2-methoxyestradiol induces interferon gene expression and apoptosis in osteosarcoma cells

A. Maran, M. Zhang, A. M. Kennedy, J. D. Sibonga, D. J. Rickard, T. C. Spelsberg, R. T. Turner

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

2-Methoxyestradiol (2-ME), a naturally occurring mammalian metabolite of 17β-estradiol, has been implicated as a physiological inhibitor of tumor cell proliferation. In this study, the effects of 2-ME on cultured osteosarcomatous cells were investigated. Dose-dependent growth inhibition was observed in MG63 and TE85 human osteosarcoma cells exposed to 2-ME. The cell killing by 2-ME was ligand-specific; the immediate precursor (2-hydroxyestradiol), the parent compound (17β-estradiol), and the equivalent metabolite of estrone (2-methoxyestrone) exhibited less potency and efficacy. Furthermore, 2-ME was similarly effective at killing immortalized human fetal osteoblastic cells (hFOB) with and without estrogen receptor-α and -β and rat osteosarcoma cells (ROS17/2.8). The cytotoxicity of 2-ME was selective to transformed and immortalized osteoblastic cells; 2-ME (2 μm) had no effect on the proliferation of primary cultures of human osteoblasts. Co-treatment with the potent estrogen receptor ligand, ICI-182,780, did not reduce 2-ME-induced osteosarcoma cell death, implying that this action is not mediated by conventional estrogen receptors. The expression levels of bone matrix protein genes, type 1 collagen and osteonectin, were transiently reduced after 2-ME treatment, suggesting that the surviving cells are capable of producing bone matrix. The 2-ME-mediated killing of osteosarcoma cells was due to the induction of apoptosis; treatment induced expression of interferon genes within 12 h and histological evidence of apoptosis within 48 h of 2-ME treatment. Thus, our results demonstrate that 2-ME is highly cytotoxic to osteosarcoma cells but not normal osteoblasts. These findings suggest that further study of 2-ME as a potential intervention for treatment of osteosarcoma is warranted.

Original languageEnglish (US)
Pages (from-to)393-398
Number of pages6
JournalBone
Volume30
Issue number2
DOIs
StatePublished - Feb 26 2002

Keywords

  • Apoptosis
  • Estrogen metabolism
  • Human bone cells
  • Interferon
  • Osteoblasts
  • Osteosarcoma

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

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    Maran, A., Zhang, M., Kennedy, A. M., Sibonga, J. D., Rickard, D. J., Spelsberg, T. C., & Turner, R. T. (2002). 2-methoxyestradiol induces interferon gene expression and apoptosis in osteosarcoma cells. Bone, 30(2), 393-398. https://doi.org/10.1016/S8756-3282(01)00681-0