Inhibitory effect of coenzyme Q₁ on eukaryotic DNA polymerase γ 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) γ, which is a mitochondrial pol. These compounds did not influence the activities of nuclear DNA replicative pols such as α, δ and ε, and nuclear DNA repair-related pols such as β, η, ι, κ and λ. 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 γ. 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 γ and topo II activities among CoQ₁-CoQ₁₀, with 50% inhibitory concentration (IC₅₀) values of 12.2 and 15.5 μM, respectively. CoQ₁ could prevent the growth of human promyelocytic leukemia cells, HL-60, and the 50% lethal dose (LD₅₀) value was 14.0 μM. 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 γ/topo II and cancer cell growth by CoQ is discussed.