title: Identification of agents that induce apoptosis of multicellular tumour spheroids: enrichment for mitotic inhibitors with hydrophobic properties.
abstract: 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 (∼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.
authors: Department of Oncology-Pathology, Karolinska Institute, S-17176 Stockholm, Sweden.
authors: Walid
authors: W
authors: Fayad
authors: Linda
authors: L
authors: Rickardson
authors: Caroline
authors: C
authors: Haglund
authors: Maria Hägg
authors: MH
authors: Olofsson
authors: Padraig
authors: P
authors: D'Arcy
authors: Rolf
authors: R
authors: Larsson
authors: Stig
authors: S
authors: Linder
authors: Mårten
authors: M
authors: Fryknäs
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma / Q000188:drug therapy; D003110:Colonic Neoplasms / Q000188:drug therapy; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D018874:Spheroids, Cellular / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents