Salinomycin is a polyether
antibiotic which effectively eliminates a variety of cancer stem cells and
chemotherapy-resistant
tumor cells in vitro and in vivo. One important caveat for its clinical application is the paucity of preclinical pharmacological and safety data. In the present study, we thus aimed to elucidate pharmacokinetic properties of
salinomycin and to assess the side effect profile of chronic treatment with this compound in C57Bl/6 mice. In addition, we tested whether neurotoxic side effects can be prevented by interference with the intracellular
calcium homeostasis. We observed that
salinomycin has a narrow therapeutic index; however, a dose of 5 mg/kg
body weight was well tolerated, and analysis of blood parameters as well as organ histology of liver, kidney, skeletal muscle, and heart showed no abnormalities after daily
salinomycin injection for 4 weeks. Pharmacokinetic evaluation revealed low micromolar peak concentrations and an almost complete systemic elimination within 5 h after injection. In contrast to low systemic toxicity, typical signs of a sensory
polyneuropathy with mechanical and cold
allodynia, distinct gait alterations, decreased sensory nerve action potential amplitudes, and loss of myelinated fibers in the sciatic nerve were observed in
salinomycin-treated animals. Inhibition of the mitochondrial
Na(+)/Ca(2+) exchanger partially prevented the development of
salinomycin-induced neuropathy in vivo, an approach which did not reduce
salinomycin's
antineoplastic efficacy in vitro. Taken together, this study establishes a framework of pharmacokinetic data for future preclinical trials and safety data for translational trials. Furthermore, we established a strategy to reduce
salinomycin's off-target neurotoxic effects.
KEY MESSAGE:
Salinomycin has a narrow therapeutic index; a dose of 5 mg/kg is tolerated in mice. Mice treated with
salinomycin develop a painful sensory
polyneuropathy. An optimized protocol was established to measure
salinomycin in serum samples. Inhibition of Na(+)/Ca(2+) exchangers prevents
salinomycin-induced neuropathy. Blocking mitochondrial Na(+)/Ca(2+) exchangers does not impair
antineoplastic efficacy.