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

Author information

Affiliations

  • 1. Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
      Authors
    • Hong JP 1
    • Choi RJ 1
    • Shim JK 1
    • Kim K 1
    • Kim RN 1
    • Cho HJ 1
    • Kim SJ 1
    • Park HH 1
    • Moon JH 1
    • Kim EH 1
    • Chang JH 1
    • Kang SG 1
    (12 authors)
  • 2. Department of Physiology, Yonsei University College of Medicine, Seoul, Republic of Korea.
      Authors
    • Kim S 2
    • Chung S 2
    (2 authors)
  • 3. Department of Premedical, Yonsei University College of Medicine, Seoul, Republic of Korea.
      Authors
    • Kim NH 3
    (1 author)
  • 4. Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.
      Authors
    • Teo WY 4
    (1 author)

ORCIDs linked to this article

Neuro-oncology, 11 Oct 2024, :noae211
https://doi.org/10.1093/neuonc/noae211 PMID: 39392921 

Abstract 

Background

Glioblastoma (GBM), a primary malignant brain tumor, has a poor prognosis, even with standard treatments such as radiotherapy and chemotherapy. In this study, we explored the anticancer effects of the synergistic combination of perphenazine (PER), a dopamine receptor D2/3 (DRD2/3) antagonist, and temozolomide (TMZ), a standard treatment for GBM, in patient-derived human GBM tumorspheres (TSs).

Methods

The biological effects of the combination of PER and TMZ in GBM TSs were assessed by measuring cell viability, ATP, stemness, invasiveness, and apoptosis. Changes in protein and mRNA expression were analyzed using western blotting and RNA sequencing. Co-administration of PER and TMZ was evaluated in vivo using a mouse orthotopic xenograft model.

Results

The Severance dataset showed that DRD2 and DRD3 expression was higher in tumor tissues than in the tumor-free cortex of patients with GBM. DRD2/3 knockout by CRISPR/Cas9 in patient-derived human GBM TSs inhibited cell growth and ATP production. The combined treatment with PER and TMZ resulted in superior effects on cell viability and ATP assays compared to those in single treatment groups. Flow cytometry, western blotting, and RNA sequencing confirmed elevated apoptosis in GBM TSs following combination treatment. Additionally, the combination of PER and TMZ downregulated the expression of protein and mRNA associated with stemness and invasiveness. In vivo evaluation showed that combining PER and TMZ extended the survival period of the mouse orthotopic xenograft model.

Conclusions

The synergistic combination of PER and TMZ has potential as a novel combination treatment strategy for GBM.

Full text links 

Read article at publisher's site: https://doi.org/10.1093/neuonc/noae211

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Funding 

Funders who supported this work.

Bio&Medical Technology Development Program

    ICT & Future Planning (1)

    Korea Health Industry Development Institute

      Korea Health Technology R&D Project

        Korean Government (4)

        Ministry of Health & Welfare, Republic of Korea (1)

        Ministry of Science

          National Research Foundation of Korea

            Pioneer Research Center Program

              Yonsei University College of Medicine (1)