Studies have suggested a possible form of
therapy based on the use of maturation-inducing compounds to induce differentiation of neoplastic cells and stimulate faster recovery of the normal cell population. The study of the effects of nine cyclic
dipeptides on
biochemical markers of differentiation implicated their potential to induce differentiation. Studies were undertaken to determine the specificity of these agents for HT-29 cell cultures as well as the identification of the signal transduction pathways affected by these agents inducing the differential gene expression observed in the cells. The cyclic
dipeptides studied showed a high degree of specificity, having no significant effect on Caco-2 cells (P > 0.05), representing the normal gastrointestinal mucosa. All inducers administered were shown to affect the total energy state of HT-29 cells, an effect which increased the probability of HT-29 cell differentiation. Results indicated that those agents which induced differential gene expression acted at different steps in the isolated signal transduction pathway.
Cyclo(Trp-Trp) and
cyclo(Phe-Pro) induced a high degree of acetylation of
histones (P < 0.05), while the remaining cyclic
dipeptides induced a high degree of phosphorylation of
histones (P < 0.05) (
cyclo(Trp-Trp) induced a moderate degree of
histone phosphorylation). The results from
histone phosphorylation and acetylation and
cyclic AMP responsive
element binding protein phosphorylation studies suggest that the cyclic
dipeptides activate a
chromatin switch, which leads to the increase in accessibility of lineage-specific genes for transcription.