MEK1/2 inhibition suppresses tamoxifen toxicity on CNS glial progenitor cells.
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.
Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York 14642.
Hsing-Yu
HY
Chen
Yin Miranda
YM
Yang
Ruolan
R
Han
Mark
M
Noble
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology; D002452:Cell Count; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000633:toxicity*; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D051379:Mice; D008808:Mice, Inbred CBA; D009457:Neuroglia / Q000187:drug effects* / Q000201:enzymology; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D013629:Tamoxifen / Q000633:toxicity*
C517975:AZD 6244; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D013629:Tamoxifen; D017479:Receptors, Platelet-Derived Growth Factor; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse