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 alpha, delta and epsilon). 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 microM, 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 alpha, delta and epsilon with IC(50) values of 30, 28 and 8 microM, respectively, but of pol beta with an IC(50) value of 27 microM. 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 microM. The cells were halted at G1 phase in the cell cycle by RAL.
Murakami
Chikako
C
Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Hyogo, Japan.
Takemura
Masaharu
M
Sugiyama
Yuichi
Y
Kamisuki
Shinji
S
Asahara
Hitomi
H
Kawasaki
Miho
M
Ishidoh
Tomomi
T
Linn
Stuart
S
Yoshida
Shonen
S
Sugawara
Fumio
F
Yoshida
Hiromi
H
Sakaguchi
Kengo
K
Mizushina
Yoshiyuki
Y
D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007700:Kinetics; D019384:Nucleic Acid Synthesis Inhibitors; D017830:Octoxynol; D011092:Polyethylene Glycols; D012172:Retinaldehyde / Q000494:pharmacology*; D012710:Serum Albumin, Bovine; D013942:Thymine Nucleotides / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014801:Vitamin A / Q000031:analogs & derivatives / Q000494:pharmacology*; D024341:Xanthophylls / Q000302:isolation & purification / Q000494:pharmacology; D019207:beta Carotene / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D013942:Thymine Nucleotides; D024341:Xanthophylls; D019207:beta Carotene; C025164:fucoxanthin; D014801:Vitamin A; D012710:Serum Albumin, Bovine; D011092:Polyethylene Glycols; D014212:Tretinoin; C005948:astaxanthine; D017830:Octoxynol; C010615:Nonidet P-40; D004256:DNA Polymerase I; D019951:DNA Polymerase beta; D004259:DNA-Directed DNA Polymerase; C024157:thymidine 5'-triphosphate; D012172:Retinaldehyde