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.
Cyclo(L-Trp-L-Pro) has shown potential for use in the treatment of cardiovascular dysfunction. The aim of the study was to determine the effects of the isomers of cyclo(Trp-Pro) - cyclo(L-Trp-L-Pro), cyclo(L-Trp-D-Pro), cyclo(D-Trp-L-Pro) and cyclo(D-Trp-D-Pro) - on heart and ion-channel activity. The effects on L-type Ca(2+)-channel, Na(+)-channel and inward rectifier K(+)-channel activity were determined by using the whole-cell patch-clamp technique on myocytes of guinea-pig origin. Dependence on the membrane potential in terms of Ca(2+)-channel activity was also investigated. A modified Langendorff method was used to determine the effects of the isomers on heart rate, coronary flow, duration of ventricular tachycardia and arrhythmia, time to sinus rhythm and QRS interval on the rat isolated heart. Cyclo(L-Trp-L-Pro), cyclo(L-Trp-D-Pro) and cyclo(D-Trp-D-Pro), 100 microM, showed agonism towards Ca(2+)-channel activity, while cyclo(D-Trp-L-Pro) caused a blockage of the current. The action of cyclo(D-Trp-L-Pro) was shown to be independent of membrane potential. No significant effect (P > 0.05) on the inward rectifier K(+) current was observed in the presence of cyclo(L-Trp-D-Pro) and cyclo(D-Trp-D-Pro), while antagonism was noted in the presence of cyclo(L-Trp-L-Pro) and cyclo(D-Trp-L-Pro). All isomers showed antagonist effects on the Na(+) channel. No adverse effects were noted on chronotropic effects in the presence of 200 microM cyclo(L-Trp-L-Pro) and cyclo(D-Trp-D-Pro) (P > 0.05), while cyclo(L-Trp-D-Pro) significantly increased the heart rate. Cyclo(D-Trp-L-Pro) significantly reduced the heart rate (P < 0.05). In addition, no significant effects were observed on the coronary flow rate in the presence of the isomers. All isomers significantly reduced the duration of ventricular tachycardia and arrhythmia, as well as the time to sinus rhythm. Furthermore, no change in the QRS intervals was noted in the presence of the isomers in comparison with the control, with a significant increase being noted for cyclo(D-Trp-D-Pro) (P < 0.05) in reference to the other isomers. The isomers thus show antiarrhythmic potential and may manifest as novel agents in the treatment of cardiovascular dysfunction, since a decrease in ventricular fibrillation may reduce the mortality rates in acute myocardial infarction.
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