4-Hydroxy-17-methylincisterol, an inhibitor of DNA polymerase-alpha activity and the growth of human cancer cells in vitro.
An ergosterol derivative, 4-hydroxy-17-methylincisterol (HMI), was found to be an inhibitor of mammalian DNA polymerases in vitro. HMI inhibited the activity of calf thymus DNA polymerase alpha (pol. alpha). Among the polymerases tested, pol. alpha was the most sensitive to inhibition by HMI, and the inhibition was concentration dependent. The inhibitory effect of HMI on pol. alpha was almost the same as that shown by aphidicolin, a well-known potent pol. alpha inhibitor. HMI had relatively less effect on rat DNA pol. beta, human immunodeficiency virus type 1 reverse transcriptase (HIV-RT), and calf thymus terminal deoxynucleotidyl transferase (TdT) in vitro, and did not influence the activities of prokaryotic DNA polymerases such as Klenow Fragment of DNA polymerase I, or the DNA-metabolic enzyme DNase I. HMI was found to be able to prevent the growth of human cancer cell lines originating from patients with leukemia or various solid tumors; its IC50 values ranged from 7.5 to 12 microM. We also synthesized other ergosterol derivatives and tested them, and found that two compounds, 17-methylincisterol and 4-acetyl-17-methylincisterol, have similar inhibitory effects.
Department of Applied Biological Science, Science University of Tokyo, Noda, Chiba, Japan.
H
H
Togashi
Y
Y
Mizushina
M
M
Takemura
F
F
Sugawara
H
H
Koshino
Y
Y
Esumi
J
J
Uzawa
H
H
Kumagai
A
A
Matsukage
S
S
Yoshida
K
K
Sakaguchi
D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D004253:DNA Nucleotidylexotransferase / Q000037:antagonists & inhibitors; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors*; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004875:Ergosterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D006801:Humans; D016014:Linear Models; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C115171:17-methylincisterol; C115170:4-acetyl-17-methylincisterol; C115169:4-hydroxy-17-methylincisterol; D004791:Enzyme Inhibitors; D004253:DNA Nucleotidylexotransferase; D054303:HIV Reverse Transcriptase; D004256:DNA Polymerase I; D019951:DNA Polymerase beta; D004875:Ergosterol