title: Anti-protozoal and anti-bacterial antibiotics that inhibit protein synthesis kill cancer subtypes enriched for stem cell-like properties.
abstract: Key players in translational regulation such as ribosomes might represent powerful, but hitherto largely unexplored, targets to eliminate drug-refractory cancer stem cells (CSCs). A recent study by the Lisanti group has documented how puromycin, an old antibiotic derived from Streptomyces alboniger that inhibits ribosomal protein translation, can efficiently suppress CSC states in tumorspheres and monolayer cultures. We have used a closely related approach based on Biolog Phenotype Microarrays (PM), which contain tens of lyophilized antimicrobial drugs, to assess the chemosensitivity profiles of breast cancer cell lines enriched for stem cell-like properties. Antibiotics directly targeting active sites of the ribosome including emetine, puromycin and cycloheximide, inhibitors of ribosome biogenesis such as dactinomycin, ribotoxic stress agents such as daunorubicin, and indirect inhibitors of protein synthesis such as acriflavine, had the largest cytotoxic impact against claudin-low and basal-like breast cancer cells. Thus, biologically aggressive, treatment-resistant breast cancer subtypes enriched for stem cell-like properties exhibit exacerbated chemosensitivities to anti-protozoal and anti-bacterial antibiotics targeting protein synthesis. These results suggest that old/existing microbicides might be repurposed not only as new cancer therapeutics, but also might provide the tools and molecular understanding needed to develop second-generation inhibitors of ribosomal translation to eradicate CSC traits in tumor tissues.
authors.affiliation: a Metabolism & Cancer Group; Translational Research Laboratory; Catalan Institute of Oncology (ICO) ; Girona; Catalonia , Spain.|b Girona Biomedical Research Institute (IDIBGI) ; Girona, Catalonia , Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Cuyàs
authors.affiliation: b Girona Biomedical Research Institute (IDIBGI) ; Girona, Catalonia , Spain.|c Unit of Clinical Research ; Catalan Institute of Oncology (ICO) ; Girona, Catalonia , Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Martin-Castillo
authors.affiliation: a Metabolism & Cancer Group; Translational Research Laboratory; Catalan Institute of Oncology (ICO) ; Girona; Catalonia , Spain.|b Girona Biomedical Research Institute (IDIBGI) ; Girona, Catalonia , Spain.
authors.forename: Bruna
authors.initials: B
authors.lastname: Corominas-Faja
authors.affiliation: d Biochemistry and Molecular Biology Unit ; Department of Biology; University of Girona ; Girona, Catalonia , Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Massaguer
authors.affiliation: b Girona Biomedical Research Institute (IDIBGI) ; Girona, Catalonia , Spain.|e Medical Oncology Department ; Catalan Institute of Oncology (ICO) ; Girona, Catalonia , Spain.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bosch-Barrera
authors.affiliation: a Metabolism & Cancer Group; Translational Research Laboratory; Catalan Institute of Oncology (ICO) ; Girona; Catalonia , Spain.|b Girona Biomedical Research Institute (IDIBGI) ; Girona, Catalonia , Spain.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
mesh_terms: D000167:Acriflavine / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D058492:Drug Repositioning; D004640:Emetine / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057166:High-Throughput Screening Assays; D006801:Humans; D042361:Mammary Glands, Human; D046228:Microarray Analysis; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011691:Puromycin / Q000494:pharmacology; D012270:Ribosomes / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D011500:Protein Synthesis Inhibitors; D003609:Dactinomycin; D000167:Acriflavine; D011691:Puromycin; D003513:Cycloheximide; D004640:Emetine
keywords: Antibiotics; Biolog; basal-like; breast cancer; cancer stem cells; claudin-low; drug repositioning; drug repurposing; phenotype; ribosomes