Azelaic acid (C9- -dicarboxylic acid) is a competitive inhibitor of
tyrosinase and some
oxidoreductase in vitro, and in vivo has a beneficial effect on
lentigo maligna and
malignant melanoma. A definite cytotoxic effect in cultures of malignant melanocytes was also reported. In order to establish if the cytotoxic effect of the diacid is exerted equally in the absence of
tyrosinase,
lymphoma- and
leukemia-derived cell lines were cultured for 72 hr with 10(-3) M, 10(-2) M and 5 X 10(-2) M C9 disodium
salt. Normal resting lymphocytes, lymphocytes activated by phytohemoagglutinin, and mouse Balb/c 3T3 fibroblasts were also tested to study a possible effect of
azelaic acid on
DNA synthesis and cell duplication.
At 10(-3) M C9 had no effect on the viability of all the cells tested;
at 10(-2) M and 5 X 10(-2) M, C9 2Na had a 50-80% cytotoxic effect on
lymphoma- and
leukemia-derived cell lines, while at the same concentrations it was not toxic to normal lymphocytes, either resting or stimulated, or to 3T3 fibroblasts. The experiments on cellular incorporation of (1-9 14C)
azelaic acid showed that the radiocarbon uptake was two to three times higher for
lymphoma- and
leukemia-derived cell lines than for lymphocytes, either resting or stimulated, or 3T3 fibroblasts. Biochemical analysis revealed that the diacid underwent beta-oxidation in all the cell cultures. Fractionated centrifugations of 3T3 fibroblasts cultured in the presence of radiolabelled
azelaic acid (2 X 10(-4) M) plus cold C9 2Na (10(-2) M), showed that the radioactivity was mainly concentrated in the cytoplasm. The results, being similar to those obtained by adding
azelaic acid to cultures of
melanoma cells, suggest that the cytotoxic effect of
azelaic acid may be due to interference with mitochondrial oxido-
reductase enzymes, rather than with
tyrosinase. The difference in reaction between
lymphoma- and
leukemia-derived cell lines and normal or stimulated lymphocytes, and 3T3 fibroblasts, could be explained on the basis of a different degree of permeability of the cell membrane, and/or to a possible different sensitivity of reaction of mitochondrial functions. A similar argument could be used to explain the absence of an effect of
dicarboxylic acids upon normal as compared with hyperactive or malignant melanocytes in vivo.