MEK1/2 Inhibition Suppresses Tamoxifen Toxicity on CNS Glial Progenitor Cells

Chen, Hsing-Yu; Yang, Yin Miranda; Han, Ruolan; Noble, Mark

doi:10.1523/jneurosci.2729-13.2013

Cited by 15 publications

(9 citation statements)

References 38 publications

(20 reference statements)

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“…Some research reported that BRAF mutation was closely related to the sensitivity of Selumetinib [ 30 ]. Chen found that Selumetinib selectively rescued primary glial progenitors from TMX toxicity, such as cognitive dysfunction and changes in CNS metabolism, hippocampal volume, and brain structure, in vitro while enhancing TMX effects on MCF7 [ 31 ]. MEK pathway also plays key role in TNBC.…”

Section: Discussionmentioning

confidence: 99%

Selumetinib suppresses cell proliferation, migration and trigger apoptosis, G1 arrest in triple-negative breast cancer cells

et al. 2016

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BackgroundTriple-negative breast cancer (TNBC) has aggressive progression with poor prognosis and ineffective treatments. Selumetinib is an allosteric, ATP-noncompetitive inhibitor of MEK1/2, which has benn known as effective antineoplastic drugs for several malignant tumors. We hypothesized that Selumetinib might be potential drug for TNBC and explore the mechanism.MethodsAfter treated with Selumetinib, the viability and mobility of HCC1937 and MDA-MB-231 were detected by MTT, tunnel, wound-healing assay, transwell assay and FCM methods. MiR array was used to analysis the change of miRs. We predicted and verified CUL1 is the target of miR-302a using Luciferase reporter assay. We also silenced the CUL1 by siRNA, to clarify whether CUL1 take part in the cell proliferation, migration and regulated its substrate TIMP1 and TRAF2. Moreover, after transfection, the antagomir of miR-302a and CUL1 over-expressed plasmid into HCC1937 and MDA-MB-231 cell accompanied with the Selumetinib treatment, we detected the proliferation and migration again.ResultsSelumetinib reduce the proliferation, migration, triggered apoptosis and G1 arrest in TNBC cell lines. In this process, the miR-302a was up-regulated and inhibited the CUL1 expression. The later negatively regulated the TIMP1 and TRAF2. As soon as we knockdown miR-302a and over-expression CUL1 in TNBC cells, the cytotoxicity of Selumetinib was reversed.ConclusionsMiR-302a targeted regulated the CUL1 expression and mediated the Selumetinib-induced cytotoxicity of triple-negative breast cancer.

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Section: Discussionmentioning

confidence: 99%

Selumetinib suppresses cell proliferation, migration and trigger apoptosis, G1 arrest in triple-negative breast cancer cells

et al. 2016

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“…A previous investigation of TAM-induced toxicity at therapeutic doses in the brain revealed a loss of oligodendrocyte progenitor cells (OPCs) in the corpus callosum [ 7 ]. This was accompanied by a reduction in their proliferation, and that of neural progenitors in the subventricular zone and dentate gyrus, and it was suggested that this may represent a cellular substrate of cognitive dysfunction experienced by breast cancer patients receiving TAM therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Changes in human brain structure and metabolism with TAM treatment have also been reported [ 5 ]. Yet, there has been surprisingly little work done in animal models to identify TAM-induced changes in structure or function of the nervous system (either central or peripheral) [ 6 ], although in one study it was associated with a loss of glial progenitor cells in the corpus callosum and with reduced cell division in neurogenic regions of the CNS [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis

Denk

Ramer

Erskine

et al. 2015

acta neuropathol commun

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BackgroundTamoxifen (TAM) is an important cancer therapeutic and an experimental tool for effecting genetic recombination using the inducible Cre-Lox technique. Despite its widespread use in the clinic and laboratory, we know little about its effects on the nervous system. This is of significant concern because TAM, via unknown mechanisms, induces cognitive impairment in humans. A hallmark of cellular stress is induction of Activating Transcription Factor 3 (Atf3), and so to determine whether TAM induces cellular stress in the adult nervous system, we generated a knock-in mouse in which Atf3 promoter activity drives transcription of TAM-dependent Cre recombinase (Cre-ERT2); when crossed with tdtomato reporter mice, Atf3 induction results in robust and permanent genetic labeling of cells in which it is up-regulated even transiently.ResultsWe found that granular neurons of the olfactory bulb and dentate gyrus, vascular cells and ependymal cells throughout the brain, and peripheral sensory neurons expressed tdtomato in response to TAM treatment. We also show that TAM induced Atf3 up-regulation through inhibition of cholesterol epoxide hydrolase (ChEH): reporter expression was mitigated by delivery in vitamin E-rich wheat germ oil (vitamin E depletes ChEH substrates), and was partially mimicked by a ChEH-specific inhibitor.ConclusionsThis work demonstrates that TAM stresses cells of the adult central and peripheral nervous systems and highlights concerns about clinical and experimental use of TAM. We propose TAM administration in vitamin E-rich vehicles such as wheat germ oil as a simple remedy.

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“…Multiple mechanisms to describe CICI development have been suggested such as genetic predisposition, hormonal changes, DNA damage secondary to increased oxidative stress, and increased levels of inflammatory cytokines (Ahles and Saykin, 2007;Argyriou et al, 2010). Impaired cognitive function accompanied by reduced hippocampal neurogenesis, loss of CNS progenitors (including glial progenitors), and myelinopathy secondary to clinically used chemotherapeutic agents in adult rodents have also been reported (Dietrich et al, 2006;Han et al, 2008;Monje, 2008;Briones and Woods, 2011;Christie et al, 2012;Chen et al, 2013a). The use of HDACi in cancer treatment has been demonstrated to prevent OPC differentiation; thus, HDACi may conceivably impact cognition as well.…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibition is cytotoxic to oligodendrocyte precursor cells in vitro and in vivo

Dincman

Beare

Ohri

et al. 2016

Intl J of Devlp Neuroscience

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Histone deacetylase (HDAC) inhibition mediated by small molecule HDAC inhibitors (HDACi) has demonstrated divergent effects including toxicity towards transformed cell lines, neuroprotection in neurological disease models, and inhibition of oligodendrocyte precursor cell (OPC) differentiation to mature oligodendrocytes (OL). However, it remains unknown if transient HDAC inhibition may promote OPC survival. Using mouse cortical OPC primary cultures, we investigated the effects of the FDA approved pan-HDACi suberoylanilide hydroxamic acid (SAHA) on OPC survival. Initial studies showed differences in the HDAC expression pattern of multiple HDAC isoforms in OPCs relative to their terminally differentiated progeny cells, OLs and astrocytes. Treatment of OPCs with SAHA for up to 72h using a maximum concentration either at or lower than those necessary for cytotoxicity in most transformed cell lines resulted in over 67% reduction in viability relative to vehicle-treated OPCs. This was at least partly due to increased apoptosis as SAHA-treated cells displayed activated caspase 3 and were protected by the general caspase inhibitor Q-VD-OPH. Additionally, SAHA treatment of whole mice at postnatal day 5 induced apoptosis of cortical OPCs. These results suggest that SAHA negatively impacts OPC survival and may be detrimental to the myelinating brain and spinal cord. Such toxicity may be relevant in a clinical context as SAHA is currently involved in numerous clinical trials and is in consideration for use in the treatment of psychiatric and neurodegenerative conditions.

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MEK1/2 Inhibition Suppresses Tamoxifen Toxicity on CNS Glial Progenitor Cells

Cited by 15 publications

References 38 publications

Selumetinib suppresses cell proliferation, migration and trigger apoptosis, G1 arrest in triple-negative breast cancer cells

Selumetinib suppresses cell proliferation, migration and trigger apoptosis, G1 arrest in triple-negative breast cancer cells

Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis

Histone deacetylase inhibition is cytotoxic to oligodendrocyte precursor cells in vitro and in vivo

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