Inhibitory effect of conjugated eicosapentaenoic acid on human DNA topoisomerases I and II

Yonezawa, Yasuo; Tsuzuki, Toshio; Eitsuka, Takahiro; Miyazawa, Teruo; Hada, Takahiko; Uryu, Keisuke; Murakami-Nakai, Chikako; Itoh, Hiroshi; Kuriyama, Isoko; Takemura, Masaharu; Oshige, Masahiko; Yoshida, Hiromi; Sakaguchi, Kengo; Mizushina, Yoshiyuki

doi:10.1016/j.abb.2004.12.011

Cited by 32 publications

(33 citation statements)

References 28 publications

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“…Nucleotides and chemically synthesized DNA template primers, such as poly(dA) and oligo(dT) [12][13][14][15][16][17][18] , and radioisotope reagents, such as [ 3 H]-dTTP (2'-deoxythymidine 5'-triphosphate) (43 Ci/mmol), were purchased from GE Healthcare Bio-Science Corp. (Piscataway, NJ, USA). All other reagents were of analytical grade and purchased from Nacalai Tesque Inc. (Kyoto, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…As n-3 PUFAs have been shown to have anticarcinogenic activity, conjugated fatty acids converted from n-3 PUFAs may show higher tumor-INTERNATIONAL JOURNAL OF ONCOLOGY 36: 577-584, 2010 Enhancement of human cancer cell radiosensitivity by conjugated eicosapentaenoic acid -a mammalian DNA polymerase inhibitor inhibiting activity than n-3 PUFAs themselves (13,14). We previously realized the importance of the two classes of n-3 PUFA; EPA and DHA, normal and conjugated, and the inhibitory effect of cEPA on pols was stronger than that of EPA, DHA and cDHA (15). Furthermore, cEPA regulates the cell cycle by DNA damage-response proteins, including the ataxia-telangiectasia mutated-and Rad3-related protein kinase (ATR)-Chk1/2 pathway without influencing the proliferation of normal cells (16,17).…”

Section: Introductionmentioning

confidence: 99%

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Enhancement of human cancer cell radiosensitivity by conjugated eicosapentaenoic acid - a mammalian DNA polymerase inhibitor

Kumamoto-Yonezawa

Sasaki²,

Suzuki³

et al. 2010

Int J Oncol

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Abstract. We previously found that conjugated eicosapentaenoic acid (cEPA) selectively inhibited the activities of mammalian DNA polymerases (pols), and suppressed human cancer cell growth. The aim of the present study was to evaluate the efficacy of concurrent radiation with cEPA in a human colon carcinoma cell line, HCT 116. Furthermore, we examined the most effective timing of irradiation. The postirradiation addition of cEPA significantly enhanced HCT116 cell radiosensitivity by decreasing the expression of pols ß, ‰ and Â, increasing damaged DNA, such as DNA double-strand breaks, inhibiting clonogenic survival, and inducing apoptosis. However, cells treated by pre-irradiation addition of cEPA did not influence radiosensitive survival and radiation-induced apoptosis. cEPA inhibited the activities of pols needed for DNA repair, thereby DNA damage must be augmented by cEPA and irradiation. These results suggested that the combination of inhibitors of DNA repair-related pols/radiation could be an effective anticancer therapy. IntroductionDNA polymerases (pol, i.e., DNA-dependent DNA polymerases, E.C. 2.7.7.7) catalyze the addition of deoxyribonucleotides to the 3'-hydroxyl terminus of primed doublestranded DNA molecules, and are involved in producing vital cellular processes, such as DNA replication, repair and recombination (1). The human genome encodes at least 15 pols to conduct cellular DNA synthesis (2,3). Eukaryotic cells contain three replicative pols (·, ‰ and Â), mitochondrial pol Á, and at least 13 repair-related pols; ß, ‰, Â, ˙, Ë, ı, È, Î, Ï, Ì, Ó, terminal deoxynucleotidyl transferase (TdT) and REV1 (2-4). Pols have recently emerged as important cellular targets for chemical intervention in the development of anticancer agents.We have been screening for pol inhibitors from natural products (5,6), and found that mammalian pols · and ß are inhibited by linear-chain fatty acids with the following characteristics: 1) C18-or more carbon chains, 2) a free carboxylic group, and 3) double bonds of cis-configuration, n-3 polyunsaturated fatty acid (PUFA) having the strongest inhibitory effect of any fatty acid tested (7,8). Eicosapentaenoic acid (EPA; 5Z8Z11Z14Z17Z-20:5) and docosahexanoic acid (DHA; 4Z7Z10Z13Z16Z19Z-22:6), both n-3 PUFAs, exert significant inhibitory effects on colon carcinoma cell growth at the primary site and metastases (9,10). PUFA are present at high concentrations in some fish oils, and have been evaluated in various clinical trials in which they have proved to be safe and well tolerated.Conjugated fatty acids are positional and geometrical isomers with several conjugated double bonds. Fatty acids with conjugated double bonds exist in nature; seaweeds such as red and green algae contain highly n-3 unsaturated conjugated fatty acids, i.e., conjugated eicosapentaenoic acid (cEPA; 5Z7E9E14Z17Z-20:5), bosseopentaenoic acid (5Z8Z10E12E14Z-20:5) and stellaheptaenoic acid (4Z7Z9 E11E13Z16Z19Z-22:7) (11,12). As n-3 PUFAs have been shown to have anticarcinogenic activity, conjugated fatty ac...

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhancement of human cancer cell radiosensitivity by conjugated eicosapentaenoic acid - a mammalian DNA polymerase inhibitor

Kumamoto-Yonezawa

Sasaki²,

Suzuki³

et al. 2010

Int J Oncol

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“…13 To a stirred solution of (trimethylsilyl)acetylene (2.9 mL, 20.4 mmol), in dry THF (20.0 mL), n-BuLi (2.5 M, 17.0 mmol) in dry hexane (6.8 mL) was added dropwise while keeping the temperature approximately at -78 o C. After 45 min, HMPA (6.8 mL) and 2 (2.00 g, 6.8 mmol) were added dropwise to the reaction mixture while maintaining the temperature approximately at -78 o C. After 24 h at rt, the reaction mixture was worked up by pouring into a large volume of water, and extracting with diethylether (2 x 20 mL). The organic layer was washed with brine (1 x 20 mL) before drying over MgSO 4 . Filtration, rotoevaporation of the solvent and fractional distillation of the impurities by Kugelrohr distillation (110-120 o C/ 3 mm Hg) afforded 4 (2.11 g) as a colorless oil for a 100 % yield, with spectral data comparable to the one previously reported in the literature.…”

Section: Trimethyl [10-(tetrahydro-2h-pyran-2-yloxy)-1-decynyl] Silanmentioning

confidence: 99%

“…1 Other interesting topo-I lipid inhibitors include conjugated C 18 and eicosapentaenoic fatty acids, 2,4 very-long chain (C 26 -C 30 ) ∆5,9 fatty acids, 5,6 and phospholipids containing unsaturated fatty acids. 7 While most of the fatty acid topoisomerase-I inhibitory work has been performed with straight-chain fatty acids, there is just one report dealing with the topoisomerase I inhibitory activity of methyl-branched iso and anteiso fatty acids.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8][9] Topoisomerase I is a key enzyme in the breaking and fixing of DNA strands and is involved in making the necessary topological changes to DNA for key cellular processes such as replication, transcription, and recombination. 1 Topoisomerases have also evolved as key cellular targets for the development of effective anticancer drugs.…”

Section: Introductionmentioning

confidence: 99%

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An improved synthesis for the (Z)-14-methyl-9-pentadecenoic acid and its topoisomerase I inhibitory activity

Carballeira¹,

Sanabria²,

Oyola³

2006

Arkivoc

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An improved synthesis for the (Z)-14-methyl-9-pentadecenoic acid was developed based on the appropriate use of (trimethylsilyl)acetylene as the key reagent in the synthesis. The reported synthesis started with commercially available 8-bromo-1-octanol and furnished the desired acid in seven steps and in a 16% overall yield, a significant improvement over the previous reported synthesis for this fatty acid. The synthesis reported herein afforded sufficient amounts to study the acid topoisomerase I inhibitory potential and it was found that the title acid inhibits the human placenta DNA topoisomerase I enzyme at concentrations of 500 µM.

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Functional and Nutraceutical Lipids

Shahidi

2010

Functional Food Product Development

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Inhibitory effect of conjugated eicosapentaenoic acid on human DNA topoisomerases I and II

Cited by 32 publications

References 28 publications

Enhancement of human cancer cell radiosensitivity by conjugated eicosapentaenoic acid - a mammalian DNA polymerase inhibitor

Enhancement of human cancer cell radiosensitivity by conjugated eicosapentaenoic acid - a mammalian DNA polymerase inhibitor

An improved synthesis for the (Z)-14-methyl-9-pentadecenoic acid and its topoisomerase I inhibitory activity

Functional and Nutraceutical Lipids

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