Three-dimensional and co-culture models for preclinical evaluation of metal-based anticancer drugs.

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Ekaterina Schreiber-Brynzak - (Author)
  • Erik Klapproth - , Institute of Pharmacology and Toxicology, University of Vienna (Author)
  • Christine Unger - (Author)
  • Irene Lichtscheidl-Schulz - (Author)
  • Simone Göschel - (Author)
  • Sarah Schweighofer - (Author)
  • Robert Trondl - (Author)
  • Helmut Dolznig - (Author)
  • Michael Jakupec - (Author)
  • Bernhardt Keppler - (Author)

Abstract

BackgroundHypoxic 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.Materials and methodsIn 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.ConclusionTaken 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.

Details

Original languageEnglish
JournalInvestigational new drugs
Publication statusPublished - 21 Jun 2015
Peer-reviewedYes

External IDs

PubMed 26091914
Scopus 84944153428

Keywords