Azelaic acid: mode of action at cellular and subcellular levels

Azelaic acid (AZA) has been reported to have an inhibitory effect on DNA synthesis of melanoma cell lines. In order to elucidate the mechanism(s) underlying this inhibitory effect, I elected to study the effects of AZA and, for control purposes, adipic acid (ADA) on DNA synthesis rate of nuclei isolated from melanoma cells and keratinocytes cultured in the presence of different concentrations of the dicarboxylic acids. Before doing so, I found, by autoradiography, that [3H]AZA is incorporated into the nuclei in a time-dependent manner. AZA, and to a lesser extent ADA, caused a dose-dependent inhibition of DNA synthesis, regardless of whether these substances were present in cell cultures before isolation of nuclei, or were incubated with already isolated nuclei. In searching for the target for this inhibitory effect on nuclear DNA synthesis, I found that AZA, and to a lesser extent ADA, is a potent inhibitor of both bacterial DNA polymerase and of multienzyme complexes isolated from cultured melanoma cells and keratinocytes. These data suggest that the inhibitory effect of the dicarboxylic acids AZA and ADA on DNA synthesis of several cell lines is due to the interference of these substances with the activation of enzymes (e.g. DNA polymerases) required for DNA synthesis.