Journal article
Novel dopamine receptor 3 antagonists inhibit the growth of primary and temozolomide resistant glioblastoma cells
PloS one, Vol.16(5), pp.e0250649-e0250649
05/04/2021
DOI: 10.1371/journal.pone.0250649
PMCID: PMC8096095
PMID: 33945569
Abstract
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.
Details
- Title: Subtitle
- Novel dopamine receptor 3 antagonists inhibit the growth of primary and temozolomide resistant glioblastoma cells
- Creators
- Sarah E. Williford - University of Alabama at BirminghamCatherine J. Libby - University of Alabama at BirminghamAdetokunbo Ayokanmbi - University of Alabama at BirminghamArphaxad Otamias - University of Alabama at BirminghamJuan J. Gordillo - University of Alabama at BirminghamEmily R. Gordon - HudsonAlpha Institute for BiotechnologySara J. Cooper - HudsonAlpha Inst Biotechnol, Huntsville, AL USAMatthew Redmann - University of Alabama at BirminghamYanjie Li - University of Alabama at BirminghamCorinne Griguer - University of IowaJianhua Zhang - University of Alabama at BirminghamMarek Napierala - University of Alabama at BirminghamSubramaniam Ananthan - Southern Research InstituteAnita B. Hjelmeland - University of Alabama at Birmingham
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.16(5), pp.e0250649-e0250649
- DOI
- 10.1371/journal.pone.0250649
- PMID
- 33945569
- PMCID
- PMC8096095
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- Public Library Science
- Number of pages
- 16
- Grant note
- Civitan International Research Center for Glial Biology in Medicine R01NS104339; R21NS096531; T32NS048039; F31NS10545801A1; R01 CA127716; P30 AG050886-01; R01NS081366; R01DA024675 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Comprehensive Cancer Center Department of Cell, Developmental and Integrative Biology Center for Free Radical Biology University of Alabama at Birmingham
- Language
- English
- Date published
- 05/04/2021
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984313860302771
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