Vitamin A-related compounds, all- trans retinal and retinoic acids, selectively inhibit activities of mammalian replicative DNA polymerases

Retinoic acids, vitamin A-related compounds, are known to be inhibitors of telomerase. We found that fucoxanthin from the sea alga Petalonia bingamiae is a potent inhibitor of mammalian replicative DNA polymerases (i.e., pol α, δ and ϵ). Since fucoxanthin is a carotenoid (provitamin A-related) compound, we characterized the biochemical modes of vitamin A-related compounds including vitamin A and provitamin A in this report. Subsequently, we found that fucoxanthin, all- trans retinal (RAL, vitamin A aldehyde) and all- trans retinoic acid (RA, vitamin A acid) inhibited the activities of replicative DNA polymerases with IC 50 values of 18–190, 14–17 and 8–30 μM, respectively. On the other hand, all- trans retinol (vitamin A) did not influence any of the DNA polymerase activities. RA inhibited not only the activities of pol α, δ and ϵ with IC 50 values of 30, 28 and 8 μM, respectively, but of pol β with an IC 50 value of 27 μM. The tested vitamin A-related compounds did not influence the activities of DNA polymerases from a higher plant, cauliflower, prokaryotic DNA polymerases, or DNA metabolic enzymes such as human immunodeficiency virus type 1 reverse transcriptase, T7 RNA polymerase and bovine deoxyribonuclease I. RAL and RA should be called selective inhibitors of mammalian DNA polymerases including telomerase, and RAL was a specific inhibitor of mammalian replicative DNA polymerases. As expected from these results in vitro, some of them could prevent the growth of NUGC-3 human gastric cancer cells, and especially RAL was a potent antineoplastic agent with an LD 50 value of 19 μM. The cells were halted at G1 phase in the cell cycle by RAL.