Inhibitory effects of docosyl p-coumarate on DNA topoisomerase activity and human cancer cell growth

• Published in: International journal of oncology Vol. 37; no. 4; pp. 993 - 1000
• Main Authors: MIZUSHINA, Yoshiyuki, NISHIMURA, Katsumi, TAKENAKA, Yukiko, TAKEUCHI, Toshifumi, SUGAWARA, Fumio, YOSHIDA, Hiromi, TANAHASHI, Takao
• Format: Journal Article
• Language: English
• Published: Athens Editorial Academy of the International Journal of Oncology 01.10.2010
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Cell Cycle - drug effects; Cell Proliferation - drug effects; Colonic Neoplasms - enzymology; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Coumaric Acids - pharmacology; DNA Topoisomerases, Type I - metabolism; Dose-Response Relationship, Drug; HCT116 Cells; Humans; Inhibitory Concentration 50; Medical sciences; Time Factors; Topoisomerase Inhibitors - pharmacology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Cell proliferation; DNA polymerase; cell cycle arrest; p53; Isomerases; Cancerology; TP53 Gene; Alkyl; Cell cycle; alkyl p-coumarates; docosyl p-coumarate; Tumor cell; Tumor suppressor gene; Human; Enzyme; Transferases; DNA topoisomerase; Enzyme inhibitor; Malignant tumor; Biological activity; anti-cancer agents; Nucleotidyltransferases; Cell death; cell growth inhibition; DNA-directed DNA polymerase; Apoptosis; Cancer
• DOI: 10.3892/ijo_00000750
• ISSN: 1019-6439

We previously found six compounds of alkyl p-coumarates from a composite plant Artemisia annua L., and chemically synthesized these compounds (cis-isomer of C20, C22 and C24, and trans-isomer of C20, C22 and C24 of p-coumarates are compounds 1-6, respectively). This report describes the inhibitory activities of these alkyl p-coumarates against DNA polymerase (pol), DNA topoisomerase (topo), and human cancer cell growth. Among the compounds tested, compounds 1 and 4 weakly inhibited repair-related pol beta activity, but no compound influenced the activity of replicative pol alpha. Compounds 4-6 and compounds 2 and 5 were potent inhibitors of human topos I and II, respectively. Compounds 2, 4, 5 and 6 also suppressed the growth of human colon carcinoma cell line, HCT116, with or without p53, suggesting that cell growth inhibition had the same tendency as the inhibition of topos rather than pols. Compound 5 (docosyl p-coumarate), which was the strongest inhibitor of topo II and cancer cell growth in the compounds tested, halted HCT116 p53(+/+) cells in G2/M phases, and induced apoptosis, although this compound did not affect the cell cycle of HCT116 p53(-/-) cells. These results suggest that the effect of p53-dependent cell cycle arrest may be effective for topo inhibition by com-pound 5. From these findings, the action mode of alkyl p-coumarates as an anti-cancer agent is discussed.