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MEK1/2 inhibition suppresses tamoxifen toxicity on CNS glial progenitor cells
Hsing-Yu Chen1, Yin Miranda Yang, Ruolan Han
1Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York 14642.
Abstract:
It is increasingly apparent that treatment with a variety of anticancer agents often is associated with adverse neurological consequences. Clinical studies indicate that exposure even to tamoxifen (TMX), a putatively benign antihormonal agent widely used in breast cancer treatment, causes cognitive dysfunction and changes in CNS metabolism, hippocampal volume, and brain structure. We found that TMX is toxic for a variety of CNS cell populations in vitro and also increased cell death in the corpus callosum and reduced cell division in the mouse subventricular zone, the hippocampal dentate gyrus, and the corpus callosum. We further discovered that MEK1/2 inhibition selectively rescued primary glial progenitors from TMX toxicity in vitro while enhancing TMX effects on MCF7 luminal human breast cancer cells. In vivo, MEK1/2 inhibition prevented TMX-induced cell death in systemically treated mice. Our results demonstrate unexpected cytotoxicity of this putatively benign antihormonal agent and offer a potential strategy for rescuing CNS cells from adverse effects of TMX.
Insights
Tamoxifen (TMX), a breast cancer drug, can harm brain cells. MEK1/2 inhibition may protect central nervous system cells from TMX toxicity, offering a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Oncology
- Pharmacology
Background:
- Anticancer agents can cause neurological side effects.
- Tamoxifen (TMX), used for breast cancer, has been linked to cognitive dysfunction and CNS changes.
- TMX exhibits toxicity to various central nervous system (CNS) cell populations.
Purpose of the Study:
- To investigate the neurotoxic effects of tamoxifen (TMX).
- To explore the potential of MEK1/2 inhibition as a neuroprotective strategy against TMX toxicity.
- To evaluate the impact of MEK1/2 inhibition on both CNS cells and breast cancer cells.
Main Methods:
- In vitro studies using primary CNS cell populations.
- In vivo studies in mice, including analysis of cell death and cell division in specific brain regions (corpus callosum, subventricular zone, hippocampal dentate gyrus).
- Assessment of MEK1/2 inhibition's effects on TMX-treated cells and in systemically treated mice.
Main Results:
- TMX demonstrated toxicity to multiple CNS cell types in vitro.
- TMX increased cell death in the corpus callosum and reduced cell division in the subventricular zone and hippocampal dentate gyrus in vivo.
- MEK1/2 inhibition selectively protected glial progenitors from TMX toxicity in vitro and prevented TMX-induced cell death in mice.
Conclusions:
- Tamoxifen exhibits unexpected cytotoxicity to CNS cells.
- MEK1/2 inhibition presents a promising strategy to mitigate TMX-induced neurotoxicity.
- This research offers a potential approach to preserve neurological function during tamoxifen therapy.
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