Enhancement of carcinostatic activity of ω-hydroxy fatty acids by their esterification through increased uptake into tumor cells

Diverse omega-hydroxy fatty acids (ωHFAs) and their derivatives were examined for their ability to diminish the cell viability of Ehrlich ascites tumor cells by the mitochondrial dehydrogenase-based WST-1 assay and trypan blue dye exclusion assay. Of the diverse ωHFAs, hydroxyhexadecanoic acid (ωH16:0) was appreciably carcinostatic, and hydroxypentadecanoic acid (ωH15:0) or hydroxypentadecenoic acid (ωH15:1) was weakly carcinostatic at a dose of 100 µM, whereas hydroxydodecanoic acid (ωH12:0) and hydroxyhexadecenoic acid (ωH16:1) acid were scarcely carcinostatic at the same dose. In contrast their sodium salt derivatives except ωH16:0 were not carcinostatic. Enhancement of the carcinostatic activity was markedly exerted by ethylesterization of ωHFAs with the saturated fatty moiety such as ωH16:0 and ωH15:0, whereas ethylesters of the unsaturated ωHFAs such as ωH15:1 and ωH16:1 were weakly carcinostatic. Thus intramolecular introduction of a double bond was shown to weaken the carcinostatic activity in case of either ωHFAs or their ethylester, being in contrast to the conventional knowledge concerning the enhancement of carcinostatic activities of non-hydroxy fatty acids appendant with more double bonds. The intracellular uptake amount of each ωHFA as quantified by gas chromatography was the following order: ωH16:0 ethylester (10.1 pg/cell) > ωH15:0 ethylester (6.4 pg/cell) > ωH16:0 (3.4 pg/cell) > ωH15:0 (2.8 pg/cell), which accords with the order of carcinostatic activities of four saturated ωHFAs in contrast to discord between both the orders for unsaturated ωHFAs which could be scarcely detected as the intact form within cells. The results indicate that enhancement of carcinostatic activity of ωH16:0 by ethylesterization was attributed to an appreciable correlation between intracellular uptake amounts and carcinostatic activities for diverse ωHFAs with saturated fatty moiety, being not true for unsaturated ωHFAs.