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

Investigational new drugs (2015-06-21)
Ekaterina Schreiber-Brynzak, Erik Klapproth, Christine Unger, Irene Lichtscheidl-Schultz, Simone Göschl, Sarah Schweighofer, Robert Trondl, Helmut Dolznig, Michael A Jakupec, Bernhard K Keppler
ABSTRACT

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. 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. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Triton X-100, laboratory grade
Sigma-Aldrich
Propidium iodide, ≥94.0% (HPLC)
Sigma-Aldrich
Sodium pyruvate, ReagentPlus®, ≥99%
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Resazurin sodium salt, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Propidium iodide solution, solution (1.0 mg/ml in water)
Sigma-Aldrich
Sodium pyruvate, powder, BioReagent, suitable for cell culture, suitable for insect cell culture, ≥99%
Sigma-Aldrich
Resazurin sodium salt, certified by the Biological Stain Commission
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Sodium pyruvate, powder, BioXtra, suitable for mouse embryo cell culture
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Sodium pyruvate, BioXtra, ≥99%
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Sodium pyruvate, Hybri-Max, powder, suitable for hybridoma
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Sodium pyruvate, anhydrous, free-flowing, Redi-Dri, ReagentPlus®, ≥99%