Inhibitory effect of tocotrienol on eukaryotic DNA polymerase λ and angiogenesis

Yoshiyuki Mizushina, Kiyotaka Nakagawa, Akira Shibata, Yasutoshi Awata, Isoko Kuriyama, Noriko Shimazaki, Osamu Koiwai, Yukinobu Uchiyama, Kengo Sakaguchi, Teruo Miyazawa, Hiromi Yoshida

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

Abstract

Tocotrienols, vitamin E compounds that have an unsaturated side chain with three double bonds, selectively inhibited the activity of mammalian DNA polymerase λ (pol λ) in vitro. These compounds did not influence the activities of replicative pols such as α, δ, and ε, or even the activity of pol β which is thought to have a very similar three-dimensional structure to the pol β-like region of pol λ. Since δ-tocotrienol had the strongest inhibitory effect among the four (α- to δ-) tocotrienols, the isomer's structure might be an important factor in the inhibition of pol λ. The inhibitory effect of δ-tocotrienol on both intact pol λ (residues 1-575) and a truncated pol λ lacking the N-terminal BRCA1 C-terminus (BRCT) domain (residues 133-575, del-1 pol λ) was dose-dependent, with 50% inhibition observed at a concentration of 18.4 and 90.1 μM, respectively. However, del-2 pol λ (residues 245-575) containing the C-terminal pol β-like region was unaffected. Tocotrienols also inhibited the proliferation of and formation of tubes by bovine aortic endothelial cells, with δ-tocotrienol having the greatest effect. These results indicated that tocotrienols targeted both pol λ and angiogenesis as anti-cancer agents. The relationship between the inhibition of pol λ and anti-angiogenesis by δ-tocotrienol was discussed.

Original languageEnglish
Pages (from-to)949-955
Number of pages7
JournalBiochemical and biophysical research communications
Volume339
Issue number3
DOIs
Publication statusPublished - 2006 Jan 20

Keywords

  • Anti-angiogenesis
  • DNA polymerase λ
  • Enzyme inhibitor
  • Tocotrienol
  • Vitamin E

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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