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http://dx.doi.org/10.4062/biomolther.2009.17.3.282

Ochnaflavone, a Natural Biflavonoid, Induces Cell Cycle Arrest and Apoptosis in HCT-15 Human Colon Cancer Cells  

Kang, You-Jin (Colloge of Pharmacy, Ewha Womans University)
Min, Hye-Young (Colloge of Pharmacy, Ewha Womans University)
Hong, Ji-Young (Colloge of Pharmacy, Ewha Womans University)
Kim, Yeong-Shik (Colloge of Pharmacy, Seoul National University)
Kang, Sam-Sik (Colloge of Pharmacy, Seoul National University)
Lee, Sang-Kook (Colloge of Pharmacy, Ewha Womans University)
Publication Information
Biomolecules & Therapeutics / v.17, no.3, 2009 , pp. 282-287 More about this Journal
Abstract
Ochnaflavone is a natural biflavonoid and mainly found in the caulis of Lonicera japonica (Caprifoliaceae). Biological activities such as anti-inflammatory and anti-atherogenic effects have been previously reported. The anticancer activity of ochnaflavone, however, has been poorly elucidated yet. In the present study, we investigated the effect of ochnaflavone on the growth inhibitory activity in cultured human colon cancer cell line HCT-15. Ochnaflavone inhibited the proliferation of the cancer cells with an $IC_{50}$ value of $4.1{\mu}M$. Flow cytometric analysis showed that ochnaflavone arrested cell cycle progression in the G2/M phase, and induced the increase of sub-G1 peak in a concentration-dependent manner. Induction of cell cycle arrest was correlated with the modulation of the expression of cell cycle regulating proteins including cdc2 (Tyr15), cyclin A, cyclin B1 and cyclin E. The increase of sub-G1 peak by the higher concentrations of ochnaflavone (over $20{\mu}M$) was closely related to the induction of apoptosis, which was evidenced by the induction of DNA fragmentation, activation of caspase-3, -8 and -9, and cleavage of poly-(ADP-ribose) polymerase. These findings suggest that the cell cycle arrest and induction of apoptosis might be one possible mechanism of actions for the anti-proliferative activity of ochnaflavone in human colon cancer cells.
Keywords
Ochnaflavone; Cell cycle arrest; Apoptosis; HCT15 human colon cancer cells;
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Times Cited By KSCI : 3  (Citation Analysis)
Times Cited By Web Of Science : 2  (Related Records In Web of Science)
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1 Chang, H. W., Baek, S. H., Chung, K. W., Son, K. H., Kim, H. P. and Kang, S. S. (1994). Inactivation of phospholipase A2 by naturally occurring biflavonoid, ochnaflavone. Biochem. Biophys. Res. Commun. 205, 843-849   DOI   ScienceOn
2 Grange, L. L., Wang, M., Watkins, R., Ortiz, D., Sanchez, M. E., Konst, J., Lee, C. and Reyes, E. (1999). Protective effects of the flavonoid mixture, silymarin, on fetal rat brain and liver. J. Ethnopharmacol. 67, 53-62   DOI   ScienceOn
3 Lee, S. K., Heo, Y. H., Steele, V. E. and Pezzuto, J. M. (2002). Induction of apoptosis by 1,4-phenylenebis(methylene)selenocyanate in cultured human colon cancer cells. Anticancer Res. 22, 97-102
4 Molina, M. F., Sanchez-Reus, I., Iglesias, I. and Benedi, J. (2003). Quercetin, a flavonoid antioxidant, prevents and protects against ethanol-induced oxidative stress in mouse liver. Biol. Pharm. Bull. 26, 1398-1402   DOI   ScienceOn
5 Rashid, I. L., Liang, Q., Steven, J. S. and Basil, R. (1997). Curcumin, a natural plant phenolic food additive, inhibits cell proliferation and induces cell cycle changes in colon adenocarcinoma cell lines by a prostaglndin-independent pathway. J. Lab. Clin. Med. 130, 576-584   DOI   ScienceOn
6 Toyoshima-Morimoto, F., Taniguchi, E., Shinya, N., Iwamatsu, A. and Nishida, E. (2001). Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase. Nature 410, 215-220   DOI   ScienceOn
7 Butenko, I. G., Gladtchenko, S. V. and Galushko, S. V. (1993). Anti-inflammatory properties and inhibition of leukotriene C4 biosynthesis in vitro by flavonoid baicalein from Scutellaria baicalensis georgy roots. Agents Actions 39, 49-51   DOI
8 Son, M. J., Moon, T. C., Lee, E. K., Son, K. H., Kim, H. P., Kang, S. S., Son, J. K., Lee, S. H. and Chang, H. W. (2006). Naturally occurring biflavonoid, ochanflavone, inhibits cyclo-oxygenases-2 and 5-lipoxygenase in mouse bone marrow-derived mast cells. Arch. Pharm. Res. 29, 282-286   DOI   ScienceOn
9 Bhanot, U. K. and Moller, P. (2009). Mechanisms of parenchymal injury and signaling pathways in ectatic ducts of chronic pancreatitis: implications for pancreatic carcinogenesis. Lab. Invest. 89, 489-497   DOI   ScienceOn
10 Lee, S. J., Choi, J. H., Son, K. H., Chang, H. W., Kang, S. S. and Kim, H. P. (1995). Suppression of mouse lymphocyte proliferation in vitro by naturally-occurring biflavonoids. Life Sci. 57, 551-558   DOI   ScienceOn
11 Chowdhury, A. R., Sharma, S., Mandal, S., Goswami, A., Mukhopadhyay, S. and Majumder, H. K. (2002). Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase I. Biochem. J. 366, 653-661   DOI   ScienceOn
12 Gu, Y., Rosenblatt, J. and Morgan, D. O. (1992). Cell cycle regulation of CDK2 activity by phosphorylation of Thr160 and Tyr15. EMBO J. 11, 3995-4005
13 Shimizu, M., Deguchi, A., Hara, Y., Moriwaki, H. and Weinstein, I. B. (2005). EGCG inhibits activation of the insulin-like growth factor-1 receptor in human colon cancer cells. Biochem. Biophys. Res. Commun. 334, 947-953   DOI   ScienceOn
14 Ielpo, M. T. L., Basile, A., Miranda, R., Moscatiello, V., Nappo, C., Sorbo, S., Laghi, E., Ricciardi, M. M., Ricciardi, L. and Vuotto, M. L. (2000). Immunopharmacological properties of flavonoids. Fitoterapia 71, 101-109   DOI   ScienceOn
15 Iwu, M. M. Igboko, O. A., Okunji, C. O. and Tempesta, M. S. (1990). Antidiabetic and aldose reductase activities of biflavanones of Garcinia kola. J. Pharm. Pharmacol. 42, 290-292   DOI
16 Lundgren, K., Walworth, N., Booher, R., Dembski, M., Kirschner, M. and Beach, D. (1991). Mik1 and wee1 cooperate in the inhibitory tyrosine phosphorylation of cdc2. Cell 64, 1111-1122   DOI   ScienceOn
17 Kim, H. P., Park, H., Son, K. H., Chang, H. W. and Kang, S. S. (2008). Biochemical pharmacology of biflavonoids: Implications for anti-inflammatory action. Arch. Pharm. Res. 31, 265-273   DOI   ScienceOn
18 Lee, S. K., Cui, B., Mehta, R. R., Kinghorn, A. D. and Pezzuto, J. M. (1998). Cytostatic mechanism and antitumor potential of novel 1H-cyclopentea[b]benzofuran lignans isolated from Aglaia elliptica. Chem. Biol. Interact. 115, 215-228   DOI   ScienceOn
19 Lee, S. J., Son, K. H., Chang, H. W., Kang, S. S. and Kim, H. P. (1997). Inhibition of arachidonate release from rat peritoneal macrophage by biflavonoids. Arch. Pharm. Res. 20, 533-538   DOI   ScienceOn
20 Moon, T. C., Hwang, H. S., Quan, Z., Son, K. H., Kim, C. H., Kim, H. P., Kang, S. S., Son, J. K. and Chang, H. W. (2006). Ochnaflavone, naturally occuring biflavonoid, inhibits phospholipase $A_2$ dependent phosphatidylethanolamine degradation in a $CCl_4$-induced rat liver. Biol. Pharm. Bull. 29, 2359-2361   DOI   ScienceOn
21 Sharon, A. A. and Nora, M. O'B. (2000). Mechanism of protection by the flavonoids, quercetin and rutin, against tert-butylhydroperoxide-and menadione-induced DNA single strand breaks in Caco-2 cells. Free Radic. Biol. Med. 29, 507-514   DOI   ScienceOn
22 Ahn, M. Y., Na, Y. J., Lee, J., Lee, B. M. and Kim, H. S. (2009). Apicidin induces apoptosis via cytochrome c-mediated intrinsic pathway in human ovarian cancer cells. Biomol. Ther. 17, 17-24   과학기술학회마을   DOI   ScienceOn
23 Amella, M., Bronner, C., Briancon, F., Haag, M., Anton, R. and Landry, Y. (1985). Inhibition of mast cell histamine release by flavonoids and biflavonoids. Planta Med. 51, 16-20   DOI   ScienceOn
24 Beretz, A., Joly, M., Stoclet, J. C. and Anton, R. (1979). Inhibition of 3', 5'-AMP phosphodiesterase by biflavonoids and xanthones. Planta Med. 36, 193-195   DOI
25 Porter, L. A. and Donoghue, D. J. (2003). Cyclin B1 and CDK1: nuclear localization and upstream regulators. Prog. Cell Cycle Res. 5, 335-347
26 Russell, P. and Nurse, P. (1987). Negative regulation of mitosis by wee1+, a gene encoding a protein kinase homolog. Cell 49, 559-567   DOI   ScienceOn
27 Suh, S. J., Chung, T. W., Son, M. J., Kim, S. H., Moon, T. C., Son, K. H., Kim, H. P., Chang, H. W. and Kim, C. H. (2006a). The naturally occurring biflavonoid, ochnaflavone, inhibits LPS-induced iNOS expression, which is mediated by ERK1/2 via NF-$_KB$ regulation, in RAW264.7 cells. Arch. Biochem. Biophys. 447, 136-146   DOI   ScienceOn
28 Suh, S. J., Jin, U. H., Kim, S. H., Chang, H. W., Son, J. K., Lee, S. H., Son, K. H. and Kim, C. H. (2006b). Ochnaflavone inhibits TNF-${\alpha}$-induced human VSMC proliferation via regulation of cell cycle, ERK1/2, and MMP-9. J. Cell. Biochem. 99, 1298-1307   DOI   ScienceOn
29 Wada, R. (2009). Proposal of a new hypothesis on the development of colorectal epithelial neoplasia: nonspecific inflammation - colorectal paneth cell metaplasia - colorectal epithelial neoplasia. Digestion 79, 9-12.   DOI   ScienceOn