8-Chloro-Cyclic AMP and Protein Kinase A I-Selective Cyclic AMP Analogs Inhibit Cancer Cell Growth through Different Mechanisms

Cyclic AMP (cAMP) inhibits the proliferation of several tumor cells. We previously reported an antiproliferative effect of PKA I-selective cAMP analogs (8-PIP-cAMP and 8-HA-cAMP) on two human cancer cell lines of different origin. 8-Cl-cAMP, another cAMP analog with known antiproliferative properties, has been investigated as a potential anticancer drug. Here, we compared the antiproliferative effect of 8-Cl-cAMP and the PKA I-selective cAMP analogs in three human cancer cell lines (ARO, NPA and WRO). 8-Cl-cAMP and the PKA I-selective cAMP analogs had similarly potent antiproliferative effects on the BRAF-positive ARO and NPA cells, but not on the BRAF-negative WRO cells, in which only 8-Cl-cAMP consistently inhibited cell growth. While treatment with the PKA I-selective cAMP analogs was associated with growth arrest, 8-Cl-cAMP induced apoptosis. To further investigate the actions of 8-Cl-cAMP and the PKA I-selective cAMP analogs, we analyzed their effects on signaling pathways involved in cell proliferation and apoptosis. Interestingly, the PKA I-selective cAMP analogs, but not 8-Cl-cAMP, inhibited ERK phosphorylation, whereas 8-Cl-cAMP alone induced a progressive phosphorylation of the p38 mitogen-activated protein kinase (MAPK), via activation of AMPK by its metabolite 8-Cl-adenosine. Importantly, the pro-apoptotic effect of 8-Cl-cAMP could be largely prevented by pharmacological inhibition of the p38 MAPK. Altogether, these data suggest that 8-Cl-cAMP and the PKA I-selective cAMP analogs, though of comparable antiproliferative potency, act through different mechanisms. PKA I-selective cAMP analogs induce growth arrest in cells carrying the BRAF oncogene, whereas 8-Cl-cAMP induce apoptosis, apparently through activation of the p38 MAPK pathway

Using the cytokinesis-block micronucleus cytome assay to evaluate Chromosomal DNA damage in chronic renal patients undergoing Bicarbonate Haemodialysis and Haemodiafiltration

Introduction. Chronic Renal Failure (CRF) patients are considered to show genomic instability and are associated with a high risk of both cardiovascular diseases and cancer. We explored DNA damage due to two dialysis treatments in 20 patients undergoing bicarbonate haemodialysis, 20 undergoing haemodiafiltration and 40 healthy subjects.Methods. The cytokinesis-block micronucleus (MN) assay was performed on peripheral blood lymphocytes to evaluate genetic damage.Results. A higher frequency of MN in the dialysis groups compared with controls was found. The results do not show a relationship between genetic instability and the type, frequency and duration of haemodialysis. The average BD and HDF treatment time was respectively 3.8±6.3 and 3.7±3.9 yrs. CAT and scintigraphy was independently correlated with high levels of MN.Discussion. Overall, the frequency of MN in CRF patients undergoing dialysis therapy was observed to be higher. Further studies need to be performed on a larger number of patients and for a longer period