Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death.
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.
Department of Clinical & Experimental Medicine (IKE), Division of Cell Biology, Integrative Regenerative Medical Center (IGEN), Linköping University, Linköping, Sweden.
Jaganmohan R
JR
Jangamreddy
Department of Clinical & Experimental Medicine (IKE), Division of Cell Biology, Integrative Regenerative Medical Center (IGEN), Linköping University, Linköping, Sweden.
Mayur V
MV
Jain
Department of Clinical and Experimental Medicine, Division of Oncology, Linköping University, County Council of Östergötland, Linköping, Sweden.
Anna-Lotta
AL
Hallbeck
Division of Oto-Rhino-Laryngology and Head and Neck Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Karin
K
Roberg
Clinical Pharmacology, Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.|Department of Hematology, County Council of Östergötland, Linköping, Sweden.
Kourosh
K
Lotfi
Department of Clinical & Experimental Medicine (IKE), Division of Cell Biology, Integrative Regenerative Medical Center (IGEN), Linköping University, Linköping, Sweden.|Department of Pathology, Pomeranian Medical University, Szczecin, Poland.
Marek J
MJ
Łos
D001343:Autophagy / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005947:Glucose / Q000008:administration & dosage* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011714:Pyrans / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000095662:Polyether Polyketides
D005947:Glucose; D011714:Pyrans; C010327:salinomycin; D000095662:Polyether Polyketides
2DG; 2FDG; glucose starvation; hypoxia; normoxia