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Early effects of the antineoplastic agent salinomycin on mitochondrial function
A Managò1, L Leanza1, L Carraretto1
1Department of Biology, University of Padua, Padua, Italy.
Cell Death & Disease
|October 23, 2015
Summary
Salinomycin induces cancer cell death by disrupting mitochondrial function, acting as a K+/H+ exchanger. This mechanism affects cancer stem cells and other tumor cells, offering a new therapeutic avenue.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Salinomycin, an antibiotic from Streptomyces albus, shows promise in inducing apoptosis in cancer stem cells.
- Its precise mechanism of action, particularly its effects on non-stem tumor cells, remains largely unelucidated.
- Previous research suggests salinomycin may function as a potassium (K+) ionophore.
Purpose of the Study:
- To investigate the mechanism by which salinomycin induces apoptosis in cancer cells.
- To explore salinomycin's impact on mitochondrial bioenergetic performance.
- To compare salinomycin's effects with known ionophores and exchangers.
Main Methods:
- Utilized mouse embryonic fibroblasts (MEFs) and cancer stem cell-like HMLE cells.
- Assessed mitochondrial function, including membrane potential, respiration, and reactive oxygen species (ROS) production.
- Compared salinomycin with valinomycin (K+ ionophore) and nigericin (K+/H+ exchanger).
- Investigated apoptosis in Bax/Bak-less double-knockout MEF cells.
- Examined salinomycin's effects on B cells from chronic lymphocytic leukemia (CLL) patients and healthy subjects, in the presence of mesenchymal stromal cells (MSCs).
Main Results:
- Salinomycin induced rapid mitochondrial hyperpolarization, matrix acidification, and decreased respiration in MEFs and HMLE cells.
- Unlike valinomycin, salinomycin mediated K+/H+ exchange across the inner mitochondrial membrane.
- Salinomycin induced cell death independently of Bax and Bak.
- While effective against B-CLL cells, salinomycin also induced apoptosis in healthy B cells, MSCs, and fibroblasts at concentrations above 10 μM.
- Mesenchymal stromal cells (MSCs) attenuated salinomycin's apoptotic effect on B-CLL cells.
Conclusions:
- Salinomycin acts as a K+/H+ exchanger, directly impacting mitochondrial function and bioenergetics.
- Its effects on mitochondria compromise cell survival, leading to apoptosis.
- Salinomycin exhibits broad cytotoxicity, affecting both cancer cells and healthy cells at higher concentrations, necessitating careful therapeutic consideration.
