Assessment of cytotoxicity of some synthetic compounds against breast carcinoma spheroids with subsequent analysis of pro-apoptotic and gene expression

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Abstract The current study examined the anticancer potential of 80 synthetic organic compounds at 50µM using in vitro two-dimensional (2D) and three-dimensional (3D) spheroids model breast adenocarcinoma (MCF7) models. The most promising six cytotoxic compounds on the 3D spheroids model (> 70% growth cytotoxicity) were counter-screened for their safety on normal cells (RPE1 cell line) grown as 3D spheroids. In parallel, the six compounds were tested for their pro-apoptotic activity using the M30 Cyto death ELISA assay. Based on the activity on MCF7 3D spheroids model, half maximum inhibitory concentration (IC 50 < 26µM), the safety on normal cells (< 35% cytotoxicity) and the pro-apoptotic activity on cancer cells (> fourfold increase of negative control), three compounds were considered the most promising and were selected for further investigation, named: F03, F06 and C02. These three candidates underwent further gene expression profiling of apoptosis and inflammatory related genes by quantitative real-time polymerase chain reaction (qRT-PCR). The gene expression results for the three compounds indicated favorable pro-apoptotic activity while unfavorable pro-inflammatory induction. Statistical analysis of the Xlog P values of the 3D spheroids model hits compared to that of the 80-compounds library showed a significant tendency for higher XlogP values in the 3D spheroids model hits sub-group, most probably due to the higher penetrability of lipophilic compounds into the tumor mass. The presented work can be considered a pilot model for an approach in anticancer drug discovery.

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