Abstract
Salinomycin is a polyether antibiotic showing anticancer activity. There are many reports of its toxicity to animals but little is known about the potential adverse effects in humans. The action of the drug may be connected to its metabolism. That is why we investigated the cytotoxicity of salinomycin and pathways of its biotransformation using human primary hepatocytes, human hepatoma cells (HepG2), and the mouse fibroblast cell line (Balb/c 3T3). The cytotoxicity of salinomycin was time-dependent, concentration-dependent, and cell-dependent with primary hepatocytes being the most resistant. Among the studied models, primary hepatocytes were the only ones to efficiently metabolize salinomycin but even they were saturated at higher concentrations. The main route of biotransformation was monooxygenation leading to the formation of monohydroxysalinomycin, dihydroxysalinomycin, and trihydroxysalinomycin. Tiamulin, which is a known inhibitor of CYP450 izoenzymes, synergistically induced cytotoxicity of salinomycin in all cell types, including non-metabolising fibroblasts. Therefore, the pharmacokinetic interaction cannot fully explain tiamulin impact on salinomycin toxicity.
Highlights
With the increasing role of cancer in public health, the search for new drugs becomes even more important
The viability of cells co-treated with tiamulin was decreased compared to SAL alone
The main route of metabolism of SAL in human hepatocytes was monooxygenation leading to the formation of monohydroxysalinomycin (n = 3), dihydroxysalinomycin (n = 14), and trihydroxysalinomycin (n = 1)
Summary
With the increasing role of cancer in public health, the search for new drugs becomes even more important. For this purpose, huge screening tests of already known chemicals are among the applied strategies. Huge screening tests of already known chemicals are among the applied strategies Using this approach, scientists have found several candidates for anticancer drugs among polyether ionophores. One of them is salinomycin (SAL)—a compound used for nearly 50 years as an anti-parasitic in veterinary practice. Gupta et al demonstrated that SAL selectively targeted breast cancer stem cells [1]. The drug shows anti-tumorigenic properties in various types of cancer
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