THE DIETARY ANTICANCER AGENT ELLAGIC ACID IS A POTENT INHIBITOR OF DNA TOPOISOMERASES IN-VITRO

被引：56

作者：

CONSTANTINOU, A

STONER, GD

MEHTA, R

RAO, K

RUNYAN, C

MOON, R

机构：

[1] UNIV ILLINOIS,COLL MED,DEPT GENET,CHICAGO,IL 60612

[2] OHIO STATE UNIV,DEPT PREVENT MED,COLUMBUS,OH 43210

[3] IIT,RES INST,DIV LIFE SCI,CHICAGO,IL 60616

来源：

NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL | 1995年 / 23卷 / 02期

关键词：

D O I：

10.1080/01635589509514368

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Ellagic acid and 12 related agents have been tested for their ability to inhibit the activities of human DNA topoisomerase (topo) I and II. Using specific in vitro assays, we found ellagic acid and flavellagic acid to be potent inhibitors of the catalytic activities of the two topoisomerases. The minimum concentration required to inhibit greater than or equal to 50% of catalytic activity (IC50) of ellagic acid was determined at 0.6 and 0.7 mu g/ml for topo I and topo II, respectively. Flavellagic acid's IC50 was determined at 3.0 and 3.6 mu g/ml for topo I and topo II, respectively. Unlike topoisomerase poisons, these two plant phenols did not trap the enzyme-DNA reaction intermediate, known as the cleavable complex. In contrast, ellagic acid prevented other topo I and topo II poisons from stabilizing the cleavable complex, suggesting that the mode of its action is that of an antagonist. Structure-activity studies identified the 3,3'-hydroxyl groups and the lactone groups as the most essential elements for the topoisomerase inhibitory actions of plant phenols. On the basis of these findings and other properties of ellagic acid, a mechanistic model for the documented anticarcinogenic effects of the agent is proposed.

引用

页码：121 / 130

页数：10

共 38 条

[21]

Constantinou A., Grdina D., Kiguchi K., Huberman E., The Effect of Topoisomerase Inhibitors on the Expression of Differentiation Markers and Cell Cycle Progression in Human K-562 Leukemia Cells, Exp Cell Res, 203, pp. 100-106, (1992)

[22]

Liu L.F., DNA Topoisomerase Poisons as Antitumor Drugs, Annu Rev Biochem, 58, pp. 351-375, (1989)

[23]

Maniatis T., Fritsch E.F., Sambrook J., Molecular Cloning: A Laboratory Manual, (1982)

[24]

Liu L.F., Novel Topologically Knotted DNA From Bacteriophage P4 Capsids: Studies With DNA Topoisomerases, Nucleic Acids Res, 9, pp. 3979-3989, (1981)

[25]

Drake F.H., Hofmann G.A., Mong S.M., Batrus J.O., Hertzberg R.P., Et al., In Vitro and Intracellular Inhibition of Topoisomerase II by the Antitumor Agent Merbarone, Cancer Res, 49, pp. 2578-2583, (1989)

[26]

Tanabe K., Ikegami Y., Ishida R., Andoh T., Inhibition of Topoisomerase II by Antitumor Agents Bis(2,6-dioxopiperazine) Derivatives, Cancer Res, 51, pp. 4903-4908, (1991)

[27]

Hussy P., Maass G., Tummler B., Grosse F., Schomburg U., Effect of 4-Quinolones and Novobiocin on Calf Thymus DNA Polymerase a Primase Complex, Topoisomerase I and II, and Growth of Mammalian Lymphoblasts, Antimicrob Agents Chemother, 29, pp. 1073-1078, (1986)

[28]

Rossi M., Erelbacher J., Zacharisa D., Carrell H., Iannucci B., The Crystal and Molecular Structure of Ellagic Acid Dihydrate: A Dietary Anti-Cancer Agent, Carcinogenesis, 12, pp. 2227-2232, (1991)

[29]

Teel R.W., Ellagic Acid Binding to DNA as a Possible Mechanism for its Antimutagenic and Anticarcinogenic Action, Cancer Lett, 30, pp. 329-336, (1986)

[30]

Robinson M.J., Osheroff N., Stabilization of the Topoisomerase II-DNA Cleavage Complex by Antineoplastic Drugs: Inhibition of Enzyme-Mediated DNA Religation by 4’-(9-Acridinylamino) Methanesulfonyl-m-anisidide, Biochemistry, 29, pp. 2511-2515, (1990)

← 1 2 3 4 →