TY - JOUR
T1 - Inhibitory effect of tocotrienol on eukaryotic DNA polymerase λ and angiogenesis
AU - Mizushina, Yoshiyuki
AU - Nakagawa, Kiyotaka
AU - Shibata, Akira
AU - Awata, Yasutoshi
AU - Kuriyama, Isoko
AU - Shimazaki, Noriko
AU - Koiwai, Osamu
AU - Uchiyama, Yukinobu
AU - Sakaguchi, Kengo
AU - Miyazawa, Teruo
AU - Yoshida, Hiromi
N1 - Funding Information:
We are grateful to Dr. M. Takemura of Mie University and Dr. A. Matsukage of Japan Women’s University for preparing calf pol α and rat pol β, respectively. This work was supported in part by a Grant-in-Aid for Kobe-Gakuin University Joint Research (A) (Y.M. and H.Y.) and “High-Tech Research Center” Project for Private Universities: matching fund subsidy from MEXT (Ministry of Education, Culture, Sports, Science and Technology), 2001–2005 (Y.M. and H.Y.). Y.M. acknowledges Grants-in-Aid from the Uehara Memorial Foundation (Japan), the Takeda Science Foundation (Japan), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (Japan), the Japan Food Chemical Research Foundation (Japan), and Grant-in-Aid 16710161 for Scientific Research, MEXT (Japan).
PY - 2006/1/20
Y1 - 2006/1/20
N2 - 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.
AB - 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.
KW - Anti-angiogenesis
KW - DNA polymerase λ
KW - Enzyme inhibitor
KW - Tocotrienol
KW - Vitamin E
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U2 - 10.1016/j.bbrc.2005.11.085
DO - 10.1016/j.bbrc.2005.11.085
M3 - Article
C2 - 16325764
AN - SCOPUS:28844440048
SN - 0006-291X
VL - 339
SP - 949
EP - 955
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -
