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Identification of Agents that Induce Apoptosis of Multicellular Tumour Spheroids: Enrichment for Mitotic Inhibitors with Hydrophobic Properties
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer Pharmacology and Informatics/Rolf Larsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer Pharmacology and Informatics/Rolf Larsson)
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2011 (English)In: Chemical Biology and Drug Design, ISSN 1747-0277, E-ISSN 1747-0285, Vol. 78, no 4, 547-557 p.Article in journal (Refereed) Published
Abstract [en]

Cell-based anticancer drug screening generally utilizes rapidly proliferating tumour cells grown as monolayer cultures. Hit compounds from such screens are not necessarily effective on hypoxic and slowly proliferating cells in 3-D tumour tissue. The aim of this study was to examine the potential usefulness of 3-D cultured tumour cells for anticancer drug screening. We used colon carcinoma multicellular spheroids containing hypoxic and quiescent cells in core areas for this purpose. Three libraries (similar to 11 000 compounds) were screened using antiproliferative activity and/or apoptosis as end-points. Screening of monolayer and spheroid cultures was found to identify different sets of hit compounds. Spheroid screening enriched for hydrophobic compounds: median XLogP values of 4.3 and 4.4 were observed for the hits in two independent screening campaigns. Mechanistic analysis revealed that the majority of spheroid screening hits were microtubuli inhibitors. One of these inhibitors was examined in detail and found to be effective against non-dividing cells in the hypoxic centres of spheroids. Spheroid screening represents a conceptually new strategy for anticancer drug discovery. Our findings have implications for drug library design and hit selection in projects aimed to develop drugs for the treatment of solid tumours.

Place, publisher, year, edition, pages
2011. Vol. 78, no 4, 547-557 p.
Keyword [en]
anticancer drugs, apoptosis, microtubuli inhibitors, solid tumours, XLogP
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-159451DOI: 10.1111/j.1747-0285.2011.01170.xISI: 000294922600006OAI: oai:DiVA.org:uu-159451DiVA: diva2:445651
Available from: 2011-10-04 Created: 2011-10-03 Last updated: 2017-12-08Bibliographically approved

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