title: Tumor-reducing effect of the clinically used drug clofazimine in a SCID mouse model of pancreatic ductal adenocarcinoma.
abstract: Pancreatic ductal adenocarcinoma (PDAC) represents the most common form of pancreatic cancer with rising incidence in developing countries. Unfortunately, the overall 5-year survival rate is still less than 5%. The most frequent oncogenic mutations in PDAC are loss-of function mutations in p53 and gain-of-function mutations in KRAS. Here we show that clofazimine (Lamprene), a drug already used in the clinic for autoimmune diseases and leprosy, is able to efficiently kill in vitro five different PDAC cell lines harboring p53 mutations. We provide evidence that clofazimine induces apoptosis in PDAC cells with an EC50 in the µM range via its specific inhibitory action on the potassium channel Kv1.3. Intraperitoneal injection of clofazimine resulted in its accumulation in the pancreas of mice 8 hours after administration. Using an orthotopic PDAC xenotransplantation model in SCID beige mouse, we show that clofazimine significantly and strongly reduced the primary tumor weight. Thus, our work identifies clofazimine as a promising therapeutic agent against PDAC and further highlights ion channels as possible oncological targets.
authors.affiliation: Institute for Experimental Cancer Research, Medical Faculty, CAU, Kiel, Arnold-Heller-Strasse 3 (Haus 17) D-24105 Kiel, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Zaccagnino
authors.affiliation: Department of Biology, University of Padova, viale G. Colombo 3. Padova, I-35121 Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Managò
authors.affiliation: Department of Biology, University of Padova, viale G. Colombo 3. Padova, I-35121 Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Leanza
authors.affiliation: Institute for Experimental Cancer Research, Medical Faculty, CAU, Kiel, Arnold-Heller-Strasse 3 (Haus 17) D-24105 Kiel, Germany.
authors.forename: Artur
authors.initials: A
authors.lastname: Gontarewitz
authors.affiliation: Institute for Experimental Cancer Research, Medical Faculty, CAU, Kiel, Arnold-Heller-Strasse 3 (Haus 17) D-24105 Kiel, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Linder
authors.affiliation: Department of Biomedical Sciences, University of Padova, I-35121 Italy.|CNR Institute of Neuroscience, Padova, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Azzolini
authors.affiliation: Department of Biomedical Sciences, University of Padova, I-35121 Italy.|CNR Institute of Neuroscience, Padova, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Biasutto
authors.affiliation: Department of Biomedical Sciences, University of Padova, I-35121 Italy.|CNR Institute of Neuroscience, Padova, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Zoratti
authors.affiliation: Department of Biology, University of Padova, viale G. Colombo 3. Padova, I-35121 Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Peruzzo
authors.affiliation: Institute for Experimental Cancer Research, Medical Faculty, CAU, Kiel, Arnold-Heller-Strasse 3 (Haus 17) D-24105 Kiel, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Legler
authors.affiliation: Institute for Experimental Cancer Research, Medical Faculty, CAU, Kiel, Arnold-Heller-Strasse 3 (Haus 17) D-24105 Kiel, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Trauzold
authors.affiliation: Institute for Experimental Cancer Research, Medical Faculty, CAU, Kiel, Arnold-Heller-Strasse 3 (Haus 17) D-24105 Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
authors.affiliation: Department of Biology, University of Padova, viale G. Colombo 3. Padova, I-35121 Italy.|CNR Institute of Neuroscience, Padova, Italy.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Szabo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D045744:Cell Line, Tumor; D002991:Clofazimine / Q000494:pharmacology*; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000187:drug effects*; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051664:Kv1.3 Potassium Channel; D002991:Clofazimine
keywords: apoptosis; clofazimine; orthotopic model; pancreatic ductal adenocarcinoma; potassium channel