MEK1/2 Inhibition Suppresses Tamoxifen Toxicity on CNS Glial Progenitor Cells
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
This was accompanied by reduction in their proliferation, and that of neural progenitors in SVZ and dentate gyrus.
“This was accompanied by a reduction in their proliferation, and that of neural progenitors in the subventricular zone and dentate gyrus”
From Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis (2015) · cites this paper as [7]
The Results section on systemic tamoxifen treatment reports reduced O-2A/OPC division in vitro and significantly suppressed cell division in the mouse subventricular zone and dentate gyrus. It does not identify the dividing cells in those two regions as neural progenitors; the Discussion says the affected precursor populations remain to be defined. Page numbers are not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn one study, TAM was associated with loss of glial progenitor cells in the corpus callosum and with reduced cell division in neurogenic regions of the CNS.
“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].”
From Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis (2015) · cites this paper as [7]
Previous investigation revealed loss of OPCs in corpus callosum at therapeutic TAM doses.
“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].”
From Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis (2015) · cites this paper as [7]
OPC loss was prevented both in vitro and in vivo by MEK1/2 inhibition.
“OPC loss was prevented both in vitro and in vivo by MEK1/2 inhibition”
From Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis (2015) · cites this paper as [7]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer
Roberts, P. J., & Der, C. J. (2007) · Oncogene · doi:10.1038/sj.onc.1210422 · Cited by 2,788 · see citing works
Metabolism and functions of glutathione in brain
Dringen, R. (2000) · Progress in Neurobiology · doi:10.1016/s0301-0082(99)00060-x · Cited by 1,702 · see citing works
Irradiation induces neural precursor-cell dysfunction
Monje, M. L., Mizumatsu, S., Fike, J. R., & Palmer, T. D. (2002) · Nature Medicine · doi:10.1038/nm749 · Cited by 1,271 · see citing works
van Dam, F. S. A. M., Boogerd, W. J., Schagen, S. B., Müller, M. J., Fortuyn, M. E. D., van der Wall, E., & Rodenhuis, S. (1998) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/90.3.210 · Cited by 764 · see citing works
Yeh, T. C., Marsh, V., Bernat, B. A., Ballard, J., Colwell, H., Evans, R. J., Parry, J., Smith, D. J., Brandhuber, B. J., Gross, S. D., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1150 · Cited by 578 · see citing works
Dietrich, J., Han, R., Yang, Y. M., Mayer‐Pröschel, M., & Noble, M. (2006) · Journal of Biology · doi:10.1186/jbiol50 · Cited by 506 · see citing works
Self-citationTargeting the RAF–MEK–ERK pathway in cancer therapy
Montagut, C. O., & Settleman, J. (2009) · Cancer Letters · doi:10.1016/j.canlet.2009.01.022 · Cited by 466 · see citing works
Thorburne, S. K., & Juurlink, B. H. J. (1996) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1996.67031014.x · Cited by 390 · see citing works
Davies, B. R., Logié, A., McKay, J. S., Martin, P. D., Steele, S. J., Jenkins, R., Cockerill, M. J., Cartlidge, S., & Smith, P. D. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-07-0231 · Cited by 388 · see citing works
Lien, E. A., Solheim, E., & Ueland, P. M. (1991) · PubMed · Cited by 362 · see citing works
Han, R., Yang, Y. M., Dietrich, J., Luebke, A., Mayer-Pröschel, M., & Noble, M. (2008) · Journal of Biology · doi:10.1186/jbiol69 · Cited by 316 · see citing works
Self-citationKirkwood, J. M., Bastholt, L., Robert, C., Sosman, J. A., Larkin, J., Hersey, P., Middleton, M. R., Cantarini, M., Zazulina, V., Kemsley, K., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1491 · Cited by 276 · see citing works
Schilder, C. M. T., Seynaeve, C., Beex, L. V. A. M., Boogerd, W. J., Linn, S. C., Gundy, C. M., Huizenga, H. M., Nortier, J. W. R., van de Velde, C. J., van Dam, F. S. A. M., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2008.21.3553 · Cited by 270 · see citing works
Distributed neural system for general intelligence revealed by lesion mapping
Gläscher, J. P., Rudrauf, D., Colom, R., Paul, L. K., Tranel, D., Damasio, H., & Adolphs, R. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910397107 · Cited by 270 · see citing works
Impact of white matter hyperintensity volume progression on rate of cognitive and motor decline
Silbert, L. C., Nelson, C., Howieson, D. B., Moore, M. M., & Kaye, J. A. (2008) · Neurology · doi:10.1212/01.wnl.0000316799.86917.37 · Cited by 263 · see citing works
Bodoky, G., Timcheva, C., Spigel, D. R., La Stella, P. J., Ciuleanu, T. E., Pover, G., & Tebbutt, N. C. (2012) · Investigational New Drugs · doi:10.1007/s10637-011-9687-4 · Cited by 236 · see citing works
Cognitive side effects of cancer therapy demonstrate a functional role for adult neurogenesis
Monje, M., & Dietrich, J. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.05.012 · Cited by 217 · see citing works
Estrogen- and tamoxifen-associated effects on brain structure and function
Eberling, J. L., Wu, C. C., Tong-Turnbeaugh, R., & Jagust, W. (2003) · NeuroImage · doi:10.1016/j.neuroimage.2003.08.037 · Cited by 211 · see citing works
Kisanga, E. R., Gjerde, J., Guerrieri‐Gonzaga, A., Pigatto, F., Pesci-Feltri, A., Robertson, C., Serrano, D., Pelosi, G., DeCensi, A., & Lien, E. A. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-03-0538 · Cited by 197 · see citing works
Guardiola‐Diaz, H. M., Ishii, A., & Bansal, R. (2012) · Glia · doi:10.1002/glia.22281 · Cited by 171 · see citing works
Gundimeda, U., Chen, Z.-H., & Gopalakrishna, R. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.23.13504 · Cited by 165 · see citing works
The ERK2 Mitogen-Activated Protein Kinase Regulates the Timing of Oligodendrocyte Differentiation
Fyffe-Maricich, S. L., Karlo, J. C., Landreth, G. E., & Miller, R. H. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.3239-10.2011 · Cited by 158 · see citing works
Lien, E., Wester, K., Lønning, P. E., Solheim, E., & Ueland, P. M. (1991) · British Journal of Cancer · doi:10.1038/bjc.1991.147 · Cited by 151 · see citing works
Elevated serum levels of transforming growth factor-?1 in patients with colorectal carcinoma
Shim, K. S., Kim, K. H., Han, W. S., & Park, E. B. (1999) · Cancer · doi:10.1002/(sici)1097-0142(19990201)85:3 · Cited by 137 · see citing works
Ferlini, C., Scambia, G., Marone, M., Distefano, M., Gaggini, C., Ferrandina, G., Fattorossi, A., Isola, G., Panici, P. B., & Mancuso, S. (1998) · British Journal of Cancer · doi:10.1038/sj.bjc.6690042 · Cited by 136 · see citing works
Cognitive Function and Reproductive Hormones in Adjuvant Therapy for Breast Cancer
Bender, C. M., Paraska, K. K., Sereika, S. M., Ryan, C. M., & Berga, S. L. (2001) · Journal of Pain and Symptom Management · doi:10.1016/s0885-3924(01)00268-8 · Cited by 118 · see citing works
Brown, M. S., Stemmer, S. M., Simon, J. H., Stears, J. C., Jones, R. B., Cagnoni, P. J., & Sheeder, J. L. (1998) · PubMed Central · Cited by 118 · see citing works
Holt, S. V., Logié, A., Odedra, R., Heier, A., Heaton, S. P., Alférez, D., Davies, B. R., Wilkinson, R. W., & Smith, P. D. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.8 · Cited by 112 · see citing works
Dietrich, J., Noble, M., & Mayer‐Pröschel, M. (2002) · Glia · doi:10.1002/glia.10116 · Cited by 103 · see citing works
Self-citationPalmer, J. L., Trotter, T., Joy, A. A., & Carlson, L. E. (2008) · Journal of Cancer Survivorship · doi:10.1007/s11764-008-0070-1 · Cited by 89 · see citing works
Cognitive functioning in cancer patients
Meyers, C. A., & Abbruzzese, J. L. (1992) · Neurology · doi:10.1212/wnl.42.2.434 · Cited by 85 · see citing works
Stemmer, S. M., Stears, J. C., Burton, B. S., Jones, R. B., & Simon, J. H. (1994) · PubMed Central · Cited by 82 · see citing works
Janelsins, M. C., Roscoe, J. A., Berg, M. J., Thompson, B. D., Gallagher, M. J., Morrow, G. R., Heckler, C. E., Jean‐Pierre, P., Opanashuk, L. A., & Gross, R. A. (2009) · Cancer Investigation · doi:10.3109/07357900903405942 · Cited by 77 · see citing works
Iusuf, D., Teunissen, S. F., Wagenaar, E., Rosing, H., Beijnen, J. H., & Schinkel, A. H. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.178301 · Cited by 75 · see citing works
Patel, S. P., Lazar, A. J., Papadopoulos, N. E., Liu, P., Infante, J. R., Glass, M. R., Vaughn, C., LoRusso, P. M., Cohen, R. B., Davies, M. A., et al. (2012) · Cancer · doi:10.1002/cncr.27790 · Cited by 66 · see citing works
Chemotherapy Associated Central Nervous System Damage
Dietrich, J. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-6306-2_11 · Cited by 44 · see citing works
Mondie, C. M., Vandergrift, K. A., Wilson, C. L., Gulinello, M. E., & Weber, E. T. (2010) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.01.016 · Cited by 43 · see citing works
Chen, H., Yang, Y. M., Stevens, B. M., & Noble, M. (2013) · EMBO Molecular Medicine · doi:10.1002/emmm.201202140 · Cited by 43 · see citing works
Self-citationQuiescent adult neural stem cells are exceptionally sensitive to cosmic radiation
Encinas, J. M., Vazquez, M. E., Switzer, R. C., Chamberland, D., Nick, H., Levine, H. G., Scarpa, P. J., Enikolopov, G., & Steindler, D. A. (2007) · Experimental Neurology · doi:10.1016/j.expneurol.2007.10.021 · Cited by 38 · see citing works
Tissue distribution of 4-hydroxy-N-desmethyltamoxifen and tamoxifen-N-oxide
Gjerde, J., Gandini, S., Guerrieri‐Gonzaga, A., Moi, L. L. H., Aristarco, V., Mellgren, G., DeCensi, A., & Lien, E. A. (2012) · Breast Cancer Research and Treatment · doi:10.1007/s10549-012-2074-9 · Cited by 36 · see citing works
Reddy, K. B., & Glaros, S. (2007) · International Journal of Oncology · doi:10.3892/ijo.30.4.971 · Cited by 31 · see citing works
Relative Effects of Tamoxifen, Raloxifene, and Conjugated Equine Estrogens on Cognition
Espeland, M. A., Shumaker, S. A., Limacher, M., Rapp, S. R., Bevers, T. B., Barad, D. H., Coker, L. H., Gaussoin, S. A., Stefanick, M. L., Lane, D. S., et al. (2010) · Journal of Women's Health · doi:10.1089/jwh.2009.1605 · Cited by 30 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Sahasrabuddhe, V., & Ghosh, H. S. (2022) · Cell Reports · doi:10.1016/j.celrep.2021.110252 · Cited by 91 · see citing works
Ganguli, M. (2015) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0000000000000086 · Cited by 99 · see citing works
Adult Neurogenesis in Mammals: Variations and Confusions
Lipp, H., & Bonfanti, L. (2016) · Brain Behavior and Evolution · doi:10.1159/000446905 · Cited by 53 · see citing works
Hu, H., Zhang, Y.-R., Aerqin, Q., Ou, Y., Wang, Z.-T., Cheng, W., Feng, J., Tan, L., & Yu, J. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02268-3 · Cited by 53 · see citing works
Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis
Denk, F., Ramer, L. M., Erskine, E. L. K. S., Nassar, M. A., Bogdanov, Y., Signore, M., Wood, J. N., McMahon, S. B., & Ramer, M. S. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0255-6 · Cited by 44 · see citing works
“Yet, there has been surprisingly little work done in animal models to identify TAMinduced 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 neu…”
Swearingen, A. E. D. V., Sambade, M. J., Siegel, M. B., Sud, S., McNeill, R. S., Bevill, S. M., Chen, X., Bash, R., Mounsey, L. A., Golitz, B. T., et al. (2017) · Neuro-Oncology · doi:10.1093/neuonc/nox052 · Cited by 42 · see citing works
Haggstrom, L., Vardy, J. L., Carson, E., Segara, D., Lim, E., & Kiely, B. E. (2022) · Cancers · doi:10.3390/cancers14040920 · Cited by 39 · see citing works
Zhou, Y., Lin, S., Tseng, K., Han, K., Wang, Y., Gan, Z.-H., Min, D., & Hu, H. (2016) · BMC Cancer · doi:10.1186/s12885-016-2773-4 · Cited by 25 · see citing works
Noble, M., Mayer‐Pröschel, M., Li, Z., Dong, T., Cui, W., Pröschel, C., Ambeskovic, I., Dietrich, J., Han, R., Yang, Y. M., et al. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.10.860 · Cited by 19 · see citing works
Self-citationHistone deacetylase inhibition is cytotoxic to oligodendrocyte precursor cells in vitro and in vivo
Dincman, T. A., Beare, J. E., Ohri, S. S., Gallo, V., Hetman, M., & Whittemore, S. R. (2016) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2016.08.006 · Cited by 18 · see citing works
Hajigholami, S., Malekshahi, Z. V., Bodaghabadi, N., Najafi, F., Shirzad, H., & Sadeghizadeh, M. (2018) · Europe PMC (PubMed Central) · Cited by 18 · see citing works
MEK inhibitor effective against proliferation in breast cancer cell
Zhou, Y., Hu, H., Meng, W., Jiang, L., Zhang, X., Sha, J., Lu, Z., & Yang, Y. (2014) · Tumor Biology · doi:10.1007/s13277-014-1901-5 · Cited by 17 · see citing works
Self-citationRegion specific knock-out reveals distinct roles of chromatin modifiers in adult neurogenic niches
Rhodes, C. T., Zunino, G., Huang, S.-W. A., Cardona, S. M., Cardona, A. E., Berger, M. S., Lemmon, V., & Lin, C. A. (2018) · Cell Cycle · doi:10.1080/15384101.2018.1426417 · Cited by 12 · see citing works
Wang, J., Chen, W., Du, W., Zhang, H., Ilmer, M., Song, L., Hu, Y. Z., & Ma, X. (2023) · International Journal of Nanomedicine · doi:10.2147/ijn.s406627 · Cited by 10 · see citing works
AEBS inhibition in macrophages: Augmenting reality for SERMs repurposing against infections
Sfogliarini, C., Tran, L. H., Cesta, C. M., Allegretti, M., Locati, M., & Vegeto, E. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116544 · Cited by 5 · see citing works
Nano Packaged Diblock and Curcumin: a New Approach Inorder To Drug Resistance in Breast Cancer
Hajigholami, S., & Malekshahi, Z. V. (2017) · Iranian South Medical Journal · doi:10.18869/acadpub.ismj.19.6.951 · Cited by 2 · see citing works
Neuropsychological manifestations of chemotherapy
Santos-Pinheiro, F., & Butts, A. M. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-15663-2.00003-1
Latifa, N., Rais, I. R., Prasasti, D., & Utami, D. (2024) · BIO Web of Conferences · doi:10.1051/bioconf/202414804013
- Authors
- Chen, H.-Y., Yang, Y. M., Han, R., & Noble, M.
- Affiliations
- University of Rochester Medicine (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-09-18
- Volume
- 33
- Issue
- 38
- Pages
- 15069-15074
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3776059
- OpenAlex
- W1995548102
- Cited by
- 18
- References
- 42
- Citations by year
- 2024: 3 · 2023: 1 · 2022: 3 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 2 · 2014: 2
- FWCI
- 1.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense (W81XWH)
- National Institutes of Health (W81XWH)
- National Cancer Institute (R01CA131385, CA131385)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- tamoxifen, MEK1/2 inhibition, glial progenitor cells, neurotoxicity, cognitive impairment, breast cancer treatment side effects, subventricular zone, dentate gyrus, corpus callosum, cell death
- MeSH terms
- Animals, Benzimidazoles, Breast Neoplasms, Cell Count, Cells, Cultured, Central Nervous System, Enzyme Inhibitors, Estrogen Antagonists, Female, Humans, Mice, Inbred CBA, Neuroglia, Stem Cells, Tamoxifen, Receptors, Platelet-Derived Growth Factor, In Situ Nick-End Labeling, MAP Kinase Kinase 1, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
