A primary aim of cancer therapy is to irradicate solid tumor masses. Anticancer drugs are nevertheless not systematically developed with this aim in mind ‐ screening and mechanistic studies are usually performed using cells grown under 2‐D monolayer conditions. We have developed a procedure to screen for compounds that induce apoptosis of 3‐D multicellular tumor spheroids. The chemical properties of spheroid screening hits differed significantly from conventional monolayer screening hits with regard to compound hydrophobicity and polar surface area. The spheroid screen resulted in hits which were more effective than standard chemotherapeutical agents in inducing wide‐spread apoptosis of tumor spheroids. Hypotheses regarding the mechanisms of action for the selected compounds were generated using the Connectivity Map (CMAP; a compendium of gene expression signatures from drug treated cell lines). One of the hits in the spheroid screen was the alkaloid thaspine from the South American tree Croton lechleri which we show to be a dual topoisomerase inhibitor. Thaspine is insensitive to overexpression of drug efflux transporters and induces apoptosis of tumor cells in vivo. Counter‐screening for compounds that do not induce apoptosis of normal epithelial cells resulted in a limited set of agents, most of which were found to be novel microtubuli inhibitors. The results show that interesting anti‐cancer drugs can be identified using spheroid screening.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A169.
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