Cancer is a leading cause of death worldwide. Two-dimensional (2D) monolayer cellular assays have been widely used as an in vitro model for anti-cancer drug screening purposes. However, the conventional monolayer cell culture screening assays fall short in predicting clinical response because they lack in vivo tumor characteristics. In contrast, three-dimensional (3D) multicellular spheroid models are symmetrical cellular aggregates that mimic the physiological environment of tumors in vivo. Studies have demonstrated that in vitro spheroids and in vivo tumors have morphological similarities and exhibit resemblance in the penetration, binding and bioactivities of drugs. Despite numerous recognized advantages of 3D cell culture models as drug screening tools, the complexity and lack of standardized protocols for 3D assays has hindered their use in the mainstream pre-clinical drug screening processes. An easy-handling and cost-effective lung cancer 3D spheroid model suitable for small molecule anti-cancer compounds screening was developed, standardized and validated with Nimesulide [N- (4-nitro-2-phenoxyphenyl) methane sulfonamide] tubulin inhibitor library of 41 compounds. A correlational study was conducted between the activity of compounds in 2D and 3D culture models and several active tubulin inhibitors were identified from the screening processes. The IC50 values generated for 2D and 3D models were compared and the results indicated a poor correlation, suggesting difference in the potency trends of the two models. The 3D data should be more reliable than 2D monolayer screening, however multiple factors affected the potency of compounds in 3D assay. The compounds that exhibited better potency in 3D spheroid model than 2D model are expected to show significant in vivo anti-tumor activity. Screening in 3D model eliminates the compounds that show artificial good potency in 2D models. Drug screening in 3D model is a novel approach for anti-cancer drug discovery research that can help identify compounds for further in vivo xenograft studies.

Development and validation of 3D multicellular lung cancer spheroid model via pharmacological evaluation with tubulin inhibitors

246th National Meeting (2013)

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