title: Salinomycin increases chemosensitivity to the effects of doxorubicin in soft tissue sarcomas.
abstract: BACKGROUND
  Chemotherapy for soft tissue sarcomas remains unsatisfactory due to their low chemosensitivity. Even the first line chemotherapeutic agent doxorubicin only yields a response rate of 18-29%. The antibiotic salinomycin, a potassium ionophore, has recently been shown to be a potent compound to deplete chemoresistant cells like cancer stem like cells (CSC) in adenocarcinomas. Here, we evaluated the effect of salinomycin on sarcoma cell lines, whereby salinomycin mono- and combination treatment with doxorubicin regimens were analyzed.
  
  
  METHODS
  To evaluate the effect of salinomycin on fibrosarcoma, rhabdomyosarcoma and liposarcoma cell lines, cells were drug exposed in single and combined treatments, respectively. The effects of the corresponding treatments were monitored by cell viability assays, cell cycle analysis, caspase 3/7 and 9 activity assays. Further we analyzed NF-κB activity; p53, p21 and PUMA transcription levels, together with p53 expression and serine 15 phosphorylation.
  
  
  RESULTS
  The combination of salinomycin with doxorubicin enhanced caspase activation and increased the sub-G1 fraction. The combined treatment yielded higher NF-κB activity, and p53, p21 and PUMA transcription, whereas the salinomycin monotreatment did not cause any significant changes.
  
  
  CONCLUSIONS
  Salinomycin increases the chemosensitivity of sarcoma cell lines - even at sub-lethal concentrations - to the cytostatic drug doxorubicin. These findings support a strategy to decrease the doxorubicin concentration in combination with salinomycin in order to reduce toxic side effects.
authors.affiliation: Institute of Pathology, Ruhr-University Bochum, Buerkle-de-la-Camp-Platz 1, 44789 Bochum, Germany. sven-thorsten.liffers@rub.de.
authors.forename: Sven-T
authors.initials: ST
authors.lastname: Liffers
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Tilkorn
authors.forename: Ingo
authors.initials: I
authors.lastname: Stricker
authors.forename: Christoph Günter
authors.initials: CG
authors.lastname: Junge
authors.forename: Sammy
authors.initials: S
authors.lastname: Al-Benna
authors.forename: Markus
authors.initials: M
authors.lastname: Vogt
authors.forename: Berlinda
authors.initials: B
authors.lastname: Verdoodt
authors.forename: Hans-U
authors.initials: HU
authors.lastname: Steinau
authors.forename: Andrea
authors.initials: A
authors.lastname: Tannapfel
authors.forename: Iris
authors.initials: I
authors.lastname: Tischoff
authors.forename: Alireza
authors.initials: A
authors.lastname: Mirmohammadsadegh
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology* / Q000633:toxicity; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D011714:Pyrans / Q000494:pharmacology* / Q000633:toxicity; D012509:Sarcoma / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D011714:Pyrans; D016159:Tumor Suppressor Protein p53; C010327:salinomycin; D000095662:Polyether Polyketides