8-Cl-cAMP, “The Old Dog with New Tricks”: A Review

Current chemotherapeutic drugs act for the most part by killing cancer cells directly. Treatment with these drugs often can be harmful to normal cells and may cause incomplete elimination of the target cells, resulting in the recurrence of the disease. To coop with current treatments the path of biomodulation rather than cytotoxicity, has been seen in the role of cAMP in normal versus malignant cells. It has been found that an increase of cAMP levels in normal cells stimulates proliferation, and that in the same time cancerous cells are inhibited to proliferate. This inverted reaction has given the momentum for synthesis of various cAMP analogues and investigation of there antitumor activity. A number of analogues, such as 8-PIP-cAMP, 8-Br-CAMP or 8-HA–cAMP showed efficacy only in millimolar concentrations. Only one of them, 8-Cl-cAMP as specific analogue has achieved inhibition of proliferation and stimulation of apoptosis of malignant cells in low or micromole concentrations. Still, 25 years later the mechanism of action of 8-clcAMP has not been fully elucidated or defined. This review is to challenge these mechanisms of action and to set a view of the nature of 8-Cl-cAMP action.