Three-Dimensional Cell Culture-Based Screening Identifies the Anthelmintic Drug Nitazoxanide as a Candidate for Treatment of Colorectal Cancer
2015 (English)In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 14, no 6, 1504-1516 p.Article in journal (Refereed) Published
Because dormant cancer cells in hypoxic and nutrient-deprived regions of solid tumors provide a major obstacle to treatment, compounds targeting those cells might have clinical benefits. Here, we describe a high-throughput drug screening approach, using glucose-deprived multicellular tumor spheroids (MCTS) with inner hypoxia, to identify compounds that specifically target this cell population. We used a concept of drug repositioning-using known molecules for new indications. This is a promising strategy to identify molecules for rapid clinical advancement. By screening 1,600 compounds with documented clinical history, we aimed to identify candidates with unforeseen potential for repositioning as anticancer drugs. Our screen identified five molecules with pronounced MCTS-selective activity: nitazoxanide, niclosamide, closantel, pyrvinium pamoate, and salinomycin. Herein, we show that all five compounds inhibit mitochondrial respiration. This suggests that cancer cells in low glucose concentrations depend on oxidative phosphorylation rather than solely glycolysis. Importantly, continuous exposure to the compounds was required to achieve effective treatment. Nitazoxanide, an FDA-approved antiprotozoal drug with excellent pharmacokinetic and safety profile, is the only molecule among the screening hits that reaches high plasma concentrations persisting for up to a few hours after single oral dose. Nitazoxanide activated the AMPK pathway and downregulated c-Myc, mTOR, and Wnt signaling at clinically achievable concentrations. Nitazoxanide combined with the cytotoxic drug irinotecan showed anticancer activity in vivo. We here report that the FDA-approved anthelmintic drug nitazoxanide could be a potential candidate for advancement into cancer clinical trials. (C) 2015 AACR.
Place, publisher, year, edition, pages
American Association for Cancer Research , 2015. Vol. 14, no 6, 1504-1516 p.
IdentifiersURN: urn:nbn:se:liu:diva-120662DOI: 10.1158/1535-7163.MCT-14-0792ISI: 000358054300025PubMedID: 25911689OAI: oai:DiVA.org:liu-120662DiVA: diva2:847544
Funding Agencies|Swedish Cancer Society; Swedish Foundation for Strategic Research; Swedish Research Council; Lions Cancer Research Fund; Strategiska Forskningsstiftelsen (SSF); Lions Cancerforskningsfond; Cancerfonden; Barncancerfonden; Radiumhemmets Forskningsfonder; Vetenskapsradet; SSF2015-08-202015-08-202015-08-26