title: Computed determination of the in vitro optimal chemocombinations of sphaeropsidin A with chemotherapeutic agents to combat melanomas.
abstract: OBJECTIVE
  Evasion to new treatments of advanced melanoma is still associated with a poor prognosis. Choosing the best combination of agents that can bypass resistance mechanisms remains a challenge. Sphaeropsidin A (Sph A) is a fungal bioactive secondary metabolite previously shown to force melanoma cells to undergo apoptosis via cell volume dysregulation. This work studied its in vitro combination with cytotoxic chemotherapeutics in a rational manner.
  
  
  METHODS
  Four melanoma cell lines harboring different sensitivity levels to pro-apoptotic stimuli were used to build a predictive response surface model allowing the determination of the optimal in vitro combinations of Sph A with two drugs, i.e., cisplatin or temozolomide, owing to a limited set of experimentations.
  
  
  RESULTS
  Testing 12 experimental combinations allowed us to build an accurate predictive model that considers the complexity of the drug interaction and determines the optimal combinations according to the endpoint chosen, i.e., the maximal cytotoxic effects. Therefore, combining 4 µM Sph A with 75 µM cisplatin concomitantly for 72 h improved its cytotoxic effects on melanoma cells in a synergistic manner. An optimal in vitro treatment schedule was also obtained for temozolomide.
  
  
  CONCLUSIONS
  The use of a response surface model offers the possibility of reducing the experiments while determining accurately the optimal combinations. We herein highlighted that combining the Na+/K+/2Cl-cotransporter and/or anion exchanger inhibitor Sph A with chemotherapeutic agents could improve the therapeutic benefits of conventional chemotherapies against advanced melanomas, particularly because Sph A exerts cytotoxic effects regardless of the genetic BRAF and NRAS status.
authors.affiliation: Laboratoire de Cancérologie et Toxicologie Expérimentale, Université Libre de Bruxelles, Boulevard du Triomphe, Accès 2, 1050, Ixelles, Belgium.
authors.forename: Aude
authors.initials: A
authors.lastname: Ingels
authors.affiliation: Department of Medicine I, Institute of Cancer Research, Medical University Vienna, Spitalgasse 23, 1090, Vienna, Austria.|Comprehensive Cancer Center, Medical University Vienna, Spitalgasse 23, 1090, Vienna, Austria.
authors.forename: Carina
authors.initials: C
authors.lastname: Dinhof
authors.affiliation: Laboratory for Cell Death Research and Therapy (CDRT), Department of Cellular and Molecular Medicine, KU Leuven University, Leuven, Belgium.
authors.forename: Abhishek D
authors.initials: AD
authors.lastname: Garg
authors.affiliation: Dipartimento di Agraria, Sezione di Patologia vegetale ed Entomologia, Università degli Studi di Sassari, Viale Italia 39, 07100, Sassari, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Maddau
authors.affiliation: Dipartimento di Scienze Chimiche, Universita' di Napoli Federico II, Complesso Universitario Monte S. Angelo, Via Cintia 4, 80126, Napoli, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Masi
authors.affiliation: Dipartimento di Scienze Chimiche, Universita' di Napoli Federico II, Complesso Universitario Monte S. Angelo, Via Cintia 4, 80126, Napoli, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Evidente
authors.affiliation: Department of Medicine I, Institute of Cancer Research, Medical University Vienna, Spitalgasse 23, 1090, Vienna, Austria.|Comprehensive Cancer Center, Medical University Vienna, Spitalgasse 23, 1090, Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.affiliation: Laboratoire d'Analyse Instrumentale et de Bioélectrochimie, Université Libre de Bruxelles, Boulevard du Triomphe, Accès 2, 1050, Ixelles, Belgium.
authors.forename: Bieke
authors.initials: B
authors.lastname: Dejaegher
authors.affiliation: Laboratoire de Cancérologie et Toxicologie Expérimentale, Université Libre de Bruxelles, Boulevard du Triomphe, Accès 2, 1050, Ixelles, Belgium. vemathie@ulb.ac.be.
authors.forename: Véronique
authors.initials: V
authors.lastname: Mathieu
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry* / Q000627:therapeutic use*; D017920:Antiporters / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004224:Diterpenes / Q000008:administration & dosage* / Q000627:therapeutic use*; D004339:Drug Compounding; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D008954:Models, Biological; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D015203:Reproducibility of Results; D028021:Sodium-Potassium-Chloride Symporters / Q000187:drug effects; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D017920:Antiporters; D004224:Diterpenes; D008565:Membrane Proteins; D028021:Sodium-Potassium-Chloride Symporters; D003606:Dacarbazine; C570422:sphaeropsidin A; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D002945:Cisplatin; D000077204:Temozolomide
keywords: Apoptosis; Cisplatin; Combination therapy; Melanoma; Sphaeropsidin A; Temozolomide