Inhibitory effect of conjugated eicosapentaenoic acid on mammalian DNA polymerase and topoisomerase activities and human cancer cell proliferation

Yonezawa, Yasuo; Hada, Takahiko; Uryu, Keisuke; Tsuzuki, Toshio; Eitsuka, Takahiro; Miyazawa, Teruo; Murakami-Nakai, Chikako; Yoshida, Hiromi; Mizushina, Yoshiyuki

doi:10.1016/j.bcp.2005.05.008

Cited by 28 publications

(20 citation statements)

References 33 publications

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“…These results suggested that selective inhibitory action by cEPA might be due to specific binding to pol enzymes. Furthermore, the mechanisms by which cEPA suppresses human cancer cell growth were investigated, and it was revealed that the inhibition of pol activity by cEPA influenced not only cell proliferation but also the cell cycle (31). Cell cycle arrest in the G1 phase by cEPA was considered to be induced by the p53/p21 pathway from the ATRChk1/2-signaling pathway in HCT116 cells (16).…”

Section: Discussionmentioning

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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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: Discussionmentioning

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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“…It must be noted that the therapeutic index value of cEPA is pretty high, its value being at least 10 times larger than any other fatty acid, or than compounds already in clinical use like mitelfosine, that has a therapeutic index of 2.5 [37], indicating that cEPA can be considered a good candidate for antileishmanial therapy. In this context, it must to be noted that cEPA synthesis is simple and that its chemical precursor EPA (from omega 3 fatty acid series) has a large natural abundance, being found in red and green algae and in fish oil [39][40][41].…”

Section: Discussionmentioning

confidence: 99%

“…Recently we have shown that another fatty acid, namely conjugated eicosapentaenoic acid (cEPA) has an inhibitory effect on human topoisomerase [38] and this is likely the molecular reason it inhibits the cell growth of human tumor cell lines, while it has not effect on human fibroblast cell lines [39][40][41]. In this work, in order to compare similarities and differences between the human and L. donovani topoisomerase I, we have investigated the effect of cEPA on both the purified enzymes and on L. donovani promastigotes in comparison to murine macrophages.…”

Section: Introductionmentioning

confidence: 99%

Conjugated Eicosapentaenoic Acid (cEPA) Inhibits L. donovani Topoisomerase I and has an Antiproliferative Activity Against L. donovani Promastigotes

Desideri¹

2011

TOANTIMJ

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Conjugated eicosapentaenoic acid inhibits the relaxation activity of purified L. donovani topoisomerase I, with an efficiency higher than that displayed by the corresponding human enzyme. Docking of the acid compound over the 3D structure of the enzyme shows that the complex is stabilized by a large network of interaction between the compound and many residues located in proximity of the active site, including the catalytic tyrosine 222, providing an explanation for its efficient inhibitory effect. The acid has also a strong antiprotozoal activity against L. donovani promastigotes ( EC 50 = 75 M) whilst it has no effect against murine macrophages (IC 50 2 mM). Taken together the results indicate that L. donovani topoisomerase I can be considered an interesting molecular target and that conjugated eicosapentaenoic acid can be taken in consideration as a possible lead compound against leishmaniasis.

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“…Based on this idea, we have found many new pol inhibitors over the past 10 years, e.g. long-chain fatty acids [3][4][5][6][7][8], conjugated fatty acids [9][10][11], bile acids such as lithocholic acid [12][13][14], steroidal glycosides [15,16], steviol derivatives [17], sulfoglycolipids [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31], catechins [32][33][34], curcumin [35][36][37][38], SQDG is a major glycolipid of the chloroplast membrane in plants [46]. We have widely screened for the glycolipids fraction containing SQDG from common vegetables that show such inhibitory activity, and found that spinach (Spinacia oleracea L.) had the largest amount of SQDG and was the strongest pol inhibitor in the tested vegetables [47].…”

Section: Introductionmentioning

confidence: 98%

Inhibitory Effect on Replicative DNA Polymerases, Human Cancer Cell Proliferation, and In Vivo Anti-Tumor Activity by Glycolipids from Spinach

Maeda

Hada²,

Yoshida³

et al. 2007

CMC

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We succeeded in purifying a major glycolipids fraction (i.e., Fraction-II) in the class of monogalactosyl diacylglycerol (MGDG), digalactosyl diacylglycerol (DGDG) and sulfoquinovosyl diacylglycerol (SQDG) from spinach using hydrophobic column chromatography. Fraction-II inhibited the activities of replicative DNA polymerases (pols) such as alpha, delta and epsilon, and mitochondrial pol gamma with IC(50) values of 43-79 microg/ml, but had no influence on the activity of repair-related pols beta and lambda. MGDG, DGDG, SQDG were purified from Fraction-II of spinach using silica gel column chromatography, and SQDG was the strongest inhibitor of mammalian pols in the three glycolipids. Therefore, SQDG and its related compounds were chemically synthesized, and the sulfate group and fatty acid moiety of the compound were suggested to be important for pol inhibition. These glycolipids showed no effect even on the activities of plant pols, prokaryotic pols and other DNA metabolic enzymes such as T4 polynucleotide kinase, T7 RNA polymerase and deoxyribonuclease I. Fraction-II also inhibited the proliferation of human cervix carcinoma (HeLa) cells with LD(50) values of 57 microg/ml, and could halt the cell cycle at the G1-phase, and subsequently induced severe apoptosis. In an in vivo anti-tumor assay on nude mice bearing solid tumors of HeLa cells, Fraction-II was shown to be a promising suppressor of solid tumors. Histopathological examination revealed that tumor necrosis with hemorrhage was significantly enhanced with Fraction-II in vivo. The spinach Fraction-II containing SQDG might be a potent anti-tumor compound, and may be a healthy food substance with anti-tumor activity.

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Inhibitory effect of conjugated eicosapentaenoic acid on mammalian DNA polymerase and topoisomerase activities and human cancer cell proliferation

Cited by 28 publications

References 33 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

Conjugated Eicosapentaenoic Acid (cEPA) Inhibits L. donovani Topoisomerase I and has an Antiproliferative Activity Against L. donovani Promastigotes

Inhibitory Effect on Replicative DNA Polymerases, Human Cancer Cell Proliferation, and In Vivo Anti-Tumor Activity by Glycolipids from Spinach

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