Oncotarget

Research Papers:

Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death

Jaganmohan R. Jangamreddy, Mayur V. Jain, Anna-Lotta Hallbeck, Karin Roberg, Kourosh Lotfi and Marek J. Łos _

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Oncotarget. 2015; 6:10134-10145. https://doi.org/10.18632/oncotarget.3548

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Abstract

Jaganmohan R. Jangamreddy1, Mayur V. Jain1, Anna-Lotta Hallbeck2, Karin Roberg3, Kourosh Lotfi4,5 and Marek J. Łos1,6

1 Department of Clinical & Experimental Medicine (IKE), Division of Cell Biology, Integrative Regenerative Medical Center (IGEN), Linköping University, Linköping, Sweden

2 Department of Clinical and Experimental Medicine, Division of Oncology, Linköping University, County Council of Östergötland, Linköping, Sweden

3 Division of Oto-Rhino-Laryngology and Head and Neck Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden

4 Clinical Pharmacology, Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden

5 Department of Hematology, County Council of Östergötland, Linköping, Sweden

6 Department of Pathology, Pomeranian Medical University, Szczecin, Poland

Correspondence to:

Marek J. Łos, email:

Keywords: glucose starvation, 2DG, 2FDG, normoxia, hypoxia

Received: January 20, 2015 Accepted: February 13, 2015 Published: March 12, 2015

Abstract

Salinomycin has been used as treatment for malignant tumors in a small number of humans, causing far less side effects than standard chemotherapy. Several studies show that Salinomycin targets cancer-initiating cells (cancer stem cells, or CSC) resistant to conventional therapies. Numerous studies show that Salinomycin not only reduces tumor volume, but also decreases tumor recurrence when used as an adjuvant to standard treatments. In this study we show that starvation triggered different stress responses in cancer cells and primary normal cells, which further improved the preferential targeting of cancer cells by Salinomycin. Our in vitro studies further demonstrate that the combined use of 2-Fluoro 2-deoxy D-glucose, or 2-deoxy D-glucose with Salinomycin is lethal in cancer cells while the use of Oxamate does not improve cell death-inducing properties of Salinomycin. Furthermore, we show that treatment of cancer cells with Salinomycin under starvation conditions not only increases the apoptotic caspase activity, but also diminishes the protective autophagy normally triggered by the treatment with Salinomycin alone. Thus, this study underlines the potential use of Salinomycin as a cancer treatment, possibly in combination with short-term starvation or starvation-mimicking pharmacologic intervention.


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