Micromolar concentrations of 2-methoxyestradiol kill glioma cells by an apoptotic mechanism, without destroying their microtubule cytoskeleton.
ABSTRACT The purpose of this study was to investigate the potential effects of 2-methoxyestradiol, a natural mammalian steroid, in glioma cells, since antiproliferative effects of this compound had been shown earlier in several leukemia and carcinoma cell lines. The effects of 0.2, 2 and 20 microM concentrations of 2-methoxyestradiol were measured in three malignant human glioma cell lines (U87MG, U138MG, LN405) and one malignant rat glioma cell line (RG-2) using a microtiter-tetrazolium (MTT) assay. In all cell lines, a significant reduction of the viable cell number by more then 75% occurred ( P < 0.05) for concentrations of 2 and 20 microM 2-methoxyestradiol after 6 days. A concentration of 0.2 microM had smaller effects (10-40% cell reduction), which were significant in two of the cell lines tested. The apoptotic nature of cell death was further analyzed in U87MG and RG-2 cells. Caspase-3 activity was significantly induced to levels between 3.4- and 23-fold after 4 days for the two higher 2-methoxyestradiol concentrations (P < 0.05). In the cell line RG-2 nuclear fragmentation was visible in many nuclei, following stains with Hoechst H33258. A round cell morphology occurred in most treated cells, which was not accompanied by a complete destruction of the microtubule network, as it can be observed with other microtubule targeting drugs.
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ABSTRACT: 2-Methoxyestradiol (2MeO-E2) is an endogenous metabolite of estrogen which was initially considered to be inactive. During the last few decades it has been shown that 2MeO-E2 is a promising anticancer drug. In vitro experiments have demonstrated that it has several anticancer activities, and potential to alleviate hypertension, glomerulosclerosis, hypercholesterolemia, and other disorders. However, due to its low solubility and extensive glucuronidation, to achieve effective concentrations large doses of 2MeO-E2 would be required. Clinical studies reflected very high inter- and intrapatient variability and oral bioavailability of 1 to 2%. Thus, this review paper highlights the origin of this compound, its therapeutic promises, and possible mechanisms of action. It also discusses the pharmacokinetic properties of 2MeO-E2 as well as current developments to overcome low drug solubility and its extensive first pass metabolism.Molecular Pharmaceutics 12/2010; 7(6):2030-9. · 4.57 Impact Factor
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ABSTRACT: 2-Methoxyestradiol (2ME) is a cytotoxic drug that interacts with tubulin and alters microtubule dynamics. It has been reported that testosterone (T) has a neuroprotective effect against oxidative stress and induces differentiation in mouse C1300 neuroblastoma cells. Here, we investigated the ability of T to attenuate the cytotoxic effects of 2ME and to induce cell differentiation in an immortalized rat glial cell line, known as C6. C6 cells were exposed for 5 days to 5 µM 2ME, 50 nM T, or both. We evaluated the morphological changes, growth rate, vitality, catalase activity, and glial fibrillary acidic protein (GFAP) immunoreactivity in control and treated C6 cells. Western blot analyses were used to quantify expression of tyrosinated tubulin (Tyr-Tub), acetylated tubulin (Acet-Tub), total α-tubulin (TOT-Tub), and GFAP. After 2ME exposure, the cells displayed a globular, shrunken shape, and retraction or absence of cytoplasmic processes; moreover, 2ME treatment significantly decreased cell growth, cell viability, catalase activity, and expression of both Tyr-Tub and Acet-Tub. However, when T was added, the cells exhibited a glial-like shape, elongated cell processes, and enhanced cell growth, cell vitality, catalase activity, and GFAP immunoreactivity. Densitometric values of Tyr-Tub, Acet-Tub, and GFAP increased significantly when T was present, while Tot-Tub values were unaltered. These results indicate that, in C6 cells, T: (i) attenuated the morpho-functional changes caused by 2ME exposure; (ii) induced glial differentiation; and (iii) exerted a direct action on the microtubule system.Journal of Cellular Physiology 10/2010; 226(6):1510-8. · 4.22 Impact Factor
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ABSTRACT: Gender-specific incidence patterns and the presence of hormonal receptors on tumor cells suggest that sex hormones may play a role in the onset of primary brain tumors. However, epidemiological studies on the relation of hormonal risk factors to the risk of brain tumors have been inconsistent. We examined the role of reproductive factors in the onset of glioma and meningioma in a case-control study conducted in the Southeastern US that included 507 glioma cases, 247 meningioma cases, and 695 community-based and friend controls. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CI) adjusting for age, race, US state of residence, and education. An older age at menarche was associated with an increased risk of glioma (≥15 vs. ≤12 years: OR 1.65; 95 % CI 1.11-2.45), with a stronger association observed in pre-menopausal (OR 2.22; 95 % CI 1.12-4.39) than post-menopausal (OR 1.55; 95 % CI 0.93-2.58) women. When compared to controls, meningioma cases were more likely to have undergone natural menopause (OR 1.52; 95 % CI 1.04-2.21) whereas glioma cases were less likely to be long term users of oral contraceptives (OR 0.47; 95 % CI 0.33-0.68). Increasing parity was not related to the risk of either tumor. Current findings are consistent with a limited role for hormones in the onset of brain tumors in women. Results contribute to a growing body of evidence that a later age at menarche increases the risk of glioma in women.Journal of Neuro-Oncology 04/2014; · 3.12 Impact Factor