Antagonistic effect of glucocorticoids on retinoic acid induced growth inhibition and morphological alterations of a human cell line.

When the human cell line NHIK 3025 was exposed to retinoic acid (1 nM; 10 microM), the cell cycle time was prolonged. Experiments using cells synchronized by mitotic selection showed that the retinoic acid induced growth delay was barely seen within the first cell cycle after exposure to 10 microM retinoic acid, whereas the next cell cycle durations were increased 30-60%. The effect was reversible as normal growth rate was restored after removal of the drug. DNA histograms indicated a prolongation of G1 of the cell cycle. We have shown earlier that glucocorticoid steroids also induce a prolongation of the cell cycle, located within G1. When the cells were exposed to the synthetic glucocorticoid, dexamethasone, in addition to retinoic acid, no additive effect was found; on the contrary, growth inhibition was less than that with retinoic acid alone. Dexamethasone from 1 nM upwards antagonized the growth inhibitory effect of retinoic acid. This glucocorticoid mediated effect seemed to be mediated via the glucocorticoid receptor, as no effect was seen when the receptor was blocked by the antagonist 17 beta hydroxy-11 beta, 4-dimethylaminophenyl-17 alpha-propynyl estra 4,9 diene-3-one [RU 38486]. The growth inhibition studies were supported by morphological observations showing that dexamethasone induced cytoskeletal alterations dominated when the cells were exposed to both drugs simultaneously. These findings might be of importance in cancer therapy where both drugs are used.