Preferences help
enabled [disable] Abstract
Number of results
2002 | 49 | 1 | 59-65
Article title

Dual effect of 2-methoxyestradiol on cell cycle events in human osteosarcoma 143B cells.

Title variants
Languages of publication
We have demonstrated for the first time that the steroid metabolite, 2-methoxyestradiol (2-ME) is a powerful growth inhibitor of human osteosarcoma 143 B cell line by pleiotropic mechanisms involving cell cycle arrest at two different points and apoptosis. The ability of 2-ME to inhibit cell cycle at the respective points has been found concentration dependent. 1 μM 2-ME inhibited cell cycle at G1 phase while 10 μM 2-ME caused G2/M cell cycle arrest. As a natural estrogen metabolite 2-ME is expected to perturb the stability of microtubules (MT) in vivo analogously to Taxol - the MT binding anticancer agent. Contrary to 2-ME, Taxol induced accumulation of osteosarcoma cells in G2/M phase of cell cycle only. The presented data strongly suggest two different mechanisms of cytotoxic action of 2-ME at the level of a single cell.
Physical description
  • 1. Zhu, B.T. & Conney, A.H. (1998) Is 2-methoxyestradiol an endogenous estrogen metabolite that inhibits mammary carcinogenesis? Cancer Res. 58, 2269-2277.
  • 2. Yue, T.L., Wang, X., Louden, C.S., Gupta, S., Pillarisetti, K., Gu, J.L., Hart, T.K., Lysko, P.G. & Feuerstein, G.Z. (1997) 2-Methoxyestradiol, an endogenous estrogen metabolite, induces apoptosis in endothelial cells and inhibits angiogenesis: Possible role for stress- activated protein kinase signaling pathway and Fas expression. Mol. Pharmacol. 51, 951-962.
  • 3. Shang, W., Konidari, I. & Schomberg, D. W. (2001) 2-Methoxyestradiol, an endogenous estradiol metabolite, differentially inhibits granulosa and endothelial cell mitosis: A potential follicular antiangiogenic regulator. Biol. Reprod. 65, 622-627.
  • 4. Dubey, R.K., Gillespie, D.G., Zacharia, L.C., Rosselli, M., Korzekwa, K.R., Fingerle, J. & Jackson, E.K. (2000) Methoxyestradiols mediate the antimitogenic effects of estradiol on vascular smooth muscle cells via estrogen receptor-independent mechanisms. Biochem. Biophys. Res. Commun. 278, 27-33.
  • 5. Banerjeei, S.K., Zoubine, M.N., Sarkar, D.K., Weston, A.P., Shah, J.H. & Campbell, D.R. (2000) 2-Methoxyestradiol blocks estrogen-induced rat pituitary tumor growth and tumor angiogenesis: Possible role of vascular endothelial growth factor. Anticancer Res. 20, 2641-2645.
  • 6. Wang, S.H., Myc, A., Koenig, R.J., Bretz, J.D., Arscott, P.L. & Baker, J.R. (2000) 2-Methoxyestradiol, an endogenous estrogen metabolite, induces thyroid cell apoptosis. Mol. Cell Endocrinol. 165, 163-172.
  • 7. Schumacher, G., Kataoka, M., Roth, J.A. & Mukhopadhyay, T. (1999) Potent antitumor activity of 2-methoxyestradiol in human pancreatic cancer cell lines. Clin. Cancer Res. 5, 493-499.
  • 8. Tsukamoto, A., Kaneko, Y., Yoshida, T., Han, K., Ichinose, M. & Kimura, S. (1998) 2-Methoxyestradiol, an endogenous metabolite of estrogen, enhances apoptosis and beta-galactosidase expression in vascular endothelial cells. Biochem. Biophys. Res. Commun. 248, 9-12.
  • 9. Mukhopadhyay, T. & Roth, J.A. (1997) Induction of apoptosis in human lung cancer cells after wild-type p53 activation by methoxyestradiol. Oncogene. 14, 379-384.
  • 10. Klauber, N., Parangi, S., Flynn, E., Hamel, E. & D’Amato, R.J. (1997) Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol. Cancer Res. 57, 81-86.
  • 11. Fotsis, T., Zhang, Y., Pepper, M.S., Adlercreutz, H., Montesano, R., Nawroth, P.P. & Schweigerer, L. (1994) The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth. Nature. 368, 237-239.
  • 12. Qadan, L.R., Perez-Stable, C.M., Anderson, C., D’Ippolito, G., Herron, A., Howard, G.A. & Roos, B.A. (2001) 2Methoxyestradiol induces G2/M arrest and apoptosis in prostate cancer. Biochem. Biophys. Res. Commun. 285, 1259-1266.
  • 13. Brueggemeier, R.W., Bhat, A.S., Lovely, C.J., Coughenour, H.D., Joomprabutra, S., Weitzel, D.H., Vandre, D.D., Yusuf, F. & Burak, W.E. (2001) 2-Methoxymethylestradiol: A new 2-methoxy estrogen analog that exhibits antiproliferative activity and alters tubulin dynamics. J. Steroid Biochem. Mol. Biol. 78, 145-156.
  • 14. Ochi, T. & Oda, T. (2001) Structure-effect relationship in the induction of mitotic phase-specific abnormality of centrosome integrity and multipolar spindles by steroidal estrogens and their derivatives in cultured mammalian cells. J. Steroid Biochem. Mol. Biol. 78, 113-122.
  • 15. Schumacher, G. & Neuhaus, P. (2001) The physiological estrogen metabolite 2-methoxyestradiol reduces tumor growth and induces apoptosis in human solid tumors. J. Cancer Res. Clin. Oncol. 127, 405-410.
  • 16. Kumar, A.P., Garcia, G.E. & Slaga, T.J. (2001) 2-Methoxyestradiol blocks cell-cycle progression at G(2)/M phase and inhibits growth of human prostate cancer cells. Mol. Carcinogen. 31, 111-124.
  • 17. Watabe, S., Wada, S., Saito, S., Matsunaga, S., Fusetani, N., Ozaki, H. & Karaki, H. (1996) Cellular changes of rat embryonic fibroblasts by an actin-polymerization inhibitor, bistheonellide A, from a marine sponge. Cell Struct. Funct. 21, 199-212.
  • 18. Nicholson, D.W., Ali, A., Thornberry, N.A., Vaillancourt, J.P., Ding, C.K., Gallant, M., Gareau, Y., Griffin, P.R., Labelle, M. & Lazebnik, Y.A. (1995) Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 376, 37-43.
  • 19. Karbowski, M., Spodnik, J.H., Teranishi, M., Wozniak, M., Nishizawa, Y., Usukura, J. & Wakabayashi, T. (2001) Opposite effects of microtubule-stabilizing and microtubule-destabilizing drugs on biogenesis of mitochondria in mammalian cells. J. Cell Sci. 114, 281-291.
  • 20. Cushman, M., He, H.M., Katzenellenbogen, J.A., Varma, R.K., Hamel, E., Lin, C.M., Ram, S. & Sachdeva, Y.P. (1997) Synthesis of analogs of 2-methoxyestradiol with enhanced inhibitory effects on tubulin polymerization and cancer cell growth. J. Med. Chem. 40, 2323-2334.
  • 21. Lin, H.L., Liu, T.Y., Chau, G.Y., Lui, W.Y. & Chi, C.W. (2000) Comparison of 2-methoxyestradiol-induced, docetaxelinduced, and paclitaxel-induced apoptosis in hepatoma cells and its correlation with reactive oxygen species. Cancer. 89, 983-994.
  • 22. Hamel, E., Lin, C.M., Flynn, E. & D’Amato, R.J. (1996) Interactions of 2-methoxyestradiol, an endogenous mammalian metabolite, with unpolymerized tubulin and with tubulin polymers. Biochemistry. 35, 1304-1310.
  • 23. Wang, Z., Yang, D., Mohanakrishnan, A.K., Fanwick, P.E., Nampoothiri, P., Hamel, E. & Cushman, M. (2000) Synthesis of B-ring homologated estradiol analogues that modulate tubulin polymerization and microtubule stability. J. Med. Chem. 43, 2419-2429.
  • 24. Attalla, H., Makela, T.P., Adlercreutz, H. & Andersson, L.C. (1996) 2-Methoxyestradiol arrests cells in mitosis without depolymerizing tubulin. Biochem. Biophys. Res. Commun. 228, 467-473.
  • 25. Attalla, H., Westberg, J.A., Andersson, L.C., Adlercreutz, H. & Makela, T.P. (1998) 2-Methoxyestradiol-induced phosphorylation of Bcl-2: Uncoupling from JNK/SAPK activation. Biochem. Biophys. Res. Commun. 247, 616-619.
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.