Selective inhibition of the activities of both eukaryotic DNA polymerases and DNA topoisomerases by elenic acid.
(R)-(-)-Elenic acid (R-2,4-dimethyl-22-(p-hydroxyphenyl)-docos-3(E)-enoic acid) (EA) is a DNA topoisomerase II inhibitor found in an Indonesian sponge, Plakinastrella sp. We found and report here that it is a potent inhibitor of calf DNA polymerase alpha (IC(50)=7.7 microM) and rat DNA polymerase beta (IC(50)=12.9 microM). EA did not bind to DNA directly. EA did not influence the activities of DNA polymerases such as plant DNA polymerases I and II and prokaryotic DNA polymerases such as Escherichia coli DNA polymerase I, or other DNA metabolic enzymes such as human immunodeficiency virus (HIV) reverse transcriptase, T7 RNA polymerase and bovine deoxyribonuclease I. Interestingly, EA was also an inhibitor of DNA topoisomerases I and II, although the enzymatic characteristics including modes of action, amino acid sequences and three-dimensional structures were markedly different from those of DNA polymerases. EA could prevent the growth of NUGC-3 cancer cells, and the LD(50) value was 22.5 microM. The cells were halted at G1 and G2/M phase in the cell cycle. From these results, the action mode of EA is discussed.
Mizushina
Yoshiyuki
Y
Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku Kobe, Hyogo, Japan. mizushin@nutr.kobegakuin.ac.jp
Murakami
Chikako
C
Ohta
Keisuke
K
Takikawa
Hirosato
H
Mori
Kenji
K
Yoshida
Hiromi
H
Sugawara
Fumio
F
Sakaguchi
Kengo
K
D000818:Animals; D017209:Apoptosis; D026942:DNA Topoisomerases / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005057:Eukaryotic Cells / Q000166:cytology / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D006801:Humans; D008322:Mammals; D019384:Nucleic Acid Synthesis Inhibitors; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D059003:Topoisomerase Inhibitors
D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D019384:Nucleic Acid Synthesis Inhibitors; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D059003:Topoisomerase Inhibitors; C452499:elenic acid; D004259:DNA-Directed DNA Polymerase; D026942:DNA Topoisomerases; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II