Inhibitory effect of coenzyme Q on eukaryotic DNA polymerase gamma and DNA topoisomerase II activities on the growth of a human cancer cell line.
Coenzyme Q (CoQ) is an isoprenoid quinine that functions as an electron carrier in the mitochondrial respiratory chain in eukaryotes. CoQ having shorter isoprenoid chains, especially CoQ1 and CoQ2, selectively inhibited the in vitro activity of eukaryotic DNA polymerase (pol) gamma, which is a mitochondrial pol. These compounds did not influence the activities of nuclear DNA replicative pols such as alpha, delta and epsilon, and nuclear DNA repair-related pols such as beta, eta, iota, kappa and lambda. CoQ also inhibited DNA topoisomerase II (topo II) activity, although the enzymatic characteristics, including modes of action, amino acid sequences and three-dimensional structures, were markedly different from those of pol gamma. These compounds did not inhibit the activities of procaryotic pols such as Escherichia coli pol I, and other DNA metabolic enzymes such as human immunodeficiency virus reverse transcriptase, T7 RNA polymerase and bovine deoxyribonuclease I. CoQ1, which has the shortest isoprenoid chains, had the strongest inhibitory effect on pol gamma and topo II activities among CoQ1-CoQ10, with 50% inhibitory concentration (IC50) values of 12.2 and 15.5 microM, respectively. CoQ1 could prevent the growth of human promyelocytic leukemia cells, HL-60, and the 50% lethal dose (LD50) value was 14.0 microM. The cells were halted at S phase and G1 phase in the cell cycle, and suppressed mitochondrial proliferation. From these results, the relationship between the inhibition of pol gamma/topo II and cancer cell growth by CoQ is discussed.
Yonezawa
Yuko
Y
Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180.
Kuriyama
Isoko
I
Fukuoh
Atsushi
A
Muta
Tsuyoshi
T
Kang
Dongchon
D
Takemura
Masaharu
M
Kato
Ikuo
I
Yoshida
Hiromi
H
Mizushina
Yoshiyuki
Y
D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007928:Lethal Dose 50; D009369:Neoplasms / Q000201:enzymology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors; D014451:Ubiquinone / Q000494:pharmacology*
D019384:Nucleic Acid Synthesis Inhibitors; D059005:Topoisomerase II Inhibitors; D014451:Ubiquinone; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C025203:Ubiquinone Q1