Oncotarget

Research Papers:

Salinomycin inhibits cholangiocarcinoma growth by inhibition of autophagic flux

Johannes Klose _, Engin Guerlevik, Tina Trostel, Florian Kühnel, Thomas Schmidt, Martin Schneider and Alexis Ulrich

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Oncotarget. 2018; 9:3619-3630. https://doi.org/10.18632/oncotarget.23339

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Abstract

Johannes Klose1, Engin Guerlevik2, Tina Trostel1, Florian Kühnel2, Thomas Schmidt1, Martin Schneider1 and Alexis Ulrich1

1Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg 69120, Germany

2Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover 30625, Germany

Correspondence to:

Johannes Klose, email: [email protected]

Keywords: Salinomycin; cholangiocarcinoma; in vivo model; autophagic flux

Abbreviations: ACH: ammonium chloride; CC: cholangiocarcinoma; CQ: chloroquine; ROS: reactive oxygen species; Sal: Salinomycin

Received: August 01, 2017    Accepted: November 26, 2017    Published: December 16, 2017

ABSTRACT

Introduction: Cholangiocarcinoma is characterized by aggressive tumor growth, high recurrence rates, and resistance against common chemotherapeutical regimes. The polyether-antibiotic Salinomycin is a promising drug in cancer therapy because of its ability to overcome apoptosis resistance of cancer cells and its selectivity against cancer stem cells. Here, we investigated the effectiveness of Salinomycin against cholangiocarcinoma in vivo, and analyzed interference of Salinomycin with autophagic flux in human cholangiocarcinoma cells.

Results: Salinomycin reduces tumor cell viability, proliferation, migration, invasion, and induced apoptosis in vitro. Subcutaneous and intrahepatic cholangiocarcinoma growth in vivo was inhibited upon Salinomycin treatment. Analysis of autophagy reveals inhibition of autophagic activity. This was accompanied by accumulation of mitochondrial mass and increased generation of reactive oxygen species.

Conclusions: This study demonstrates the effectiveness of Salinomycin against cholangiocarcinoma in vivo. Inhibition of autophagic flux represents an underlying molecular mechanism of Salinomycin against cholangiocarcinoma.

Methods: The two murine cholangiocarcinoma cell lines p246 and p254 were used to analyze tumor cell proliferation, viability, migration, invasion, and apoptosis in vitro. For in vivo studies, murine cholangiocarcinoma cells were injected into syngeneic C57-BL/6-mice to initiate subcutaneous cholangiocarcinoma growth. Intrahepatic tumor growth was induced by electroporation of oncogenic transposon-plasmids into the left liver lobe. For mechanistic studies in human cells, TFK-1 and EGI-1 were used, and activation of autophagy was analyzed after exposure to Salinomycin.


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