Synergistic combination of perphenazine and temozolomide suppresses patient-derived glioblastoma tumorspheres

Jun Pyo Hong ^1,2, Ran Joo Choi ^1,2, Jin-Kyoung Shim ^1,2

⁰Brain Tumor Translational Research Laboratory, Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.

Neuro-Oncology +

|

October 11, 2024

View abstract on PubMed

Summary

The combination of perphenazine (PER) and temozolomide (TMZ) shows promise for treating glioblastoma (GBM). This synergistic approach enhanced anticancer effects in patient-derived GBM tumorspheres and extended survival in mice.

Area Of Science

Neuro-oncology
Pharmacology
Molecular Biology

Background

Glioblastoma (GBM) presents a significant therapeutic challenge with a poor prognosis.
Standard treatments like radiotherapy and chemotherapy offer limited efficacy.
Dopamine receptor D2/3 (DRD2/3) antagonists, such as perphenazine (PER), are being investigated for their potential in GBM treatment.

Purpose Of The Study

To investigate the synergistic anticancer effects of combining perphenazine (PER) and temozolomide (TMZ) in patient-derived human GBM tumorspheres (TSs).
To evaluate the impact of this combination on GBM cell viability, stemness, invasiveness, and apoptosis.
To assess the efficacy of the PER and TMZ combination in an in vivo mouse model of GBM.

Main Methods

Assessed biological effects in GBM TSs by measuring cell viability, ATP levels, stemness, invasiveness, and apoptosis.
Analyzed protein and mRNA expression changes using western blotting and RNA sequencing.
Evaluated co-administration of PER and TMZ in an in vivo mouse orthotopic xenograft model.

Main Results

DRD2 and DRD3 expressions were elevated in GBM tumor tissues.
DRD2/3 knockout inhibited GBM cell growth and ATP production.
Combined PER and TMZ treatment demonstrated superior efficacy in reducing cell viability and ATP production compared to single treatments.
Combination therapy significantly increased apoptosis and downregulated stemness and invasiveness markers.
In vivo studies showed that PER and TMZ combination extended survival in a mouse GBM model.

Conclusions

The synergistic combination of perphenazine (PER) and temozolomide (TMZ) exhibits significant potential as a novel therapeutic strategy for glioblastoma (GBM).
This combination effectively targets GBM by enhancing apoptosis and reducing stemness and invasiveness.
Further clinical investigation is warranted to explore this combination therapy for GBM patients.

Keywords:

DRD2/3 glioblastoma perphenazine temozolomide tumorsphere

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