Abstract
(–)‐Epigallocatechin gallate (EGCG), the main constituent of green tea, and green tea extract show growth inhibition of various cancer cell lines, such as lung, mammary, and stomach. We studied how tea polyphenols induce growth inhibition of cancer cells. Since green tea extract contains various tea polyphenols, such as EGCG, (–)‐epigallocatechin (EGC), (–)‐epicatechin gallate (ECG), and (–)‐epicatechin (EC), the inhibitory potential of each tea polyphenol on the growth of a human lung cancer cell line, PC‐9 cells, was first examined. EGC and ECG inhibited the growth of PC‐9 cells as potently as did EGCG, but EC did not show significant growth inhibition. The mechanism of growth inhibition by EGCG was studied in relation to cell cycle regulation. Flow cytometric analysis revealed that treatment with 50 μM and 100 μM EGCG increased the percentages of cells in the G2‐M phase from 13.8% to 15.6% and 24.1%, respectively. The DNA histogram after treatment with 100 μM EGCG was similar to that after treatment with genistein, suggesting that EGCG induces G2‐M arrest in PC‐9 cells. Moreover, we found by microautoradiography that [3H]EGCG was incorporated into the cytosol, as well as the nuclei. These results provide new insights into the mechanisms of action of EGCG and green tea extract as cancer‐preventive agents in humans.
Keywords: EGCG, [3H]EGCG, G2‐M arrest, Tea polyphenol, Cancer prevention
Full Text
The Full Text of this article is available as a PDF (410.2 KB).
REFERENCES
- 1. ) Yoshizawa , S. , Horiuchi , T. , Fujiki , H. , Yoshida , T. , Okuda , T. and Sugimura , T.Antitumor promoting activity of (‐)‐epigallocatechin gallate, the main constituent of “tannin” in green tea . Phytother. Res. , 1 , 44 – 47 ( 1987. ). [Google Scholar]
- 2. ) Fujiki , H. and Okuda , T.(‐)‐Epigallocatechin gallate . Drugs Future , 17 , 462 – 464 ( 1992. ). [Google Scholar]
- 3. ) Fujiki , H. , Komori , A. and Suganuma , M.Chemoprevention of cancer . In “ Comprehensive Toxicology ,” ed. Bowden T. and Fischer S. ( 1997. ). CRC Press; , London , in press . [Google Scholar]
- 4. ) Nakachi , K. , Imai , K. and Suga , K.Epidemiological evidence for prevention of cancer and cardiovascular disease by drinking green tea . In “ Proceedings of International Conference on Food Factors ‐Chemistry and Cancer Prevention‐ ,” ed Osawa T. and Ohigashi H. ( 1997. ). Springer Verlag Tokyo Inc. Press; , Tokyo , in press . [Google Scholar]
- 5. ) Yamane , T. , Takahashi , T. , Kuwata , K. , Oya , K. , Inagaki , M. , Kitao , Y. , Suganuma , M. and Fujiki , H.Inhibition of N‐methyl‐N'‐nitro‐N‐nitrosoguanidine‐induced carcinogenesis by (‐)‐epigallocatechin gallate in the rat glandular stomach . Cancer Res. , 55 , 2081 – 2084 ( 1995. ). [PubMed] [Google Scholar]
- 6. ) Fujita , Y. , Yamane , T. , Tanaka , M. , Kuwata , K. , Okuzumi , J. , Takahashi , T. , Fujiki , H. and Okuda , T.Inhibitory effect of (‐)‐epigallocatechin gallate on carcinogenesis with N‐ethyl‐N'‐nitro‐N‐nitrosoguanidine in mouse duodenum . Jpn. J. Cancer Res. , 80 , 503 – 505 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. ) Narisawa , T. and Fukaura , Y.A very low dose of green tea polyphenols in drinking water prevents N‐methyl‐N‐nitrosourea‐induced colon carcinogenesis in F344 rats . Jpn. J. Cancer Res. , 84 , 1007 – 1009 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. ) Nishida , H. , Omori , M. , Fukutomi , Y. , Ninomiya , M. , Nishiwaki , S. , Suganuma , M. , Moriwaki , H. and Muto , Y.Inhibitory effects of (‐)‐epigallocatechin gallate on spontaneous hepatoma in C3H/HeNCrj mice and human hepatoma‐derived PLC/PRF/5 cells . Jpn. J. Cancer Res. , 85 , 221 – 225 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. ) Xu , Y. , Ho , C.‐T. , Amin , S. G. , Han , C. and Chung , F.‐L.Inhibition of tobacco‐specific nitrosamine‐induced lung tumorigenesis in A/J mice by green tea and its major polyphenol as antioxidants . Cancer Res. , 52 , 3875 – 3879 ( 1992. ). [PubMed] [Google Scholar]
- 10. ) Wang , Z.‐Y. , Huang , M.‐T. , Ferraro , T. , Wong , C.‐Q. , Lou , Y.‐R. , Reuhl , K. , Iatropoulos , M. , Yang , C. S. and Conney , A. H.Inhibitory effect of green tea in the drinking water on tumorigenesis by ultraviolet light and 12‐O‐tetradecanoylphorbol‐13‐acetate in the skin of SKH‐1 mice . Cancer Res. , 52 , 1162 – 1170 ( 1992. ). [PubMed] [Google Scholar]
- 11. ) Taniguchi , S. , Fujiki , H. , Kobayashi , H. , Go , H. , Miyado , K. , Sadano , H. and Shimokawa , R.Effect of (‐)‐epigallocatechin gallate, the main constituent of green tea, on lung metastasis with mouse B16 melanoma cell lines . Cancer Lett. , 65 , 51 – 54 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Yoshizawa , S. , Horiuchi , T. , Suganuma , M. , Nishiwaki , S. , Yatsunami , J. , Okabe , S. , Okuda , T. , Muto , Y. , Frenkel , K. , Troll , W. and Fujiki , H.Penta‐O‐galloyl‐β‐D‐glucose and (‐)‐epigallocatechin gallate . In “ Phenolic Compounds in Food and Their Effect on Health II ,” ed. Huang M.‐T. , Ho C.‐T. and Lee C. Y. , pp. 316 – 325 ( 1992. ). American Chemical Society Press; , Washington D.C . [Google Scholar]
- 13. ) Komori , A. , Yatsunami , J. , Okabe , S. , Abe , S. , Kara , K. , Suganuma , M. , Kim , S.‐J. and Fujiki , H.Anticarcinogenic activity of green tea polyphenols . Jpn. J. Clin. Oncol , 23 , 186 – 190 ( 1993. ). [PubMed] [Google Scholar]
- 14. ) Yoshida , M. , Sakai , T. , Hosokawa , N. , Marui , N. , Matsumoto , K. , Fujioka , A. , Nishino , H. and Aoike , A.The effect of quercetin on cell cycle progression and growth of human gastric cancer cells . FEES Lett. , 260 , 10 – 13 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 15. ) Matsukawa , Y. , Marui , N. , Sakai , T. , Satomi , Y. , Yoshida , M. , Matsumoto , K. , Nishino , H. and Aoike , A.Genistein arrests cell cycle progression at G2‐M . Cancer Res. , 53 , 1328 – 1331 ( 1993. ). [PubMed] [Google Scholar]
- 16. ) Avila , M. A. , Velasco , J. A. , Cansado , J. and Notario , V.Quercetin mediates the down‐regulation of mutant p53 in the human breast cancer cell line MDA‐MB468 . Cancer Res. , 54 , 2424 – 2428 ( 1994. ). [PubMed] [Google Scholar]
- 17. ) Nishio , K. , Sugimoto , Y. , Nakagawa , K. , Niimi , S. , Fujiwara , Y. , Bungo , M. , Kasahara , K. , Fujiki , H. and Saijo , N.Cross‐resistance to tumor promoters in human cancer cell lines resistant to adriamycin or cisplatin . Br. J. Cancer , 62 , 415 – 419 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. ) Akiyama , T. , Ishida , J. , Nakagawa , S. , Ogawara , H. , Watanabe , S. , Itoh , N. , Shibuya , M. and Fukami , Y.Genistein, a specific inhibitor of tyrosine‐specific protein kinases . J. Biol. Chem. , 262 , 5592 – 5595 ( 1987. ). [PubMed] [Google Scholar]