2-methoxyestradiol induces interferon gene expression and apoptosis in osteosarcoma cells.
2-Methoxyestradiol (2-ME), a naturally occurring mammalian metabolite of 17beta-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 (17beta-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-alpha and -beta and rat osteosarcoma cells (ROS17/2.8). The cytotoxicity of 2-ME was selective to transformed and immortalized osteoblastic cells; 2-ME (2 microm) 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.
Maran
A
A
Department of Orthopedics, Mayo Foundation, MN, Rochester 55905, USA. maran@mayo.edu
Zhang
M
M
Kennedy
A M
AM
Sibonga
J D
JD
Rickard
D J
DJ
Spelsberg
T C
TC
Turner
R T
RT
D000077584:2-Methoxyestradiol; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001857:Bone Matrix / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D001859:Bone Neoplasms; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000235:genetics; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000493:pharmacokinetics; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006133:Growth Substances / Q000235:genetics; D006801:Humans; D007372:Interferons / Q000235:genetics*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D012516:Osteosarcoma; D051381:Rats; D014407:Tumor Cells, Cultured
D016207:Cytokines; D004965:Estrogen Antagonists; D004967:Estrogens; D006133:Growth Substances; D000077267:Fulvestrant; D004958:Estradiol; D000077584:2-Methoxyestradiol; D007372:Interferons