title: Three-dimensional and co-culture models for preclinical evaluation of metal-based anticancer drugs.
abstract: BACKGROUND
  Hypoxic and necrotic regions that accrue within solid tumors in vivo are known to be associated with metastasis formation, radio- and chemotherapy resistance, and drug metabolism. Therefore, integration of these tumor characteristics into in vitro drug screening models is advantageous for any reliable investigation of the anticancer activity of novel drug candidates. In general, usage of cell culture models with in vivo like characteristics has become essential in preclinical drug studies and allows evaluation of complex problems such as tumor selectivity and anti-invasive properties of the drug candidates.
  
  
  METHODS
  In this study, we investigated the anticancer activity of clinically approved, investigational and experimental drugs based on platinum (cisplatin, oxaliplatin and KP1537), gallium (KP46), ruthenium (KP1339) and lanthanum (KP772) in different cell culture models such as monolayers, multicellular spheroids, as well as invasion and metastasis models. Results Application of the Alamar Blue assay to multicellular spheroids and a spheroid-based invasion assay resulted in an altered rating of compounds with regard to their cytotoxicity and ability to inhibit invasion when compared with monolayer-based cytotoxicity and transwell assays. For example, the gallium-based drug candidate KP46 showed in spheroid cultures significantly enhanced properties to inhibit protrusion formation and fibroblast mediated invasiveness, and improved cancer cell selectivity.
  
  
  CONCLUSIONS
  Taken together, our results demonstrate the advantages of spheroid-based assays and underline the necessity of using different experimental models for reliable preclinical investigations assessing and better predicting the anticancer potential of new compounds.
authors.affiliation: University of Vienna, Faculty of Chemistry, Institute of Inorganic Chemistry, Waehringer Str. 42, A-1090, Vienna, Austria.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Schreiber-Brynzak
authors.forename: Erik
authors.initials: E
authors.lastname: Klapproth
authors.forename: Christine
authors.initials: C
authors.lastname: Unger
authors.forename: Irene
authors.initials: I
authors.lastname: Lichtscheidl-Schultz
authors.forename: Simone
authors.initials: S
authors.lastname: Göschl
authors.forename: Sarah
authors.initials: S
authors.lastname: Schweighofer
authors.forename: Robert
authors.initials: R
authors.lastname: Trondl
authors.forename: Helmut
authors.initials: H
authors.lastname: Dolznig
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D018920:Coculture Techniques; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D000860:Hypoxia; D009942:Organometallic Compounds / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D015125:Oxyquinoline / Q000031:analogs & derivatives / Q000494:pharmacology; D010618:Phenanthrolines / Q000494:pharmacology; D018874:Spheroids, Cellular / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C551585:KP 1339; D009942:Organometallic Compounds; D009944:Organoplatinum Compounds; D010618:Phenanthrolines; C508982:tris(1,10-phenanthroline)lanthanum(III); C408502:tris(8-quinolinolato)gallium (III); D000077150:Oxaliplatin; D015125:Oxyquinoline; D002945:Cisplatin