volume":"17","author":"Castillo","year":"2012","journal-title":"Oncologist"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1007\/s12020-018-1547-y","article-title":"Practical issues for the management of hyponatremia in oncology","volume":"61","author":"Berardi","year":"2018","journal-title":"Endocrine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.lungcan.2009.05.015","article-title":"The occurrence of hyponatremia in SCLC and the influence on prognosis: A retrospective study of 453 patients treated in a single institution in a 10-year period","volume":"68","author":"Hansen","year":"2010","journal-title":"Lung Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Balachandran, K., Okines, A., Gunapala, R., Morganstein, D., and Popat, S. (2015). Resolution of severe hyponatraemia is associated with improved survival in patients with cancer. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-1156-6"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"23871","DOI":"10.18632\/oncotarget.13372","article-title":"Hyponatremia normalization as an independent prognostic factor in patients with advanced non-small cell lung cancer treated with first-line therapy","volume":"8","author":"Berardi","year":"2017","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1038\/nm935","article-title":"Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist","volume":"9","author":"Gattone","year":"2003","journal-title":"Nat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1056\/NEJMoa1710030","article-title":"Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease","volume":"377","author":"Torres","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.1056\/NEJMoa1205511","article-title":"Tolvaptan in patients with autosomal dominant polycystic kidney disease","volume":"367","author":"Torres","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.bcp.2015.03.015","article-title":"Mechanisms of tolvaptan-induced toxicity in HepG2 cells","volume":"95","author":"Wu","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1038\/s41388-019-1059-0","article-title":"Targeting the vasopressin type-2 receptor for renal cell carcinoma therapy","volume":"39","author":"Sinha","year":"2020","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1007\/s40618-022-01807-5","article-title":"The V2 receptor antagonist tolvaptan counteracts proliferation and invasivity in human cancer cells","volume":"45","author":"Marroncini","year":"2022","journal-title":"J. Endocrinol. Invest."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Castillo, J.J., Glezerman, I.G., Boklage, S.H., Chiodo, J., Tidwell, B.A., Lamerato, L.E., and Schulman, K.L. (2016). The occurrence of hyponatremia and its importance as a prognostic factor in a cross-section of cancer patients. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2610-9"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1007\/s005200050284","article-title":"A prospective study on hyponatraemia in medical cancer patients: Epidemiology, aetiology and differential diagnosis","volume":"8","author":"Berghmans","year":"2000","journal-title":"Support. Care Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"649","DOI":"10.2147\/TCRM.S286952","article-title":"Safety Profile of Tolvaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease","volume":"17","author":"Bellos","year":"2021","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1038\/sj.bjc.6690623","article-title":"Tumour-specific arginine vasopressin promoter activation in small-cell lung cancer","volume":"80","author":"Coulson","year":"1999","journal-title":"Br. J. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.urolonc.2008.12.014","article-title":"Aquaretic inhibits renal cancer proliferation: Role of vasopressin receptor-2 (V2-R)","volume":"28","author":"Bolignano","year":"2010","journal-title":"Urol. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/sj.cdd.4400476","article-title":"Emerging roles of caspase-3 in apoptosis","volume":"6","author":"Porter","year":"1999","journal-title":"Cell Death Differ."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez-Maga\u00f1a, A., and Blanco, F.J. (2020). Human PCNA Structure, Function and Interactions. Biomolecules, 10.","DOI":"10.3390\/biom10040570"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1091\/mbc.4.9.897","article-title":"Proliferating cell nuclear antigen and p21 are components of multiple cell cycle kinase complexes","volume":"4","author":"Zhang","year":"1993","journal-title":"Mol. Biol. Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"643","DOI":"10.37349\/etat.2022.00105","article-title":"Potential role of resveratrol and its nano-formulation as anti-cancer agent","volume":"3","author":"Kumar","year":"2022","journal-title":"Explor. Target. Antitumor Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1042\/CS20040370","article-title":"The vascular endothelial growth factor (VEGF)\/VEGF receptor system and its role under physiological and pathological conditions","volume":"109","author":"Takahashi","year":"2005","journal-title":"Clin. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Zeng, J., Deng, Q., Chen, Z., Yan, S., Dong, Q., Zhang, Y., Cui, Y., Li, L., He, Y., and Shi, J. (2024). Recent development of VEGFR small molecule inhibitors as anticancer agents: A patent review (2021\u20132023). Bioorg. Chem., 146.","DOI":"10.1016\/j.bioorg.2024.107278"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"157","DOI":"10.4049\/jimmunol.133.1.157","article-title":"Antigenic analysis of hematopoiesis. III. A hematopoietic progenitor cell surface antigen defined by a monoclonal antibody raisedagainst KG-1a cells","volume":"133","author":"Civin","year":"1984","journal-title":"J. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3058","DOI":"10.1002\/jcb.29571","article-title":"CD34 cells in somatic, regenerative and cancer stem cells: Developmental biology, cell therapy, and omics big data perspective","volume":"121","author":"Kapoor","year":"2020","journal-title":"J. Cell Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1124\/jpet.114.213256","article-title":"Tolvaptan delays the onset of end-stage renal disease in a polycystic kidney disease model by suppressing increases in kidney volume and renal injury","volume":"349","author":"Aihara","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/bs.vh.2019.08.010","article-title":"Development and therapeutic potential of vasopressin synthetic analog [V4Q5]dDAVP as a novel anticancer agent","volume":"113","author":"Garona","year":"2020","journal-title":"Vitam. Horm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"566","DOI":"10.3892\/etm.2021.9998","article-title":"Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2-expressing human osteosarcoma","volume":"21","author":"Sobol","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"540","DOI":"10.14740\/wjon1715","article-title":"Vasopressin Analog [V4Q5] dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models","volume":"14","author":"Sobol","year":"2023","journal-title":"World J. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/0143-4179(95)90114-0","article-title":"Factors regulating the production of vasopressin-associated human neurophysin by small-cell carcinoma of the lung: Evaluation by computer-enhanced quantitative immunocytochemistry","volume":"28","author":"Friedmann","year":"1995","journal-title":"Neuropeptides"},{"key":"ref_47","first-page":"1866","article-title":"Expression of all known vasopressin receptor subtypes by small cell tumors implies a multifaceted role for this neuropeptide","volume":"58","author":"North","year":"1998","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"27S","DOI":"10.1111\/j.1469-445X.2000.tb00005.x","article-title":"Gene regulation of vasopressin and vasopressin receptors in cancer","volume":"85","author":"North","year":"2000","journal-title":"Exp. Physiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/15\/8402\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:28:01Z","timestamp":1760110081000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/15\/8402"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,1]]},"references-count":48,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["ijms25158402"],"URL":"https:\/\/doi.org\/10.3390\/ijms25158402","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,1]]}}}