Efficacy of chemopreventive agents for growth inhibition of Apc [+/-] 1638NCOL colonic epithelial cells

Germline mutations of the Apc tumor suppressor gene result in increased risk for gastrointestinal carcinogenesis. The Apc1638N [+/-] mouse exhibits accelerated gastrointestinal carcinogenesis that is modifiable by select pharmacological and dietary agents. Experiments in the present study were conducted on a subculturable epithelial 1638NCOL cell line established from histologically normal colon of Apc1638N [+/-] mouse to examine the effects of selected chemopreventive agents that differ in their mechanism of action. Extent of growth arrest, number of cell population doublings, cell cycle progression and aneuploid G0/G1: S + G2/M ratio represented the quantitative endpoints for the susceptibility and efficacy of chemopreventive agents. Treatment of exponentially growing 1638NCOL cells with maximum cytostatic dose of 9cisRA, DFMO or SUL (100 microM) produced a 60-70% growth arrest, that with TAM and AMF (10 microM) produced a 20-40% growth arrest, while that with OLT (100 microM) produced a 25% growth arrest. This response was associated with corresponding decrease in the number of cell population doubling. 9cisRA, SUL or AMF increased the aneuploid G0/G1: S + G2/M ratio by inducing G1 checkpoint arrest, while DFMO, TAM and OLT decreased the ratio by inducing G2 checkpoint arrest. Thus, cell cycle phase-dependent susceptibility of the Apc [+/-] 1638NCOL cell line to mechanistically distinct chemopreventive agents validates a novel colon epithelial cell culture model for mechanistic, preventive or therapeutic studies on Apc regulated colon carcinogenesis.