Micromolar concentrations of 2-methoxyestradiol kill glioma cells by an apoptotic mechanism, without destroying their microtubule cytoskeleton

Department of Neuropathology, University of Magdeburg, Magdeburg, Germany.
Journal of Neuro-Oncology (Impact Factor: 2.79). 03/2005; 72(1):11-6. DOI: 10.1007/s11060-004-2158-4
Source: PubMed

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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Previous investigations of glioma risk in women have focused on oral contraceptive (OC), hormone replacement therapy (HRT), and reproductive factors. However, the results of published studies were inconclusive and inconsistent. Thus, a meta-analysis based on published case-control studies was performed to assess the role of exogenous and endogenous hormones factors in glioma risk. The PubMed and EMBASE databases were searched without any restrictions on language or publication year. Reference lists from retrieved articles were also reviewed. We included case-control studies reporting relative risks (RRs) with corresponding 95% confidence intervals (CIs) (or data to calculate them) between oral contraceptive (OC) and hormone replacement therapy (HRT) use, reproductive factors and glioma. Random-effects models were used to calculate the summary risk estimates. Finally, 11 eligible studies with 4860 cases and 14,740 controls were identified. A lower risk of glioma was observed among women who were ever users of exogenous hormones (OC RR = 0.707, 95% CI = 0.604-0.828; HRT: RR = 0.683, 95% CI = 0.577-0.808) compared with never users. An increased glioma risk was associated with older age at menarche (RR = 1.401, 95% CI = 1.052-1.865). No association was observed for menopause status, parous status, age at menopause, or age at first birth and glioma risk. The results of our study support the hypothesis female sex hormones play a role in the development of glioma in women. Additional studies are warranted to validate the conclusion from this meta-analysis and clarity the underlying mechanisms.
    PLoS ONE 07/2013; 8(7):e68695. DOI:10.1371/journal.pone.0068695 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background This study was undertaken to examine whether there is an association between parity and age at first birth and risk of death from brain cancer. Methods The study cohort consisted of 1,292,462 women who had a first and singleton childbirth between Jan. 1, 1978 and Dec. 31, 1987. We tracked each woman from the time of their first childbirth to December 31, 2009, and their vital status was ascertained by linking records with the computerized mortality database. Cox proportional hazard regression models were used to estimate the hazard ratios (HR) of death from brain cancer associated with parity and age at first birth. Results There were 316 brain cancer deaths during 34,980,246 person-years of follow-up. The mortality rate of brain cancer was 0.90 cases per 100,000 person-years. The adjusted HR was 1.35 (95% CI= 0.91-2.01) for women who gave birth between 21 and 25, 1.61 (95% CI=1.05-2.45) for women who gave birth after 25 years of age, respectively, when compared with women who gave birth less than 20 years. A trend of increasing risk of brain cancer was seen with increasing age at first birth. The adjusted HR were 0.73 (95% CI= 0.53-0.99) for women who had 2 children, and 0.60 (95% CI =0.43-0.83) for women with 3 or more births, respectively, when compared with women who had given birth to only 1 child. There was a significant decreasing trend in the HRs of brain cancer with increasing parity. Conclusions This study provides evidence that reproductive factors (parity and early age at first birth) may confer a protective effect on the risk of death from brain cancer.
    BMC Public Health 10/2012; 12(1):857. DOI:10.1186/1471-2458-12-857 · 2.32 Impact Factor
  • [Show abstract] [Hide abstract]
    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; 118(2). DOI:10.1007/s11060-014-1427-0 · 2.79 Impact Factor