Neurotransmitters: Potential Targets in Glioblastoma

Huang, Qiqi; Chen, Lishi; Liang, Junchao; Huang, Qiongzhen; Sun, Haitao

doi:10.3390/cancers14163970

Cited by 14 publications

(6 citation statements)

References 244 publications

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“…Dopamine receptors have been linked to multiple physiological and pathological functions [29,30]. More recently, studies have shown that dopamine receptors are important in glioma initiation and progression and therefore represent potential therapeutic targets [31][32][33]. Our team has previously shown that thioridazine, a DRD antagonist, inhibits late autophagy by impairing the fusion between autophagosomes and lysosomes.…”

Section: Discussionmentioning

confidence: 99%

The dopamine receptor D1 inhibitor, SKF83566, suppresses GBM stemness and invasion through the DRD1-c-Myc-UHRF1 interactions

Xue,

Zhang,

Zhao

et al. 2024

J Exp Clin Cancer Res

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Background Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs). Using ultra-low input RNA sequencing (ui-RNA Seq), an invasive gene signature was obtained that was exploited in a therapeutic context. Methods GFP-labeled tumor cells were sorted from invasive and non-invasive regions within co-cultures. Ui-RNA sequencing analysis was performed to find a gene cluster up-regulated in the invasive compartment. This gene cluster was further analyzed using the Connectivity MAP (CMap) database. This led to the identification of SKF83566, an antagonist of the D1 dopamine receptor (DRD1), as a candidate therapeutic molecule. Knockdown and overexpression experiments were performed to find molecular pathways responsible for the therapeutic effects of SKF83566. Finally, the effects of SKF83566 were validated in orthotopic xenograft models in vivo. Results Ui-RNA seq analysis of three GSC cell models (P3, BG5 and BG7) yielded a set of 27 differentially expressed genes between invasive and non-invasive cells. Using CMap analysis, SKF83566 was identified as a selective inhibitor targeting both DRD1 and DRD5. In vitro studies demonstrated that SKF83566 inhibited tumor cell proliferation, GSC sphere formation, and invasion. RNA sequencing analysis of SKF83566-treated P3, BG5, BG7, and control cell populations yielded a total of 32 differentially expressed genes, that were predicted to be regulated by c-Myc. Of these, the UHRF1 gene emerged as the most downregulated gene following treatment, and ChIP experiments revealed that c-Myc binds to its promoter region. Finally, SKF83566, or stable DRD1 knockdown, inhibited the growth of orthotopic GSC (BG5) derived xenografts in nude mice. Conclusions DRD1 contributes to GBM invasion and progression by regulating c-Myc entry into the nucleus that affects the transcription of the UHRF1 gene. SKF83566 inhibits the transmembrane protein DRD1, and as such represents a candidate small therapeutic molecule for GBMs.

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Section: Discussionmentioning

confidence: 99%

The dopamine receptor D1 inhibitor, SKF83566, suppresses GBM stemness and invasion through the DRD1-c-Myc-UHRF1 interactions

Xue,

Zhang,

Zhao

et al. 2024

J Exp Clin Cancer Res

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“…It is possible, however, that the decreased number of mRNA encoding GABAAR subunits and loss of GABAAR in GBM may indicate a relationship between the number of functional GABAAR and the severity of the disease [120][121][122]. In addition, GBM may counteract the attenuation of GABA on cell proliferation through a decrease in the expression of GABAAR [123,124].…”

Section: Discussionmentioning

confidence: 99%

Integrating Multi-Omics Analysis for Enhanced Diagnosis and Treatment of Glioblastoma: A Comprehensive Data-Driven Approach

Behrooz¹,

Latifi-Navid²,

Rosa³

et al. 2023

Preprint

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The most aggressive primary malignant brain tumor in adults is glioblastoma (GBM), which has poor overall survival (OS). There is a high relapse rate among patients with GBM despite maxi-mally safe surgery, radiation therapy, temozolomide (TMZ), and aggressive treatment. Hence, there is an urgent and unmet clinical need for new approaches to managing GBM. The current study identified modules (MYC, EGFR, PIK3CA, SUZ12, and SPRK2) involved in GBM disease through the NeDRex plugin. Furthermore, hub genes were identified in a comprehensive interaction network containing 7,560 proteins related to GBM disease and 3,860 proteins associated with signaling pathways involved in GBM. By integrating the results of the aforementioned analyses and performing centrality analysis again, eleven key genes involved in GBM disease were identi-fied. ProteomicsDB or Gliovis databases were used for determining the gene expression in normal or tumor brain tissue. The NetworkAnalyst and the mGWAS-Explorer tools identified miRNAs, SNPs, and metabolites associated with these 11 genes. Moreover, a literature review of recent studies revealed other lists of metabolites related to GBM disease. The enrichment analysis of iden-tified genes, miRNAs, and metabolites associated with GBM disease was done using ExpressAna-lyst, miEAA, and MetaboAnalyst tools. Further investigation of metabolite roles in GBM was done through the pathway, joint pathway, and network analyses. The results of this study identified 11 genes (UBC, HDAC1, CTNNB1, TRIM28, CSNK2A1, RBBP4, TP53, APP, DAB1, PINK1, and RELN), five miRNAs (hsa-mir-221-3p, hsa-mir-30a-5p, hsa-mir-15a-5p, hsa-mir-130a-3p, hsa-let-7b-5p), six metabolites (HDL, N6-acetyl-L-lysine, cholesterol, formate, N, N-dimethylglycine/xylose and X2. piperidinone) and 15 distinct signaling pathways that play an indispensable role in the GBM disease development. To establish early diagnostic methods and plan personalized GBM treatment strategies, the identified top genes-miRNAs and metabolite signatures can be targeted.

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“…Different studies suggest GBM overexpresses 5HT 7 R; hence, this receptor has attracted much attention as a potential therapeutic and diagnostic target [27]. Our previous studies evaluated aryl piperazines such as 1-( 99m Tc(CO) 3 - [6], and 99m Tc(CO) 3 - [7] were also applied as SPECT imaging agents.…”

Section: Discussionmentioning

confidence: 99%

99mTc(CO)3-labeled 1-(2-Pyridyl)piperazine derivatives as radioligands for 5-HT7 receptors

Mardanshahi,

Vaseghi,

Hosseinimehr

et al. 2023

Ann Nucl Med

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The 5-hydroxytryptamine receptor (5-HTR) family involves seven classes of receptors. The 5-HT 7 R is the newest member of this family and contributes to different physiological and pathological processes. As a pathology, Glioblastoma multiform (GBM) overexpresses 5-HT 7 R; hence, this study aims to develop radiolabeled aryl piperazine derivatives as 5-HT 7 R imaging agents. To that end, compounds 6 and 7 as 1-(3-nitropyridin-2-yl)piperazine derivatives were radiolabeled with fac-[ 99m Tc (CO) 3 (H 2 O) 3 ] + and ( 99m Tc(CO) 3 -[6] and 99m Tc(CO)3-[7]) were obtained with high radiochemical purity (RCP>94%).99m Tc(CO) 3 -[6] and 99m Tc(CO)3-[7] possess high a nity toward 5-HT 7 R of the U-87 MG cell line. The calculated K i for them was 26.85±0.78 nM and 36.67±0.89 nM. The biodistribution study in normal mice indicates that the brain uptake of 99m Tc(CO) 3 -[6] and 99m Tc(CO)3-[7] is the highest at 30 min postinjection (0.8±0.25 and 0.64±0.18 %ID/g, respectively). The data of the biodistribution study in the U87-MG xenograft model revealed that these radiotracers could accumulate in the tumor site, and the highest tumor uptake was observed at 60 min post-injection (3.38±0.65 and 3.27±0.5 %ID/g, respectively). The injection of pimozide can block the tumor's radiotracer uptake, indicating the binding of these radiotracers to the 5-HT 7 R. The imaging study in the xenograft model also con rms the biodistribution data. The acquired images clearly show the tumor site, and the tumor-to-muscle ratio for 99m Tc(CO) 3 -[6] and 99m Tc(CO)3-[7] at 60 min was 3.33 and 3.88, respectively.

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Neurotransmitters: Potential Targets in Glioblastoma

Cited by 14 publications

References 244 publications

The dopamine receptor D1 inhibitor, SKF83566, suppresses GBM stemness and invasion through the DRD1-c-Myc-UHRF1 interactions

The dopamine receptor D1 inhibitor, SKF83566, suppresses GBM stemness and invasion through the DRD1-c-Myc-UHRF1 interactions

Integrating Multi-Omics Analysis for Enhanced Diagnosis and Treatment of Glioblastoma: A Comprehensive Data-Driven Approach

99mTc(CO)3-labeled 1-(2-Pyridyl)piperazine derivatives as radioligands for 5-HT7 receptors

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