Targeting Telomerase Enhances Cytotoxicity of Salinomycin in Cancer Cells.

Abstract

Salinomycin exhibits significant systemic adverse reactions such as tachycardia and myoglobinuria in mammals, which hinders its application as a drug for human cancers. Although many strategies aimed at increasing salinomycin’s toxicity to cancer cells have been identified to allow a lower dose of salinomycin to be used, they often cause normal cell damage by themselves. Thus, it is urgent to find more effective methods to increase salinomycin’s toxicity to cancer cells with little influences on normal cells. Telomerase, which is expressed highly in most cancer cells rather than normal somatic cells, plays central roles in cancer cell fate regulation. Targeting telomerase represents a potential method for enhancing salinomycin’s cytotoxicity to cancer cells with little effects on normal cells. Herein, we improve the toxicity of salinomycin against cancer cells by telomerase inhibition BIBR1532 (BIBR), which binds to the active site of telomerase reverse transcriptase. We find that a non-toxic dose of BIBR can enhance cytotoxicity of salinomycin in MCF-7 and MDA-MB-231 cells. Moreover, BIBR enhances mammosphere formation inhibition mediated by salinomycin in MCF-7 and MDA-MB-231 cells. Further studies show that BIBR enhances tumor growth inhibition induced by salinomycin in vivo. To our knowledge, this is the first example that targeting telomerase improves anti-cancer effects of salinomycin.