salinomycin and Peripheral-Nervous-System-Diseases

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.. 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.

Topics: Animals; Antineoplastic Agents; Behavior, Animal; Cell Line, Tumor; Ganglia, Spinal; Male; Mice; Mitochondria; Muscles; Neoplastic Stem Cells; Peripheral Nervous System Diseases; Pilot Projects; Pyrans; Toxicity Tests

In April 1996, an outbreak of toxic polyneuropathy in cats occurred in the Netherlands. All cats had been fed one of two brands of dry cat food from one manufacturer. Chemical analyses of these foods, stomach contents, and liver and kidney of affected cats revealed contamination with the ionophor salinomycin. Epidemiologic and clinical data were collected from 823 cats, or about 1% of the cats at risk. In 21 affected cats, postmortem examination was performed. The affected cats had acute onset of lameness and paralysis of the hindlimbs followed by the forelimbs. Clinical and pathologic examination indicated a distal polyneuropathy involving both the sensory and motor nerves.

Topics: Animal Feed; Animals; Cat Diseases; Cats; Coccidiostats; Disease Outbreaks; Female; Food Contamination; Forelimb; Hindlimb; Ionophores; Lameness, Animal; Male; Netherlands; Peripheral Nerves; Peripheral Nervous System Diseases; Pyrans