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Novel dopamine receptor 3 antagonists inhibit the growth of primary and temozolomide resistant glioblastoma cells

Treatment for the lethal primary adult brain tumor glioblastoma (GBM) includes the chemotherapy temozolomide (TMZ), but TMZ resistance is common and correlates with promoter methylation of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT). To improve treatment of GBMs, including t...

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Autores principales: Williford, Sarah E., Libby, Catherine J., Ayokanmbi, Adetokunbo, Otamias, Arphaxad, Gordillo, Juan J., Gordon, Emily R., Cooper, Sara J., Redmann, Matthew, Li, Yanjie, Griguer, Corinne, Zhang, Jianhua, Napierala, Marek, Ananthan, Subramaniam, Hjelmeland, Anita B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096095/
https://www.ncbi.nlm.nih.gov/pubmed/33945569
http://dx.doi.org/10.1371/journal.pone.0250649
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author Williford, Sarah E.
Libby, Catherine J.
Ayokanmbi, Adetokunbo
Otamias, Arphaxad
Gordillo, Juan J.
Gordon, Emily R.
Cooper, Sara J.
Redmann, Matthew
Li, Yanjie
Griguer, Corinne
Zhang, Jianhua
Napierala, Marek
Ananthan, Subramaniam
Hjelmeland, Anita B.
author_facet Williford, Sarah E.
Libby, Catherine J.
Ayokanmbi, Adetokunbo
Otamias, Arphaxad
Gordillo, Juan J.
Gordon, Emily R.
Cooper, Sara J.
Redmann, Matthew
Li, Yanjie
Griguer, Corinne
Zhang, Jianhua
Napierala, Marek
Ananthan, Subramaniam
Hjelmeland, Anita B.
author_sort Williford, Sarah E.
collection PubMed
description Treatment for the lethal primary adult brain tumor glioblastoma (GBM) includes the chemotherapy temozolomide (TMZ), but TMZ resistance is common and correlates with promoter methylation of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT). To improve treatment of GBMs, including those resistant to TMZ, we explored the potential of targeting dopamine receptor signaling. We found that dopamine receptor 3 (DRD3) is expressed in GBM and is also a previously unexplored target for therapy. We identified novel antagonists of DRD3 that decreased the growth of GBM xenograft-derived neurosphere cultures with minimal toxicity against human astrocytes and/or induced pluripotent stem cell-derived neurons. Among a set of DRD3 antagonists, we identified two compounds, SRI-21979 and SRI-30052, that were brain penetrant and displayed a favorable therapeutic window analysis of The Cancer Genome Atlas data demonstrated that higher levels of DRD3 (but not DRD2 or DRD4) were associated with worse prognosis in primary, MGMT unmethylated tumors. These data suggested that DRD3 antagonists may remain efficacious in TMZ-resistant GBMs. Indeed, SRI-21979, but not haloperidol, significantly reduced the growth of TMZ-resistant GBM cells. Together our data suggest that DRD3 antagonist-based therapies may provide a novel therapeutic option for the treatment of GBM.
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spelling pubmed-80960952021-05-17 Novel dopamine receptor 3 antagonists inhibit the growth of primary and temozolomide resistant glioblastoma cells Williford, Sarah E. Libby, Catherine J. Ayokanmbi, Adetokunbo Otamias, Arphaxad Gordillo, Juan J. Gordon, Emily R. Cooper, Sara J. Redmann, Matthew Li, Yanjie Griguer, Corinne Zhang, Jianhua Napierala, Marek Ananthan, Subramaniam Hjelmeland, Anita B. PLoS One Research Article Treatment for the lethal primary adult brain tumor glioblastoma (GBM) includes the chemotherapy temozolomide (TMZ), but TMZ resistance is common and correlates with promoter methylation of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT). To improve treatment of GBMs, including those resistant to TMZ, we explored the potential of targeting dopamine receptor signaling. We found that dopamine receptor 3 (DRD3) is expressed in GBM and is also a previously unexplored target for therapy. We identified novel antagonists of DRD3 that decreased the growth of GBM xenograft-derived neurosphere cultures with minimal toxicity against human astrocytes and/or induced pluripotent stem cell-derived neurons. Among a set of DRD3 antagonists, we identified two compounds, SRI-21979 and SRI-30052, that were brain penetrant and displayed a favorable therapeutic window analysis of The Cancer Genome Atlas data demonstrated that higher levels of DRD3 (but not DRD2 or DRD4) were associated with worse prognosis in primary, MGMT unmethylated tumors. These data suggested that DRD3 antagonists may remain efficacious in TMZ-resistant GBMs. Indeed, SRI-21979, but not haloperidol, significantly reduced the growth of TMZ-resistant GBM cells. Together our data suggest that DRD3 antagonist-based therapies may provide a novel therapeutic option for the treatment of GBM. Public Library of Science 2021-05-04 /pmc/articles/PMC8096095/ /pubmed/33945569 http://dx.doi.org/10.1371/journal.pone.0250649 Text en © 2021 Williford et al 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 author and source are credited.
spellingShingle Research Article
Williford, Sarah E.
Libby, Catherine J.
Ayokanmbi, Adetokunbo
Otamias, Arphaxad
Gordillo, Juan J.
Gordon, Emily R.
Cooper, Sara J.
Redmann, Matthew
Li, Yanjie
Griguer, Corinne
Zhang, Jianhua
Napierala, Marek
Ananthan, Subramaniam
Hjelmeland, Anita B.
Novel dopamine receptor 3 antagonists inhibit the growth of primary and temozolomide resistant glioblastoma cells
title Novel dopamine receptor 3 antagonists inhibit the growth of primary and temozolomide resistant glioblastoma cells
title_full Novel dopamine receptor 3 antagonists inhibit the growth of primary and temozolomide resistant glioblastoma cells
title_fullStr Novel dopamine receptor 3 antagonists inhibit the growth of primary and temozolomide resistant glioblastoma cells
title_full_unstemmed Novel dopamine receptor 3 antagonists inhibit the growth of primary and temozolomide resistant glioblastoma cells
title_short Novel dopamine receptor 3 antagonists inhibit the growth of primary and temozolomide resistant glioblastoma cells
title_sort novel dopamine receptor 3 antagonists inhibit the growth of primary and temozolomide resistant glioblastoma cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096095/
https://www.ncbi.nlm.nih.gov/pubmed/33945569
http://dx.doi.org/10.1371/journal.pone.0250649
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