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Ferroptosis in Neurons and Cancer Cells Is Similar But Differentially Regulated by Histone Deacetylase Inhibitors.
eNeuro. 2019 Jan-Feb; 6(1)E

Abstract

Ferroptotic death is a mechanism for tumor suppression by pharmacological inhibitors that target the Xc - transporter (cystine/glutamate antiporter) in a host of non-CNS and CNS tumors. Inhibition of this transporter leads to reduction of cystine uptake, cyst(e)ine deprivation, subsequent depletion of the versatile antioxidant glutathione, and reactive lipid species-dependent death. Accordingly, pharmacological inhibitors of the Xc - transporter can also induce neuronal cell death raising concerns about toxicity in the CNS and PNS if these agents are used for chemotherapy. Here, we show that ferroptotic death induced by the canonical ferroptosis inducer erastin is similar in HT1080 fibrosarcoma cells and primary cortical neurons although cell death is mediated more potently in cancer cells. Reducing the toxicity of ferroptosis inducers will require, among other things, the identification of agents that protect neurons from ferroptosis but exacerbate it in tumor cells. Although we show that a number of agents known to block ferroptosis in primary mouse neurons also inhibit ferroptosis in fibrosarcoma cells, class I histone deacetylase (HDAC) inhibitors selectively protect neurons while augmenting ferroptosis in cancer cells. Our results further suggest that cell death pathways induced by erastin in these two cell types are statistically identical to each other and identical to oxidative glutamate toxicity in neurons, where death is also mediated via inhibition of Xc - cystine transport. Together, these studies identify HDACs inhibitors as a novel class of agents to augment tumor suppression by ferroptosis induction and to minimize neuronal toxicity that could manifest as peripheral neuropathy or chemo brain.

Authors+Show Affiliations

Burke Neurological Institute, White Plains, New York 10605. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065. Fraunhofer Research Institution for Marine Biotechnology and Cell Technology and Institute for Medical and Marine Biotechnology, University of Lübeck, Lübeck, 23562, Germany. Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, 23562, Germany.Burke Neurological Institute, White Plains, New York 10605. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065.Burke Neurological Institute, White Plains, New York 10605. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065.Burke Neurological Institute, White Plains, New York 10605. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065.Burke Neurological Institute, White Plains, New York 10605. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065.Burke Neurological Institute, White Plains, New York 10605. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065.Burke Neurological Institute, White Plains, New York 10605. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065.Burke Neurological Institute, White Plains, New York 10605. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30783618

Citation

Zille, Marietta, et al. "Ferroptosis in Neurons and Cancer Cells Is Similar but Differentially Regulated By Histone Deacetylase Inhibitors." ENeuro, vol. 6, no. 1, 2019.
Zille M, Kumar A, Kundu N, et al. Ferroptosis in Neurons and Cancer Cells Is Similar But Differentially Regulated by Histone Deacetylase Inhibitors. eNeuro. 2019;6(1).
Zille, M., Kumar, A., Kundu, N., Bourassa, M. W., Wong, V. S. C., Willis, D., Karuppagounder, S. S., & Ratan, R. R. (2019). Ferroptosis in Neurons and Cancer Cells Is Similar But Differentially Regulated by Histone Deacetylase Inhibitors. ENeuro, 6(1). https://doi.org/10.1523/ENEURO.0263-18.2019
Zille M, et al. Ferroptosis in Neurons and Cancer Cells Is Similar but Differentially Regulated By Histone Deacetylase Inhibitors. eNeuro. 2019 Jan-Feb;6(1) PubMed PMID: 30783618.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ferroptosis in Neurons and Cancer Cells Is Similar But Differentially Regulated by Histone Deacetylase Inhibitors. AU - Zille,Marietta, AU - Kumar,Amit, AU - Kundu,Nandini, AU - Bourassa,Megan W, AU - Wong,Victor S C, AU - Willis,Dianna, AU - Karuppagounder,Saravanan S, AU - Ratan,Rajiv R, Y1 - 2019/02/15/ PY - 2018/06/28/received PY - 2019/01/15/revised PY - 2019/01/18/accepted PY - 2019/2/21/entrez PY - 2019/2/21/pubmed PY - 2019/5/22/medline KW - apoptosis KW - cell death KW - chemotherapy KW - ferroptosis KW - necroptosis KW - necrosis JF - eNeuro JO - eNeuro VL - 6 IS - 1 N2 - Ferroptotic death is a mechanism for tumor suppression by pharmacological inhibitors that target the Xc - transporter (cystine/glutamate antiporter) in a host of non-CNS and CNS tumors. Inhibition of this transporter leads to reduction of cystine uptake, cyst(e)ine deprivation, subsequent depletion of the versatile antioxidant glutathione, and reactive lipid species-dependent death. Accordingly, pharmacological inhibitors of the Xc - transporter can also induce neuronal cell death raising concerns about toxicity in the CNS and PNS if these agents are used for chemotherapy. Here, we show that ferroptotic death induced by the canonical ferroptosis inducer erastin is similar in HT1080 fibrosarcoma cells and primary cortical neurons although cell death is mediated more potently in cancer cells. Reducing the toxicity of ferroptosis inducers will require, among other things, the identification of agents that protect neurons from ferroptosis but exacerbate it in tumor cells. Although we show that a number of agents known to block ferroptosis in primary mouse neurons also inhibit ferroptosis in fibrosarcoma cells, class I histone deacetylase (HDAC) inhibitors selectively protect neurons while augmenting ferroptosis in cancer cells. Our results further suggest that cell death pathways induced by erastin in these two cell types are statistically identical to each other and identical to oxidative glutamate toxicity in neurons, where death is also mediated via inhibition of Xc - cystine transport. Together, these studies identify HDACs inhibitors as a novel class of agents to augment tumor suppression by ferroptosis induction and to minimize neuronal toxicity that could manifest as peripheral neuropathy or chemo brain. SN - 2373-2822 UR - https://www.unboundmedicine.com/medline/citation/30783618/Ferroptosis_in_Neurons_and_Cancer_Cells_Is_Similar_But_Differentially_Regulated_by_Histone_Deacetylase_Inhibitors_ L2 - http://eneuro.org/cgi/pmidlookup?view=long&pmid=30783618 DB - PRIME DP - Unbound Medicine ER -