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.
Highlights
Proposed in 1930’s, Warburg effect or the dependence of cancer cells on aerobic glycolysis, is considered the ‘Achilles heel’ of cancer [1]
We further studied the reversibility of cell death and effect on cell proliferation by Salinomycin treatment
MTT assay results showed that LK0412 cells treated with 10μM Salinomycin for 24h, after which the medium was replaced with Salinomycinfree media for another 48h, did not show increase in cell proliferation but instead further decrease in cells viability (Fig. 1D)
Summary
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]. 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]
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