Some anti-chronic inflammatory compounds are DNA polymerase lambda-specific inhibitors.

Abstract

We previously reported that a phenolic compound, petasiphenol, was a selective inhibitor of DNA polymerase lambda (pol lambda) in vitro. We found here that another phenolic compound, curcumin (diferuloylmethane), which is known as an anti-chronic inflammatory agent and is structurally quite similar to petasiphenol, was also a potent pol lambda inhibitor. The IC(50) values of petasiphenol and curcumin were 7.8 and 7.0 microM, respectively. Curcumin, as well as petasiphenol, did not influence the activities of replicative DNA polymerases, such as alpha, gamma, delta, and epsilon, but also showed no effect even on the pol beta activity belonging to the X family. Curcumin could prevent the growth of human NUGC-3 cancer cells with LD(50) values of 13 microM, and halted them at the G2/M phase in the cell cycle, whereas petasiphenol suppressed the cell growth at 66 microM and arrested the cells at the G1 phase. These data showed that curcumin and petasiphenol were slightly different functionally. We also previously reported that novel anti-inflammatory terpeno benzoic acids and triterpenoids were inhibitors of mammalian DNA polymerases. They could also efficiently inhibit the pol lambda activity, although they influenced the other polymerase species to the same extent, suggesting that there may be a physiological relationship between pol lambda inhibition and anti-12-O-tetradecanoylphorbol-13-acetate-induced inflammation. Expectedly, petasiphenol also showed an anti-12-O-tetradecanoylphorbol-13-acetate-induced inflammatory effect in mice. This finding may provide clues to investigating the molecular mechanism of inflammation.

• Authors: Yoshiyuki Mizushina, Mitsuru Hirota, Chikako Murakami, Tomomi Ishidoh, Shinji Kamisuki, Noriko Shimazaki, Masaharu Takemura, Marinela Perpelescu, Motoshi Suzuki, Hiromi Yoshida, Fumio Sugawara, Osamu Koiwai, Kengo Sakaguchi
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 66 Issue 10 Pg. 1935-44 (Nov 15 2003) ISSN: 0006-2952 [Print] England
• PMID: 14599551 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Caffeic Acids
• Enzyme Inhibitors
• Phenols
• petasiphenol
• DNA polymerase beta2
• DNA Polymerase beta
• Curcumin
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Caffeic Acids (pharmacology)
• Cell Division (drug effects)
• Curcumin (pharmacology)
• DNA Polymerase beta (antagonists & inhibitors)
• Enzyme Inhibitors (pharmacology)
• Humans
• Inflammation (chemically induced, drug therapy)
• Mice
• Phenols (pharmacology, therapeutic use)
• Tetradecanoylphorbol Acetate