Cyclic dipeptides in the induction of maturation for cancer therapy

Studies have suggested a possible form of therapy based on the use of matur ation-inducing compounds to induce differentiation of neoplastic cells and stimulate faster recovery of the normal cell population. The study of the e ffects of nine cyclic dipeptides on biochemical markers of differentiation implicated their potential to induce differentiation. Studies were undertak en 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 cell s. The cyclic dipeptides studied showed a high degree of specificity, having n o significant effect on Caco-2 cells (P > 0.05), representing the normal ga strointestinal mucosa. All inducers administered were shown to affect the t otal energy state of HT-29 cells, an effect which increased the probability of HT-29 cell differentiation. Results indicated that those agents which i nduced differential gene expression acted art different steps in the isolat ed signal transduction pathway. Cyclo(Trp-Trp) and cyclo(Phe-Pro) induced a high degree of acetylation of histones (P < 0.05), while the remaining cyc lic 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 res ponsive element binding protein phosphorylation studies suggest that the cy clic dipeptides activate a chromatin switch, which leads to the increase in accessibility of lineage-specific genes for transcription.