Summary
Flavone acetic acid (FAA) is a synthetic flavonoid that demonstrated extraordinary anti-tumour properties in murine models but was not effective in clinical trials. In an effort to better understand the molecular mechanisms by which FAA asserts its tumouricidal activities, we have examined the effect of FAA on the cell cycle. We observed FAA-mediated G2/M cell cycle arrest in mammary carcinoma cells at a concentration previously demonstrated to have anti-tumour effects in rodent models. The cell cycle arrest was accompanied by an increase in the P34cdc2 (cdc2) cyclin-dependent kinase activity. Morphological cytogenetic analysis demonstrated a colcemid-like effect of FAA on cytokinesis by causing accumulation of condensed C-metaphases of a sustained mitotic block. The cell cycle effect was blocked by the antioxidants ADPC and ascorbate, the superoxide scavenger Tiron, and the sphingosine kinase inhibitor L-cycloserine, but not by inhibitors of nitric oxide synthase. Based on these data, we propose that FAA may induce cell cycle arrest by stimulating the activity of acidic sphingomyelinase leading to the generation of reactive oxygen species.
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References
Bibby, M. C. & Double, J. A. (1993). Flavone acetic acid: from laboratory to clinic and back. Anti-Cancer Drugs 4: 3–13.
Bibby, M. C., Double, J. A., Loadman, P. M. & Duke, C. V. (1989). Reduction of tumor blood flow by flavone acetic acid: a possible component of therapy. J Natl Cancer Inst 81: 216–220.
Bible, K. C. & Kaufman, S. H. (1996). Flavopiridol: a cytotoxic flavone that induces cell death in noncycling A549 human lung carcinoma cells. Cancer Res 56: 4856–4861.
Bowler, K. & Pearson, J. A. (1992). Long term effects of flavone acetic acid on the growth of a rat tumor. Anticancer Res 12: 1275–1280.
Cahill, D. P., Lenguaer, C., Yu, J., Riggins, G. J., Wilson, K. V., Markowitz, S. D., Kinzler, K. W. & Vogelstein, B. (1998). Mutations of mitotic checkpoint genes in human cancers. Nature 392: 300–303.
Candeias, L. P., Everett, S. A. & Wardman, P. (1993). Free radical intermediates in the oxidation of flavone-8-acetic acid: possible involvement in its antitumor activity. Free Radical Biol Med 15: 385–394.
Cao, G., Sofic, E. & Prior, R. L. (1997). Antioxidant and prooxidant behavior of flavonoids: structure–activity relationships. Free Radical Biol Med 22: 749–760.
Carlson, B. A., DuBay, M. M., Sausville, E. A., Brizuela, L. & Worland, P. J. (1996). Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK)2 and CDK4 in human breast carcinoma cells. Cancer Res 56: 2973–2978.
Chabot, G. G., Branellec, D., Sassi, A., Armand, J. P., Gouyette, A. & Chouaib, S. (1993). Tumour necrosis factor-alpha plasma levels after flavone acetic acid administration in man and mouse. Eur J Cancer 29A(5): 729–733.
Ching, L. M. & Baguley, B. C. (1987). Induction of natural killer cell activity by the antitumor compound flavone acetic acid (NSC 347512). Eur J Cancer Clin Oncol 23: 1047–1050.
Cummings, J. & Smyth, J. F. (1989). Flavone 8-acetic acid: our current understanding of its mechanism of action in solid tumours. Cancer Chemother Pharmacol 24: 269–272.
Donaldson, K. L., Goolsby, G. L., Kiene, P. A. & Wahl, A. F. (1994). Activation of p34cdc2 coincident with taxol-induced apoptosis. Cell Growth Diff 5: 1041–1050.
Draetta, G. & Beach, D. (1988). Activation of cdc2 kinase during mitosis in human cells: cell cycle-dependent phosphorylation and subunit rearrangement. Cell 54: 17–26.
Feinstein, E., Kimchi, A., Wallach, D., Boldin, M. & Varfolomeev, E. (1995). The death domain: a module shared by proteins with diverse cellular functions. Trends Biochem Sci 20: 342–344.
Finlay, G. J., Smith, G. P., Fray, L. M. & Baguley, B. C. (1988). Effect of flavone acetic acid on Lewis lung carcinoma: evidence for an indirect effect. J Natl Cancer Inst 80: 241–245.
Futami, H., Eader, L. A., Komschlies, K. L., Bull, R., Gruys, M. E., Ortaldo, J. R., Young, H. A. & Wiltrout, R. H. (1991). Flavone acetic acid directly induces expression of cytokine genes in mouse splenic leukocytes but not in human peripheral blood leukocytes. Cancer Res 51: 6596–6602.
Harris, S. R. & Thorgeirsson, U. P. (1997). Flavone acetic acid stimulates nitric oxide and peroxynitrate production in subcutaneous mouse tumors. Biochem Biophys Res Commun 235: 509–514.
Hill, S. A., Williams, K. B. & Denekemp, J. (1991). Studies with a panel of tumours having a variable sensitivity to FAA, to investigate its mechanism of action. Int J Radiat Biol 60: 379–384.
Hodnick, W. F., Duval, D. L. & Pardini, R. S. (1994). Inhibitor of mitochondrial respiration and cyanide-stimulated generation of reactive oxygen species by selected flavonoids. Biochem Pharmacol 47: 573–580.
Kung, A. L., Sherwood, S. W. & Schimke, R. T. (1990). Cell line-specific differences in the control cell cycle progression in the absence of mitosis. Proc Natl Acad Sci USA 87: 9553–9557.
Lepley, D. M., Li, B., Birt, D. F. & Pelling, J. C. (1996). The chemopreventive flavonoid apigenyin induces G2/M arrest in keratinocytes. Carcinogenesis 17: 2367–2375.
Lindsay, C. K., Gomez, D. E. & Thorgeirsson, U. P. (1996). Effect of flavone acetic acid on endothelial cell proliferation: evidence for antiangiogenic properties. Anticancer Res 16: 425–432.
Madhevan, V. & Hart, I. R. (1991). Divergent effects of flavone acetic acid on established versus developing tumour blood flow. Br J Cancer 63: 889–892.
Matsukawa, Y., Marui, N., Sakai, T., Satomi, Y., Yoshida, M., Matsumoto, K., Nishino, H. & Aoike, A. (1993). Genistein arrests cell cycle progression at G2-M. Cancer Res 53: 1328–1331.
Mitra, J. & Schultz, R. M. (1996). Regulation of the acquisition of meiotic competence in the mouse: changes in the subcellular localization of cdc2, cyclin B1, cdc25 and weel, and in the concentration of these proteins and their transcripts. J Cell Sci 109: 2407–2415.
Muschel, R. J., Zhang, H. B., Iliakis, G. & McKenna, W. G. (1991). Cyclin B expression in HeLa cells during the G2 block induced by ionizing radiation. Cancer Res 51: 5113–5117.
Muschel, R. J., Zhang, H. B. & McKenna, W. G. (1993). Differential effect of ionizing radiation on the expression of cyclin A and cyclin B in HeLa cells. Cancer Res 53: 1128–1135.
Pahan, K., Sheikh, F. G., Khan, M., Namboodiri, A. M. & Singh, I. (1998). Sphingomyelinase and ceramide stimulate the expression of inducible nitric oxide synthase in rat primary astrocytes. J Biol Chem 273: 2591–2600.
Pratesi, G., Rodolpho, M., Rovetta, G. & Parminiani, G. (1990). Role of T cells and tumour necrosis factor in antitumor activity and toxicity of flavone acetic acid. Eur J Cancer 26: 1079–1083.
Sato, F., Matsukawa, Y., Matsumoto, K., Nishino, H. & Sakai, T. (1994). Apigenin induces morphological differentiation and G2-M arrest in rat neuronal cells. Biochem Biophys Res Commun 204: 578–584.
Therman, E. (1980). Human Chromosomes: Structure, Behavior, Effects. Springer-Verlag: New York
Thomsen, L. L., Ching, L. M. & Baguley, B. C. (1990). Evidence for the production of nitric oxide by activated macrophages treated with the antitumor agents flavone-8-acetic and xanthenone-4-acetic acid. Cancer Res 50: 6966–6970.
Thomsen, L. L., Ching, L. M., Zhuang, L., Gavin, J. B. & Baguley, B. C. (1991). Tumor-dependent increased plasma nitrate concentrations as an indication of the anti-tumor effect of flavone-8-acetic acid and analogues in mice. Cancer Res 51: 77–81.
Thomsen LL Ching, L. M., Joseph, W. R., Baguley, B. C. & Gavin, J. B. (1992). Nitric oxide production in endotoxin-resistant C3H/HeJ mice stimulated with flavone-8-acetic acid and xanthenone-4-acetic acid analogues. Biochem Pharmacol 43: 2401–2406.
Wu, L., Shiozaki, K., Aligue, R. & Russell, P. (1996). Spatial organization of the Nim1-Wee1-cdc2 mitotic control network in Schizosaccharomyces pombe. Mol Biol Cell 7: 1749–1758.
Yoshidia, M., Sakai, T., Hosokawa, N., Marui, N., Matsumoto, K., Fujioka, A., Nishino, H. & Aoike, A. (1990). The effect of quercetin on the cell cycle progression and growth of human gastric cancer cells. FEBS Lett 260: 10–13.
Zwi, L. J., Baguley, B. C., Gavin, J. B. & Wilson, W. R. (1989). Blood flow failure as a major determinant in the antitumor action of flavone acetic acid. J Natl Cancer Inst 81: 1005–1013.
Zwi, L. J., Baguley, B. C., Gavin, J. B. & Wilson, W. R. (1990). The use of vascularised spheroids to investigate the action of flavone acetic acid on tumor blood vessels. Br J Cancer 62: 231–237.
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Panaro, N., Popescu, N., Harris, S. et al. Flavone acetic acid induces a G2/M cell cycle arrest in mammary carcinoma cells. Br J Cancer 80, 1905–1911 (1999). https://doi.org/10.1038/sj.bjc.6690619
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DOI: https://doi.org/10.1038/sj.bjc.6690619