Functional inactivation of the oestrogen receptor by the antioestrogen, ZM 182780, sensitises tumour cells to reactive oxygen species

C. J. Newton, N. Drummond, C. H. Burgoyne, V. Speirs, G. K. Stalla, Stephen Atkin

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Reactive oxygen species (ROS) play a fundamental role in both apoptotic and necrotic cell death. Their importance is highlighted by studies showing that they mediate cell death in response to radiotherapy and to some forms of chemotherapy. Here we provide the first evidence for a role of ROS in response to an antiendocrine agent currently undergoing clinical trials. Using the oestrogen receptor (ER) containing rat pituitary GH3 cell line, we show that cell death is induced by the pure steroidal antioestrogen, ZM 182780, and that this is blocked by the antioxidant, N-acetyl cysteine (NAC). By flow cytometry, we show that, prior to the onset of DNA breakdown measured by ELISA, ZM 182780 exposure has no significant effect on intracellular oxidant concentrations. In contrast, ZM 182780 exposure greatly increases sensitivity to oxidants generated by blocking cellular antioxidant pathways and from exogenous administration of hydrogen peroxide (H2O2). As both necrosis and apoptosis are controlled by mitochondrial function, further experiments conducted to determine mitochondrial membrane potential (ΔΨ(m)) have indicated that the ZM 182780-induced loss of ER function increases the ease with which oxidants collapse mitochondrial activity and, as a consequence, cell death.

Original languageEnglish
Pages (from-to)199-210
Number of pages12
JournalJournal of Endocrinology
Volume161
Issue number2
DOIs
Publication statusPublished - 1999
Externally publishedYes

Fingerprint

Estrogen Receptor Modulators
Estrogen Receptors
Reactive Oxygen Species
Cell Death
Oxidants
Neoplasms
Antioxidants
Mitochondrial Membrane Potential
Hydrogen Peroxide
Cysteine
Flow Cytometry
Necrosis
Radiotherapy
Enzyme-Linked Immunosorbent Assay
Clinical Trials
Apoptosis
Drug Therapy
Cell Line
fulvestrant
DNA

ASJC Scopus subject areas

  • Endocrinology

Cite this

Functional inactivation of the oestrogen receptor by the antioestrogen, ZM 182780, sensitises tumour cells to reactive oxygen species. / Newton, C. J.; Drummond, N.; Burgoyne, C. H.; Speirs, V.; Stalla, G. K.; Atkin, Stephen.

In: Journal of Endocrinology, Vol. 161, No. 2, 1999, p. 199-210.

Research output: Contribution to journalArticle

Newton, C. J. ; Drummond, N. ; Burgoyne, C. H. ; Speirs, V. ; Stalla, G. K. ; Atkin, Stephen. / Functional inactivation of the oestrogen receptor by the antioestrogen, ZM 182780, sensitises tumour cells to reactive oxygen species. In: Journal of Endocrinology. 1999 ; Vol. 161, No. 2. pp. 199-210.
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