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

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

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 histone γ-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 to γ 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.

Original languageEnglish (US)
Pages (from-to)231-239
Number of pages9
JournalInternational Journal of Radiation Oncology Biology Physics
Volume80
Issue number1
DOIs
StatePublished - May 1 2011

Fingerprint

estrogens
metabolites
breast
Estrogens
cancer
MCF-7 Cells
Breast Neoplasms
radiation
Radiation
cells
apoptosis
Radiation-Sensitizing Agents
Reactive Oxygen Species
Radiation Effects
oxygen
Cell Cycle
phosphorylation
cycles
phenotype
cytometry

Keywords

  • γ radiation
  • 2-Methoxyestradiol
  • Breast cancer
  • Radiosensitizer

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation
  • Cancer Research

Cite this

2-methoxyestradiol, an endogenous estrogen metabolite, sensitizes radioresistant MCF-7/FIR breast cancer cells through multiple mechanisms. / Salama, Salama; Diaz-Arrastia, Concepcion; Patel, Deepa; Botting, Shaleen; Hatch, Sandra.

In: International Journal of Radiation Oncology Biology Physics, Vol. 80, No. 1, 01.05.2011, p. 231-239.

Research output: Contribution to journalArticle

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T1 - 2-methoxyestradiol, an endogenous estrogen metabolite, sensitizes radioresistant MCF-7/FIR breast cancer cells through multiple mechanisms

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AU - Patel, Deepa

AU - Botting, Shaleen

AU - Hatch, Sandra

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