Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Aug;80(12):1905–1911. doi: 10.1038/sj.bjc.6690619

Flavone acetic acid induces a G2/M cell cycle arrest in mammary carcinoma cells

N J Panaro 1, N C Popescu 2, S R Harris 1, U P Thorgeirsson 1
PMCID: PMC2363136  PMID: 10471038

Abstract

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. © 1999 Cancer Research Campaign

Keywords: FAA, cell cycle, mammary, rat

Full Text

The Full Text of this article is available as a PDF (324.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bibby M. C., Double J. A. Flavone acetic acid--from laboratory to clinic and back. Anticancer Drugs. 1993 Feb;4(1):3–17. doi: 10.1097/00001813-199302000-00001. [DOI] [PubMed] [Google Scholar]
  2. Bibby M. C., Double J. A., Loadman P. M., Duke C. V. Reduction of tumor blood flow by flavone acetic acid: a possible component of therapy. J Natl Cancer Inst. 1989 Feb 1;81(3):216–220. doi: 10.1093/jnci/81.3.216. [DOI] [PubMed] [Google Scholar]
  3. Bible K. C., Kaufmann S. H. Flavopiridol: a cytotoxic flavone that induces cell death in noncycling A549 human lung carcinoma cells. Cancer Res. 1996 Nov 1;56(21):4856–4861. [PubMed] [Google Scholar]
  4. Bowler K., Pearson J. A. Long-term effects of flavone acetic acid on the growth of a rat tumour. Anticancer Res. 1992 Jul-Aug;12(4):1275–1279. [PubMed] [Google Scholar]
  5. Cahill D. P., Lengauer C., Yu J., Riggins G. J., Willson J. K., Markowitz S. D., Kinzler K. W., Vogelstein B. Mutations of mitotic checkpoint genes in human cancers. Nature. 1998 Mar 19;392(6673):300–303. doi: 10.1038/32688. [DOI] [PubMed] [Google Scholar]
  6. Candeias L. P., Everett S. A., Wardman P. Free radical intermediates in the oxidation of flavone-8-acetic acid: possible involvement in its antitumour activity. Free Radic Biol Med. 1993 Oct;15(4):385–394. doi: 10.1016/0891-5849(93)90038-v. [DOI] [PubMed] [Google Scholar]
  7. Cao G., Sofic E., Prior R. L. Antioxidant and prooxidant behavior of flavonoids: structure-activity relationships. Free Radic Biol Med. 1997;22(5):749–760. doi: 10.1016/s0891-5849(96)00351-6. [DOI] [PubMed] [Google Scholar]
  8. Carlson B. A., Dubay M. M., Sausville E. A., Brizuela L., Worland P. J. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res. 1996 Jul 1;56(13):2973–2978. [PubMed] [Google Scholar]
  9. Chabot G. G., Branellec D., Sassi A., Armand J. P., Gouyette A., Chouaib S. Tumour necrosis factor-alpha plasma levels after flavone acetic acid administration in man and mouse. Eur J Cancer. 1993;29A(5):729–733. doi: 10.1016/s0959-8049(05)80355-7. [DOI] [PubMed] [Google Scholar]
  10. Ching L. M., Baguley B. C. Induction of natural killer cell activity by the antitumour compound flavone acetic acid (NSC 347 512). Eur J Cancer Clin Oncol. 1987 Jul;23(7):1047–1050. doi: 10.1016/0277-5379(87)90357-9. [DOI] [PubMed] [Google Scholar]
  11. Cummings J., Smyth J. F. Flavone 8-acetic acid: our current understanding of its mechanism of action in solid tumours. Cancer Chemother Pharmacol. 1989;24(5):269–272. doi: 10.1007/BF00304756. [DOI] [PubMed] [Google Scholar]
  12. Donaldson K. L., Goolsby G. L., Kiener P. A., Wahl A. F. Activation of p34cdc2 coincident with taxol-induced apoptosis. Cell Growth Differ. 1994 Oct;5(10):1041–1050. [PubMed] [Google Scholar]
  13. Draetta G., Beach D. Activation of cdc2 protein kinase during mitosis in human cells: cell cycle-dependent phosphorylation and subunit rearrangement. Cell. 1988 Jul 1;54(1):17–26. doi: 10.1016/0092-8674(88)90175-4. [DOI] [PubMed] [Google Scholar]
  14. Feinstein E., Kimchi A., Wallach D., Boldin M., Varfolomeev E. The death domain: a module shared by proteins with diverse cellular functions. Trends Biochem Sci. 1995 Sep;20(9):342–344. doi: 10.1016/s0968-0004(00)89070-2. [DOI] [PubMed] [Google Scholar]
  15. Finlay G. J., Smith G. P., Fray L. M., Baguley B. C. Effect of flavone acetic acid on Lewis lung carcinoma: evidence for an indirect effect. J Natl Cancer Inst. 1988 Apr 20;80(4):241–245. doi: 10.1093/jnci/80.4.241. [DOI] [PubMed] [Google Scholar]
  16. Futami H., Eader L. A., Komschlies K. L., Bull R., Gruys M. E., Ortaldo J. R., Young H. A., Wiltrout R. H. Flavone acetic acid directly induces expression of cytokine genes in mouse splenic leukocytes but not in human peripheral blood leukocytes. Cancer Res. 1991 Dec 15;51(24):6596–6602. [PubMed] [Google Scholar]
  17. Harris S. R., Thorgeirsson U. P. Flavone acetic acid stimulates nitric oxide and peroxynitrite production in subcutaneous mouse tumors. Biochem Biophys Res Commun. 1997 Jun 27;235(3):509–514. doi: 10.1006/bbrc.1997.6820. [DOI] [PubMed] [Google Scholar]
  18. Hill S. A., Williams K. B., Denekamp J. Studies with a panel of tumours having a variable sensitivity to FAA, to investigate its mechanism of action. Int J Radiat Biol. 1991 Jul-Aug;60(1-2):379–384. doi: 10.1080/09553009114552191. [DOI] [PubMed] [Google Scholar]
  19. Hodnick W. F., Duval D. L., Pardini R. S. Inhibition of mitochondrial respiration and cyanide-stimulated generation of reactive oxygen species by selected flavonoids. Biochem Pharmacol. 1994 Feb 9;47(3):573–580. doi: 10.1016/0006-2952(94)90190-2. [DOI] [PubMed] [Google Scholar]
  20. Kung A. L., Sherwood S. W., Schimke R. T. Cell line-specific differences in the control of cell cycle progression in the absence of mitosis. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9553–9557. doi: 10.1073/pnas.87.24.9553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lepley D. M., Li B., Birt D. F., Pelling J. C. The chemopreventive flavonoid apigenin induces G2/M arrest in keratinocytes. Carcinogenesis. 1996 Nov;17(11):2367–2375. doi: 10.1093/carcin/17.11.2367. [DOI] [PubMed] [Google Scholar]
  22. Lindsay C. K., Gomez D. E., Thorgeirsson U. P. Effect of flavone acetic acid on endothelial cell proliferation: evidence for antiangiogenic properties. Anticancer Res. 1996 Jan-Feb;16(1):425–431. [PubMed] [Google Scholar]
  23. Mahadevan V., Hart I. R. Divergent effects of flavone acetic acid on established versus developing tumour blood flow. Br J Cancer. 1991 Jun;63(6):889–892. doi: 10.1038/bjc.1991.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Matsukawa Y., Marui N., Sakai T., Satomi Y., Yoshida M., Matsumoto K., Nishino H., Aoike A. Genistein arrests cell cycle progression at G2-M. Cancer Res. 1993 Mar 15;53(6):1328–1331. [PubMed] [Google Scholar]
  25. Mitra J., Schultz R. M. Regulation of the acquisition of meiotic competence in the mouse: changes in the subcellular localization of cdc2, cyclin B1, cdc25C and wee1, and in the concentration of these proteins and their transcripts. J Cell Sci. 1996 Sep;109(Pt 9):2407–2415. doi: 10.1242/jcs.109.9.2407. [DOI] [PubMed] [Google Scholar]
  26. Muschel R. J., Zhang H. B., Iliakis G., McKenna W. G. Cyclin B expression in HeLa cells during the G2 block induced by ionizing radiation. Cancer Res. 1991 Oct 1;51(19):5113–5117. [PubMed] [Google Scholar]
  27. Muschel R. J., Zhang H. B., McKenna W. G. Differential effect of ionizing radiation on the expression of cyclin A and cyclin B in HeLa cells. Cancer Res. 1993 Mar 1;53(5):1128–1135. [PubMed] [Google Scholar]
  28. Pahan K., Sheikh F. G., Khan M., Namboodiri A. M., Singh I. Sphingomyelinase and ceramide stimulate the expression of inducible nitric-oxide synthase in rat primary astrocytes. J Biol Chem. 1998 Jan 30;273(5):2591–2600. doi: 10.1074/jbc.273.5.2591. [DOI] [PubMed] [Google Scholar]
  29. Pratesi G., Rodolfo M., Rovetta G., Parmiani G. Role of T cells and tumour necrosis factor in antitumour activity and toxicity of flavone acetic acid. Eur J Cancer. 1990;26(10):1079–1083. doi: 10.1016/0277-5379(90)90056-y. [DOI] [PubMed] [Google Scholar]
  30. Sato F., Matsukawa Y., Matsumoto K., Nishino H., Sakai T. Apigenin induces morphological differentiation and G2-M arrest in rat neuronal cells. Biochem Biophys Res Commun. 1994 Oct 28;204(2):578–584. doi: 10.1006/bbrc.1994.2498. [DOI] [PubMed] [Google Scholar]
  31. Thomsen L. L., Ching L. M., Baguley B. C. Evidence for the production of nitric oxide by activated macrophages treated with the antitumor agents flavone-8-acetic acid and xanthenone-4-acetic acid. Cancer Res. 1990 Nov 1;50(21):6966–6970. [PubMed] [Google Scholar]
  32. Thomsen L. L., Ching L. M., Joseph W. R., Baguley B. C., Gavin J. B. Nitric oxide production in endotoxin-resistant C3H/HeJ mice stimulated with flavone-8-acetic acid and xanthenone-4-acetic acid analogues. Biochem Pharmacol. 1992 Jun 9;43(11):2401–2406. doi: 10.1016/0006-2952(92)90319-e. [DOI] [PubMed] [Google Scholar]
  33. Thomsen L. L., Ching L. M., Zhuang L., Gavin J. B., Baguley B. C. Tumor-dependent increased plasma nitrate concentrations as an indication of the antitumor effect of flavone-8-acetic acid and analogues in mice. Cancer Res. 1991 Jan 1;51(1):77–81. [PubMed] [Google Scholar]
  34. Wu L., Shiozaki K., Aligue R., Russell P. Spatial organization of the Nim1-Wee1-Cdc2 mitotic control network in Schizosaccharomyces pombe. Mol Biol Cell. 1996 Nov;7(11):1749–1758. doi: 10.1091/mbc.7.11.1749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Yoshida M., Sakai T., Hosokawa N., Marui N., Matsumoto K., Fujioka A., Nishino H., Aoike A. The effect of quercetin on cell cycle progression and growth of human gastric cancer cells. FEBS Lett. 1990 Jan 15;260(1):10–13. doi: 10.1016/0014-5793(90)80053-l. [DOI] [PubMed] [Google Scholar]
  36. Zwi L. J., Baguley B. C., Gavin J. B., Wilson W. R. Blood flow failure as a major determinant in the antitumor action of flavone acetic acid. J Natl Cancer Inst. 1989 Jul 5;81(13):1005–1013. doi: 10.1093/jnci/81.13.1005. [DOI] [PubMed] [Google Scholar]
  37. Zwi L. J., Baguley B. C., Gavin J. B., Wilson W. R. The use of vascularised spheroids to investigate the action of flavone acetic acid on tumour blood vessels. Br J Cancer. 1990 Aug;62(2):231–237. doi: 10.1038/bjc.1990.266. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES