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Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma

Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here, we examined the...

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Autores principales: Stringer, Brett W., De Silva, Manam Inushi, Greenberg, Zarina, Noreña Puerta, Alejandra, Adams, Robert, Milky, Bridget, Zabolocki, Michael, van den Hurk, Mark, Ebert, Lisa M., Fairly Bishop, Christine, Conn, Simon J., Kichenadasse, Ganessan, Michael, Michael Z., Ormsby, Rebecca J., Poonoose, Santosh, Bardy, Cedric
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10599627/
https://www.ncbi.nlm.nih.gov/pubmed/37878712
http://dx.doi.org/10.1126/sciadv.adf1332
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author Stringer, Brett W.
De Silva, Manam Inushi
Greenberg, Zarina
Noreña Puerta, Alejandra
Adams, Robert
Milky, Bridget
Zabolocki, Michael
van den Hurk, Mark
Ebert, Lisa M.
Fairly Bishop, Christine
Conn, Simon J.
Kichenadasse, Ganessan
Michael, Michael Z.
Ormsby, Rebecca J.
Poonoose, Santosh
Bardy, Cedric
author_facet Stringer, Brett W.
De Silva, Manam Inushi
Greenberg, Zarina
Noreña Puerta, Alejandra
Adams, Robert
Milky, Bridget
Zabolocki, Michael
van den Hurk, Mark
Ebert, Lisa M.
Fairly Bishop, Christine
Conn, Simon J.
Kichenadasse, Ganessan
Michael, Michael Z.
Ormsby, Rebecca J.
Poonoose, Santosh
Bardy, Cedric
author_sort Stringer, Brett W.
collection PubMed
description Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here, we examined the effect of human CSF on glioblastoma (GBM) tumors from 25 patients. We found that CSF induces tumor cell plasticity and resistance to standard GBM treatments (temozolomide and irradiation). We identified nuclear protein 1 (NUPR1), a transcription factor hampering ferroptosis, as a mediator of therapeutic resistance in CSF. NUPR1 inhibition with a repurposed antipsychotic, trifluoperazine, enhanced the killing of GBM cells resistant to chemoradiation in CSF. The same chemo-effective doses of trifluoperazine were safe for human neurons and astrocytes derived from pluripotent stem cells. These findings reveal that chemoradiation efficacy decreases in human CSF and suggest that combining trifluoperazine with standard care may improve the survival of patients with GBM.
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spelling pubmed-105996272023-10-26 Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma Stringer, Brett W. De Silva, Manam Inushi Greenberg, Zarina Noreña Puerta, Alejandra Adams, Robert Milky, Bridget Zabolocki, Michael van den Hurk, Mark Ebert, Lisa M. Fairly Bishop, Christine Conn, Simon J. Kichenadasse, Ganessan Michael, Michael Z. Ormsby, Rebecca J. Poonoose, Santosh Bardy, Cedric Sci Adv Biomedicine and Life Sciences Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here, we examined the effect of human CSF on glioblastoma (GBM) tumors from 25 patients. We found that CSF induces tumor cell plasticity and resistance to standard GBM treatments (temozolomide and irradiation). We identified nuclear protein 1 (NUPR1), a transcription factor hampering ferroptosis, as a mediator of therapeutic resistance in CSF. NUPR1 inhibition with a repurposed antipsychotic, trifluoperazine, enhanced the killing of GBM cells resistant to chemoradiation in CSF. The same chemo-effective doses of trifluoperazine were safe for human neurons and astrocytes derived from pluripotent stem cells. These findings reveal that chemoradiation efficacy decreases in human CSF and suggest that combining trifluoperazine with standard care may improve the survival of patients with GBM. American Association for the Advancement of Science 2023-10-25 /pmc/articles/PMC10599627/ /pubmed/37878712 http://dx.doi.org/10.1126/sciadv.adf1332 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Stringer, Brett W.
De Silva, Manam Inushi
Greenberg, Zarina
Noreña Puerta, Alejandra
Adams, Robert
Milky, Bridget
Zabolocki, Michael
van den Hurk, Mark
Ebert, Lisa M.
Fairly Bishop, Christine
Conn, Simon J.
Kichenadasse, Ganessan
Michael, Michael Z.
Ormsby, Rebecca J.
Poonoose, Santosh
Bardy, Cedric
Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma
title Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma
title_full Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma
title_fullStr Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma
title_full_unstemmed Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma
title_short Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma
title_sort human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10599627/
https://www.ncbi.nlm.nih.gov/pubmed/37878712
http://dx.doi.org/10.1126/sciadv.adf1332
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