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Depression: 21st Century Solutions + The Dark Side of Wheat

Abstract Title:

2-Methoxyestradiol, an endogenous estrogen metabolite, sensitizes radioresistant MCF-7/FIR breast cancer cells through multiple mechanisms.

Abstract Source:

Int J Radiat Oncol Biol Phys. 2011 May 1 ;80(1):231-9. Epub 2011 Mar 9. PMID: 21392897

Abstract Author(s):

Salama Salama, Concepcion Diaz-Arrastia, Deepa Patel, Shaleen Botting, Sandra Hatch

Article Affiliation:

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Baylor College of Medicine, Houston, Texas 77030, USA. salama@bcm.edu

Abstract:

PURPOSE: The requirement for a well-tolerated and highly effective radiosensitizer that preferentially sensitizes tumor cells at multiple levels of radioresistance remains largely unmet. 2-Methoxyestradiol (2ME) has polypharmacological profiles that target multiple signaling pathways involved in the development of radioresistance. In the current study, we investigated the radiosensitizing effect of 2ME on the radioresistant breast cancer MCF-7/FIR cell line and explored the underlying mechanisms.

METHODS AND MATERIALS: The radiosensitizing effect of 2ME was evaluated on the basis of cell death and clonogenic survival. Formation of reactive oxygen species (ROS), apoptosis, and cell cycle progression were assessed by flow cytometry. Radiation-induced DNA damage was evaluated on the basis of histoneγ-H2AX phosphorylation and foci formation. Immunoblotting was used to assess the effects of γ radiation and/or 2ME on radioresistance pathways.

RESULTS: Our data demonstrate that MCF-7/FIR cells expressed higher levels of Bcl-2 and HIF-1α and displayed a lower ROS phenotype than the parental MCF-7 cells. Treatment of parental MCF-7 cells with 2ME (0.5 μM) had minimal effect on γ radiation-induced cell proliferation and surviving fractions. On the contrary, in MCF-7/FIR cells, treatment with 2ME significantly enhanced γ radiation-induced reduction in cell proliferation and surviving fraction. This combination was effective in activating apoptosis, arresting the cell cycle at the G(2)/M phase, and increasing the level of γ radiation-induced ROS and the number of γ-H2AX foci. In addition, 2ME significantly ameliorated γ radiation-induced expression of the HIF-1α transcription factor and its downstream targets AKT/mTOR.

CONCLUSION: 2ME preferentially sensitizes radioresistant MCF-7/FIR cells toγ radiation by targeting multiple signaling pathways involved in the development of radioresistance. This polypharmacological profile qualifies 2ME as a promising radiosensitizer in the treatment of radioresistant breast cancer cells and warrants systematic preclinical and clinical studies.

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Sayer Ji
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Depression: 21st Century Solutions + The Dark Side of Wheat

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