title: Reverse chemomodulatory effects of the SIRT1 activators resveratrol and SRT1720 in Ewing's sarcoma cells: resveratrol suppresses and SRT1720 enhances etoposide- and vincristine-induced anticancer activity.
abstract: OBJECTIVE
  SIRT1-activating compounds (STACs) may have potential in the management of cancer. However, the best-studied STAC, the naturally occurring compound resveratrol, is reported to have contradictory effects in combination chemotherapy regimens: It has been shown both to increase and to decrease the action of anticancer agents. To shed more light on this issue, we comparatively investigated the impact of resveratrol and the synthetic STAC SRT1720 on the responsiveness of Ewing's sarcoma (ES) cells to the chemotherapeutic drugs etoposide and vincristine.
  
  
  METHODS
  Because the effects of STACs can depend on the functionality of the tumor suppressor protein p53, we used three ES cell lines differing in their p53 status, i.e., wild-type p53 WE-68 cells, mutant p53 SK-ES-1 cells and p53 null SK-N-MC cells. Single agent and combination therapy effects were assessed by flow cytometric analyses of propidium iodide uptake and mitochondrial depolarization, by measuring caspase 3/7 activity and by gene expression profiling.
  
  
  RESULTS
  When applied as single agents, both STACs were effective in ES cells irrespective of their p53 status. Strikingly, however, when applied in conjunction with cytostatic agents, the STACs displayed reverse effects: SRT1720 largely enhanced etoposide- and vincristine-induced cell death, while resveratrol inhibited it. Combination index analyses validated the antipodal impact of the STACs on the effectiveness of the chemotherapeutics.
  
  
  CONCLUSIONS
  These findings suggest that the synthetic STAC SRT1720 may be useful to enhance the efficacy of anticancer therapy in ES. But they also suggest that the dietary intake of the natural STAC resveratrol may be detrimental during chemotherapy of ES.
authors.affiliation: Children's Clinic, Department of Pediatric Hematology and Oncology, Jena University Hospital, Jena, Germany. juergen.sonnemann@med.uni-jena.de.|Klinik für Kinder- und Jugendmedizin, Friedrich-Schiller-Universität Jena, Kochstr. 2, 07745, Jena, Germany. juergen.sonnemann@med.uni-jena.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Sonnemann
authors.affiliation: Children's Clinic, Department of Pediatric Hematology and Oncology, Jena University Hospital, Jena, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Kahl
authors.affiliation: Children's Clinic, Department of Pediatric Hematology and Oncology, Jena University Hospital, Jena, Germany.
authors.forename: Priyanka M
authors.initials: PM
authors.lastname: Siranjeevi
authors.affiliation: Children's Clinic, Department of Pediatric Hematology and Oncology, Jena University Hospital, Jena, Germany.
authors.forename: Annelie
authors.initials: A
authors.lastname: Blumrich
authors.affiliation: Children's Clinic, Department of Pediatric Hematology and Oncology, Jena University Hospital, Jena, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Blümel
authors.affiliation: Children's Clinic, Department of Pediatric Hematology and Oncology, Jena University Hospital, Jena, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Becker
authors.affiliation: Children's Clinic, Department of Pediatric Hematology and Oncology, Jena University Hospital, Jena, Germany.
authors.forename: Susan
authors.initials: S
authors.lastname: Wittig
authors.affiliation: Children's Clinic, Department of Pediatric Hematology and Oncology, Jena University Hospital, Jena, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Winkler
authors.affiliation: Department of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, 55131, Mainz, Germany.
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Krämer
authors.affiliation: Children's Clinic, Department of Pediatric Hematology and Oncology, Jena University Hospital, Jena, Germany.
authors.forename: James F
authors.initials: JF
authors.lastname: Beck
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005047:Etoposide / Q000008:administration & dosage; D005434:Flow Cytometry; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D012333:RNA, Messenger; C525422:SRT1720; D013267:Stilbenes; D014750:Vincristine; D005047:Etoposide; D020169:Caspases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: Cancer therapy; Ewing’s sarcoma; Resveratrol; SIRT1; SRT1720; STACs