title: Antitumorigenic and antiinsulinogenic effects of calcitriol on insulinoma cells and solid beta-cell tumors.
abstract: Malignant insulinoma is a rare form of cancer with a poor prognosis because of metastatic dissemination and untreatable hypoglycemia. Effective chemotherapy of patients who are not cured by surgery is needed. Calcitriol has known anticancer properties on different neoplastic cell lines, but no data are available regarding its activity on tumorigenic pancreatic beta-cells. We analyzed the in vitro effects of calcitriol on the murine insulinoma cell line betaTC(3) and primary cultures of human isolated islets and benign insulinoma. The effect of in vivo calcitriol administration on insulinoma of recombinant insulin/Simian virus 40 oncogene-expressing transgenic mice was also investigated. In betaTC(3), calcitriol induced growth inhibition; apoptosis; down-regulation of insulin gene expression; and nongenomic activation of the MAPK pathway. MAPK kinase inhibitor (UO126) and staurosporine reduced calcitriol-mediated betaTC(3) death, and down-regulation of insulin gene transcription was prevented by staurosporine but not UO126. Calcitriol significantly decreased insulin release and mRNA levels of human islets and insulinoma cells. Finally, recombinant insulin/Simian virus 40 oncogene-expressing transgenic mice treated with calcitriol showed reduced insulinoma volumes because of increased apoptosis of adenomatous cells. Together, these findings provide the rationale for testing the efficacy of calcitriol in the treatment of patients with solid beta-cell tumors.
authors.affiliation: Department of Medicine, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Galbiati
authors.forename: Luca
authors.initials: L
authors.lastname: Polastri
authors.forename: Silvia
authors.initials: S
authors.lastname: Gregori
authors.forename: Massimo
authors.initials: M
authors.lastname: Freschi
authors.forename: Mara
authors.initials: M
authors.lastname: Casorati
authors.forename: Ugo
authors.initials: U
authors.lastname: Cavallaro
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
authors.forename: Federico
authors.initials: F
authors.lastname: Bertuzzi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zerbi
authors.forename: Guido
authors.initials: G
authors.lastname: Pozza
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
authors.forename: Franco
authors.initials: F
authors.lastname: Folli
authors.forename: Gerhard
authors.initials: G
authors.lastname: Christofori
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Davalli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002117:Calcitriol / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007329:Insulin Antagonists / Q000494:pharmacology*; D007340:Insulinoma / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007328:Insulin; D007329:Insulin Antagonists; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D002117:Calcitriol