Studies on a novel DNA polymerase inhibitor group, synthetic sulfoquinovosylacylglycerols: inhibitory action on cell proliferation.
Some chemically synthesized sulfoquinovosylmonoacylglycerols (SQMG)-sulfoquinovosyldiacylglycerols (SQDG) have been reported to selectively and strongly inhibit the activities of mammalian DNA polymerases alpha and beta in vitro. In this study, using human cancer cell lines, we investigated the effects of SQMG-SQDG on the DNA polymerase in the cells. In the presence of n-decane, the IC(50) values on cell growth were approximately 1-5 microM for SQMG and about 0.3-1 microM for SQDG. The values were almost the same as the in vitro enzyme inhibitory levels. The cell lines were arrested in early S-phase by SQMG-SQDG at the concentrations of 0.1-4.7 microM in a manner dependent on incubation time, suggesting that SQMG-SQDG blocked the primary step of DNA replication by inhibiting DNA polymerase, possibly alpha-type. We also demonstrated the localization of SQMG in the cell using the fluorescent SQMG analog, SQMGalpha-NBDD, which was synthesized in our laboratory. SQMGalpha-NBDD was localized in the nucleus and on the nuclear surface, but the binding site seemed not to be the DNA/chromatin, suggesting that the SQMG-SQDG might interact with molecules located close to the DNA/chromatin and on the nuclear surface. These results suggested a correlation between the in vitro biochemical action of the SQMG-SQDGs and their intracellular mode of action.
Ohta
K
K
Department of Applied Biological Science, Faculty of Science and Technology, Science University of Tokyo, Chiba-ken 278-8510, Noda, Japan.
Hanashima
S
S
Mizushina
Y
Y
Yamazaki
T
T
Saneyoshi
M
M
Sugawara
F
F
Sakaguchi
K
K
D000818:Animals; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006017:Glycolipids / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D008856:Microscopy, Fluorescence; D019384:Nucleic Acid Synthesis Inhibitors; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D013950:Thymus Gland / Q000201:enzymology; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D006017:Glycolipids; D019384:Nucleic Acid Synthesis Inhibitors; D011506:Proteins; D012334:RNA, Neoplasm; C013694:sulfoquinovosyl diglyceride; D004256:DNA Polymerase I; D019951:DNA Polymerase beta