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

Autor:	Hong JP; Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.; Brain Tumor Translational Research Laboratory, Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea., Choi RJ; Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.; Brain Tumor Translational Research Laboratory, Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea., Shim JK; Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.; Brain Tumor Translational Research Laboratory, Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea., Kim K; Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.; Brain Tumor Translational Research Laboratory, Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea., Kim RN; Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.; Brain Tumor Translational Research Laboratory, Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea., Cho HJ; Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.; Brain Tumor Translational Research Laboratory, Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea., Kim SJ; Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.; Brain Tumor Translational Research Laboratory, Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea., Kim S; Department of Physiology, Yonsei University College of Medicine, Seoul, Republic of Korea., Kim NH; Department of Premedical, Yonsei University College of Medicine, Seoul, Republic of Korea., Park HH; Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea., Moon JH; Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea., Kim EH; Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea., Teo WY; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.; Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore., Chung S; Department of Physiology, Yonsei University College of Medicine, Seoul, Republic of Korea., Chang JH; Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea., Kang SG; Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.; Brain Tumor Translational Research Laboratory, Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.; Department of Medical Science, Yonsei University Graduate School, Seoul, Republic of Korea.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2024 Oct 11. Date of Electronic Publication: 2024 Oct 11.
DOI:	10.1093/neuonc/noae211
Abstrakt:	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. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
Databáze:	MEDLINE
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