Oncotarget

Research Papers:

Tumor-reducing effect of the clinically used drug clofazimine in a SCID mouse model of pancreatic ductal adenocarcinoma

Angela Zaccagnino, Antonella Managò, Luigi Leanza, Artur Gontarewitz, Bernhard Linder, Michele Azzolini, Lucia Biasutto, Mario Zoratti, Roberta Peruzzo, Karen Legler, Anna Trauzold, Holger Kalthoff and Ildiko Szabo _

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Oncotarget. 2017; 8:38276-38293. https://doi.org/10.18632/oncotarget.11299

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Abstract

Angela Zaccagnino1,*, Antonella Managò2,*, Luigi Leanza2, Artur Gontarewitz1, Bernhard Linder1, Michele Azzolini3,4, Lucia Biasutto3,4, Mario Zoratti3,4, Roberta Peruzzo2, Karen Legler1, Anna Trauzold1, Holger Kalthoff1,* and Ildiko Szabo2,4,*

1Institute for Experimental Cancer Research, Medical Faculty, CAU, Kiel, Arnold-Heller-Strasse 3 (Haus 17), Germany

2Department of Biology, University of Padova, viale G. Colombo 3. Padova, Italy

3Department of Biomedical Sciences, University of Padova, Italy

4CNR Institute of Neuroscience, Padova, Italy

*These authors have contributed equally to this work

Correspondence to:

Ildiko Szabo, email: ildi@civ.bio.unipd.it

Luigi Leanza, email: luigi.leanza@unipd.it

Keywords: apoptosis, pancreatic ductal adenocarcinoma, potassium channel, clofazimine, orthotopic model

Received: February 04, 2016    Accepted: July 09, 2016    Published: August 16, 2016

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.


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