Salinomycin and Cancer Stem Cells



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Oncotarget. 2015 Apr 30; 6(12): 10134–10145.

Published online 2015 Mar 12. doi:  [10.18632/oncotarget.3548]

PMCID: PMC4496345

PMID: 25912307

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

Jaganmohan R. Jangamreddy,1 Mayur V. Jain,1 Anna-Lotta Hallbeck,2 Karin Roberg,3 Kourosh Lotfi,4,5 and Marek J. Łos1,6

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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.

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

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Initially proposed in 1930’s, Warburg effect or the dependence of cancer cells on aerobic glycolysis, is considered the ‘Achilles heel’ of cancer [1]. The addiction of cancer cells to accumulate the cellular mass increases uptake of glucose as opposed to normal cells that undergo quiescence/senescence under nutrient deprivation, even in the presence of growth factors. This adoption of proliferative cancer cells for survival can be exploited for preferential targeting [1].

Even though current treatment procedures are able to effectively target the bulk of the tumor, cancer recurrence and metastasis formation are major reasons leading to therapy failure. Studies over the last decade show that the drug-resistant cancer initiating cells (cancer stem cells, CSC) have similar characteristics to stem cells as far as self-renewal and to some extent also differentiation capacities [2-4]. In 2009, Gupta and colleagues screened about 16000 compounds in the quest to identify molecules that are preferentially toxic to CSC. The screen identified, an antibiotic with K+-ionophore properties Salinomycin, which has been used for decades in animal farming for both increasing nutrient absorption and treatment for parasitic infections (e.g. coccidiosis) [5].

Consistent with these findings, the effective targeting of CSC by Salinomycin in several malignancies including breast-, prostrate-, brain-, blood-, liver-, pancreatic-, and lung cancers was further established [6-11]. Salinomycin kills cancer cells by a mixed apoptotic and autophagic form of cell death, while the latter one is initially induced as a protective mechanism [9, 12-14]. So far, lethal toxicity of Salinomycin to humans was not reported. One case of accidental high dose exposure to Salinomycin of a farm-worker has been documented [15]. Using in vitro-studies, Boehmerle and colleagues showed that Salinomycin is toxic to normal neuronal cells (murine dorsal root ganglion neurons, toxicity at 1μM, cell viability ~25%, in vitro-experiment), and thus is expected to cause mild to severe neuropathies [16]. More recently, the work from the same group, using mouse models, show that a combination of Salinomycin (5mg/kg daily injection), with inhibition of mitochondrial Na+/K+ exchanger was able to show no such neuronal toxicity, without altering the cancer cell cytotoxicity [17]. Furthermore, partially successful pilot study in humans showed minor secondary symptoms while causing the regression of metastatic tumor [6]. Thus, the efficacy of Salinomycin will likely be further clinically tested among wide range of cancer patients [6].

Salinomycin’s ability to specifically kill slowly proliferating cancer stem-like cells more robustly than the differentiated cancer cells, even at lower concentrations, lead to studies using commonly used chemotherapeutic agents in combination with Salinomycin [6, 18, 19]. We have previously observed that salimomycin caused mitochondrial dysfunction, decrease of cellular ATP, and induction of autophagy [9, 14]. Thus, following on our previous findings, in this study, we tested the response of normal- and cancer cells under starvation conditions (natural autophagy inducer). We studied Salinomycin’s toxicity under glucose starvation, or under competitive inhibition of glycolytic pathway (pharmacological triggered starvation-like conditions), as well as under hypoxia (natural inhibition of phosphorylative oxiation).

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