HOMEPRODUCTSSERVICESCOMPANYCONTACTFAQResearchDictionaryPharmaMobileSign Up FREE or Login

Specific targeting of neurotoxic side effects and pharmacological profile of the novel cancer stem cell drug salinomycin in mice.

AbstractUNLABELLED:
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.
AuthorsWolfgang Boehmerle, Hanna Muenzfeld, Andreas Springer, Petra Huehnchen, Matthias Endres
JournalJournal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 92 Issue 8 Pg. 889-900 (Aug 2014) ISSN: 1432-1440 [Electronic] Germany
PMID24770997 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Pyrans
  • salinomycin
Topics
  • Animals
  • Antineoplastic Agents (administration & dosage, pharmacology, toxicity)
  • Behavior, Animal (drug effects)
  • Cell Line, Tumor
  • Ganglia, Spinal (drug effects)
  • Male
  • Mice
  • Mitochondria (drug effects, metabolism)
  • Muscles (drug effects, metabolism, pathology)
  • Neoplastic Stem Cells (drug effects, metabolism)
  • Peripheral Nervous System Diseases (chemically induced, pathology, physiopathology)
  • Pilot Projects
  • Pyrans (administration & dosage, pharmacology, toxicity)
  • Toxicity Tests

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!


Choose Username:
Email:
Password:
Verify Password: