title: Inhibitory effect of tocotrienol on eukaryotic DNA polymerase lambda and angiogenesis.
abstract: Tocotrienols, vitamin E compounds that have an unsaturated side chain with three double bonds, selectively inhibited the activity of mammalian DNA polymerase lambda (pol lambda) in vitro. These compounds did not influence the activities of replicative pols such as alpha, delta, and epsilon, or even the activity of pol beta which is thought to have a very similar three-dimensional structure to the pol beta-like region of pol lambda. Since delta-tocotrienol had the strongest inhibitory effect among the four (alpha- to delta-) tocotrienols, the isomer's structure might be an important factor in the inhibition of pol lambda. The inhibitory effect of delta-tocotrienol on both intact pol lambda (residues 1-575) and a truncated pol lambda lacking the N-terminal BRCA1 C-terminus (BRCT) domain (residues 133-575, del-1 pol lambda) was dose-dependent, with 50% inhibition observed at a concentration of 18.4 and 90.1microM, respectively. However, del-2 pol lambda (residues 245-575) containing the C-terminal pol beta-like region was unaffected. Tocotrienols also inhibited the proliferation of and formation of tubes by bovine aortic endothelial cells, with delta-tocotrienol having the greatest effect. These results indicated that tocotrienols targeted both pol lambda and angiogenesis as anti-cancer agents. The relationship between the inhibition of pol lambda and anti-angiogenesis by delta-tocotrienol was discussed.
authors.affiliation: Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan. mizushin@nutr.kobegakuin.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mizushina
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Akira
authors.initials: A
authors.lastname: Shibata
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Awata
authors.forename: Isoko
authors.initials: I
authors.lastname: Kuriyama
authors.forename: Noriko
authors.initials: N
authors.lastname: Shimazaki
authors.forename: Osamu
authors.initials: O
authors.lastname: Koiwai
authors.forename: Yukinobu
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Kengo
authors.initials: K
authors.lastname: Sakaguchi
authors.forename: Teruo
authors.initials: T
authors.lastname: Miyazawa
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors*; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology*; D024508:Tocotrienols / Q000008:administration & dosage*
chemical_list: D004791:Enzyme Inhibitors; D024508:Tocotrienols; C415367:DNA polymerase beta2; D004258:DNA Polymerase III; D019951:DNA Polymerase beta