Epolactaene, a novel neuritogenic compound in human neuroblastoma cells, selectively inhibits the activities of mammalian DNA polymerases and human DNA topoisomerase II.
We chemically synthesized epolactaene, a neuritogenic compound in human neuroblastoma cells, and investigated its biochemical action in vitro. Epolactaene and its derivatives selectively inhibited the activities of mammalian DNA polymerase alpha and beta and human DNA topoisomerase II, with IC(50) values of 25, 94, and 10 microM, respectively. By comparison with its structural derivatives, the long alkyl side chain in epolactaene seemed to have an important role in this inhibitory effect. The compound did not influence the activities of plant or prokaryotic DNA polymerases or of other DNA metabolic enzymes such as telomerase, RNA polymerase, and deoxyribonuclease I. Epolactaene did not intercalate into DNA. These results suggested that the neuritogenic compound epolactaene influences both DNA polymerases and topoisomerase II despite the dissimilarity in both structure and properties of these two enzymes and that inhibition of these enzymes could be related to the neuritogenic effect in human neuroblastoma cells. The relationship between the neuritogenic mechanism and cell cycle regulation by epolactaene was also discussed.
Mizushina
Y
Y
Department of Applied Biological Science, Faculty of Science and Technology, Science University of Tokyo, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan.
Kobayashi
S
S
Kuramochi
K
K
Nagata
S
S
Sugawara
F
F
Sakaguchi
K
K
D000818:Animals; D004247:DNA / Q000378:metabolism; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D009447:Neuroblastoma / Q000737:chemistry*; D019384:Nucleic Acid Synthesis Inhibitors; D011090:Polyenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D019384:Nucleic Acid Synthesis Inhibitors; D011090:Polyenes; D059005:Topoisomerase II Inhibitors; C095351:epolactaene; D004247:DNA; D004256:DNA Polymerase I; D019951:DNA Polymerase beta