The dopamine receptor antagonist trifluoperazine prevents phenotype conversion and improves survival in mouse models of glioblastoma

Glioblastoma (GBM) is the deadliest adult brain cancer, and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 mo over surgery alone, but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype, and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP causes loss of radiation-induced Nanog mRNA expression, and activation of GSK3 with consecutive posttranslational reduction in p-Akt, Sox2, and β-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that the combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment-resistant, induced GICs (iGICs).

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The Dopamine Receptor Antagonist TFP Prevents Phenotype Conversion and Improves Survival in Mouse Models of Glioblastoma

10.1101/870394 ◽

2019 ◽

Cited By ~ 1

Author(s):

Kruttika Bhat ◽

Mohammad Saki ◽

Erina Vlashi ◽

Fei Cheng ◽

Sara Duhachek-Muggy ◽

...

Keyword(s):

Receptor Antagonist ◽

Dopamine Receptor ◽

Blood Brain Barrier ◽

Mouse Models ◽

Brain Cancer ◽

Adult Brain ◽

Brain Barrier ◽

Dopamine Receptor Antagonist ◽

Glioma Initiating Cells ◽

Radiation Induced

AbstractGlioblastoma (GBM) is the deadliest adult brain cancer and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 months over surgery alone but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP caused loss of radiation-induced Nanog mRNA expression, activation of GSK3 with consecutive post-translational reduction in p-Akt, Sox2 and β-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment resistant, induced GICs.SignificanceGBM is the most common and most deadly adult brain cancer. The current standard-of-care is surgery followed by RT and temozolomide, which results in a median survival time of only 15 months. The efficacy of chemotherapies and targeted therapies in GBM is very limited because most of these drugs do not pass the blood-brain-barrier. Ultimately, all patients succumb to the disease. Our study describes radiation-induced cellular plasticity as a novel resistance mechanism in GBM. We identified a dopamine receptor antagonist as a readily available, FDA-approved drug known to penetrate the blood-brain-barrier which prevents phenotype conversion of glioma cells into glioma-initiating cells and prologs survival in mouse models of GBM, thus suggesting that it will improve the efficacy of RT without increasing toxicity.

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Is domperidone a selective peripheral dopamine-receptor antagonist in vivo?

Neuropharmacology ◽

10.1016/0028-3908(82)90140-x ◽

1982 ◽

Vol 21 (12) ◽

pp. 1317-1321 ◽

Cited By ~ 10

Author(s):

S.P. Arnerić ◽

E.D. Collins ◽

R.K. Bhatnagar ◽

J.P. Long

Keyword(s):

Receptor Antagonist ◽

Dopamine Receptor ◽

Dopamine Receptor Antagonist

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In vitro and in vivo genotoxicity assessment of the dopamine receptor antagonist molindone hydrochloride

Environmental and Molecular Mutagenesis ◽

10.1002/em.22007 ◽

2016 ◽

Vol 57 (4) ◽

pp. 288-298 ◽

Cited By ~ 4

Author(s):

Gopala Krishna ◽

Gopa Gopalakrishnan ◽

Saryu Goel

Keyword(s):

Receptor Antagonist ◽

Dopamine Receptor ◽

Dopamine Receptor Antagonist

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Combined Treatment with Dopamine Receptor Antagonists and Radiation Creates a Metabolic Vulnerability in Mouse Models of Glioblastoma

10.1101/2020.01.13.905380 ◽

2020 ◽

Author(s):

Mohammad Saki ◽

Kruttika Bhat ◽

Fei Cheng ◽

Ling He ◽

Le Zhang ◽

...

Keyword(s):

Receptor Antagonist ◽

Dopamine Receptor ◽

Mouse Models ◽

Cholesterol Biosynthesis ◽

Combined Treatment ◽

Unmet Need ◽

Survival Times ◽

Self Renewal ◽

Dopamine Receptor Antagonist

AbstractBackgroundGlioblastoma is the deadliest brain tumor in adults and the standard-of-care consists of surgery followed by radiation and treatment with temozolomide. Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options.MethodsUsing patient-derived glioblastoma lines and mouse models of glioblastoma we test the effect of radiation and the dopamine receptor antagonist on glioblastoma self-renewal in vitro and survival in vivo. A possible resistance mechanism is investigated using RNA-Sequencing.ResultsTreatment of glioma cells with the dopamine receptor antagonist quetiapine reduced glioma cell self-renewal in vitro and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing animals. The combined treatment induced the expression of genes involved in cholesterol biosynthesis. This rendered the tumors vulnerable to simultaneous treatment with atorvastatin and further significantly prolonged the survival of the animals.ConclusionsOur results indicate high efficacy of a triple combination of quetiapine, atorvastatin and radiation against glioblastoma without increasing the toxicity of radiation. With both drugs readily available for clinical use our study could be rapidly translated into a clinical trial.

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