Early effects of the antineoplastic agent salinomycin on mitochondrial function.
Salinomycin, isolated from Streptomyces albus, displays antimicrobial activity. Recently, a large-scale screening approach identified salinomycin and nigericin as selective apoptosis inducers of cancer stem cells. Growing evidence suggests that salinomycin is able to kill different types of non-stem tumor cells that usually display resistance to common therapeutic approaches, but the mechanism of action of this molecule is still poorly understood. Since salinomycin has been suggested to act as a K(+) ionophore, we explored its impact on mitochondrial bioenergetic performance at an early time point following drug application. In contrast to the K(+) ionophore valinomycin, salinomycin induced a rapid hyperpolarization. In addition, mitochondrial matrix acidification and a significant decrease of respiration were observed in intact mouse embryonic fibroblasts (MEFs) and in cancer stem cell-like HMLE cells within tens of minutes, while increased production of reactive oxygen species was not detected. By comparing the chemical structures and cellular effects of this drug with those of valinomycin (K(+) ionophore) and nigericin (K(+)/H(+) exchanger), we conclude that salinomycin mediates K(+)/H(+) exchange across the inner mitochondrial membrane. Compatible with its direct modulation of mitochondrial function, salinomycin was able to induce cell death also in Bax/Bak-less double-knockout MEF cells. Since at the concentration range used in most studies (around 10 μM) salinomycin exerts its effect at the level of mitochondria and alters bioenergetic performance, the specificity of its action on pathologic B cells isolated from patients with chronic lymphocytic leukemia (CLL) versus B cells from healthy subjects was investigated. Mesenchymal stromal cells (MSCs), proposed to mimic the tumor environment, attenuated the apoptotic effect of salinomycin on B-CLL cells. Apoptosis occurred to a significant extent in healthy B cells as well as in MSCs and human primary fibroblasts. The results indicate that salinomycin, when used above μM concentrations, exerts direct, mitochondrial effects, thus compromising cell survival.
Department of Biology, University of Padua, Padua, Italy.
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Managò
Department of Biology, University of Padua, Padua, Italy.
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Leanza
Department of Biology, University of Padua, Padua, Italy.
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Carraretto
Department of Biology, University of Padua, Padua, Italy.|Department of Biomedical Sciences, University of Padua, Padua, Italy.
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Sassi
Department of Biomedical Sciences, University of Padua, Padua, Italy.
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Grancara
Department of Biology, University of Padua, Padua, Italy.|Venetian Institute for Molecular Medicine, University of Padua, Padua, Italy.
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Quintana-Cabrera
Venetian Institute for Molecular Medicine, University of Padua, Padua, Italy.
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Trimarco
Department of Biomedical Sciences, University of Padua, Padua, Italy.
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Toninello
Department of Biology, University of Padua, Padua, Italy.|Venetian Institute for Molecular Medicine, University of Padua, Padua, Italy.
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Scorrano
Venetian Institute for Molecular Medicine, University of Padua, Padua, Italy.
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Trentin
Venetian Institute for Molecular Medicine, University of Padua, Padua, Italy.
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Semenzato
Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
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Gulbins
Department of Biomedical Sciences, University of Padua, Padua, Italy.|CNR Institute of Neuroscience, Padua, Italy.
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Zoratti
Department of Biology, University of Padua, Padua, Italy.|CNR Institute of Neuroscience, Padua, Italy.
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Szabò
D000136:Acid-Base Equilibrium; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D019069:Cell Respiration; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects*; D009550:Nigericin / Q000494:pharmacology; D010101:Oxygen Consumption; D011714:Pyrans / Q000494:pharmacology*; D014634:Valinomycin / Q000494:pharmacology; D000095662:Polyether Polyketides
D000903:Antibiotics, Antineoplastic; D009550:Nigericin; D011714:Pyrans; D014634:Valinomycin; C010327:salinomycin; D000095662:Polyether Polyketides