title: The naturally born fusariotoxin enniatin B and sorafenib exert synergistic activity against cervical cancer in vitro and in vivo.
abstract: During the last decades substantial progress has been made in developing systemic cancer therapy. However, tumors are frequently intrinsically resistant against structurally and mechanistically unrelated drugs. Thus, it is of predominant interest to overcome drug resistance and to encourage the research for novel chemotherapeutic approaches. Recently, we have introduced enniatins, naturally occurring cyclohexadepsipeptides produced by filamentous fungi of the genus Fusarium, as potential anticancer drugs. Here, we expend this approach by demonstrating antiangiogenic properties for enniatin B (Enn B) indicated by a strong inhibition of human endothelial cell migration and tube formation. Moreover, combination of Enn B with the clinically approved multi-kinase inhibitor sorafenib (Sora) displayed profound synergistic in vitro and in vivo anticancer effects against cervical cancer. Subsequent studies showed that this strong synergism is accompanied by a marked increase in mitochondrial injury and apoptosis induction reflected by mitochondrial membrane depolarization, caspase-7 activation, and subsequent cleavage of PARP. Additionally, cells were shown to stop DNA synthesis and accumulate in S and G2/M phase of the cell cycle. The multifaceted characteristics underlying this strong synergism were suggested to be based on interference with the p38 MAPK as well as the ERK signaling pathways. Finally, also in vivo studies revealed that the combination treatment is distinctly superior to single drug treatments against the KB-3-1 cervix carcinoma xenograft model. Taken together, our data confirm the anticancer benefits of the naturally occurring fusariotoxin Enn B and further present Enn B/Sora as a novel combination strategy especially for the treatment of cervical cancer.
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstr. 14, A-1090 Vienna, Austria.|Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, and Comprehensive Cancer Center of the Medical University, Borschkegasse 8a, 1090 Vienna, Austria, as well as Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
authors.forename: Rita
authors.initials: R
authors.lastname: Dornetshuber-Fleiss
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstr. 14, A-1090 Vienna, Austria.|Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, and Comprehensive Cancer Center of the Medical University, Borschkegasse 8a, 1090 Vienna, Austria, as well as Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Heilos
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, and Comprehensive Cancer Center of the Medical University, Borschkegasse 8a, 1090 Vienna, Austria, as well as Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mohr
authors.affiliation: Technische Universität Berlin, Institut für Chemie, Straße des 17. Juni 124, Berlin 10623, Germany.
authors.forename: Lennart
authors.initials: L
authors.lastname: Richter
authors.affiliation: Technische Universität Berlin, Institut für Chemie, Straße des 17. Juni 124, Berlin 10623, Germany.
authors.forename: Roderich D
authors.initials: RD
authors.lastname: Süssmuth
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstr. 14, A-1090 Vienna, Austria.|Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, and Comprehensive Cancer Center of the Medical University, Borschkegasse 8a, 1090 Vienna, Austria, as well as Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Zlesak
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstr. 14, A-1090 Vienna, Austria.|Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, and Comprehensive Cancer Center of the Medical University, Borschkegasse 8a, 1090 Vienna, Austria, as well as Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
authors.forename: Astrid
authors.initials: A
authors.lastname: Novicky
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, and Comprehensive Cancer Center of the Medical University, Borschkegasse 8a, 1090 Vienna, Austria, as well as Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstr. 14, A-1090 Vienna, Austria.
authors.forename: Rosa
authors.initials: R
authors.lastname: Lemmens-Gruber
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, and Comprehensive Cancer Center of the Medical University, Borschkegasse 8a, 1090 Vienna, Austria, as well as Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D000077157:Sorafenib; D013605:T-2 Toxin / Q000008:administration & dosage*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D010671:Phenylurea Compounds; C100264:enniatins; D009536:Niacinamide; D000077157:Sorafenib; D013605:T-2 Toxin
keywords: Angiogenesis; Anticancer; Cyclohexadepsipeptide; Enniatin; Sorafenib; Synergism