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Updated: Oct 1, 2025
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas
Shiyou Wei1,2,3, Delong Yin2,3,4, Shengnan Yu2,3,5
1Department of Thoracic Surgery, Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Purpose:
To investigate the antitumor activity of a mitochondrial-localized HSP90 inhibitor, Gamitrinib, in multiple glioma models, and to elucidate the antitumor mechanisms of Gamitrinib in gliomas.
Experimental Design:
A broad panel of primary and temozolomide (TMZ)-resistant human glioma cell lines were screened by cell viability assays, flow cytometry, and crystal violet assays to investigate the therapeutic efficacy of Gamitrinib. Seahorse assays were used to measure the mitochondrial respiration of glioma cells. Integrated analyses of RNA sequencing (RNAseq) and reverse phase protein array (RPPA) data were performed to reveal the potential antitumor mechanisms of Gamitrinib. Neurospheres, patient-derived organoids (PDO), cell line-derived xenografts (CDX), and patient-derived xenografts (PDX) models were generated to further evaluate the therapeutic efficacy of Gamitrinib.
Results:
Gamitrinib inhibited cell proliferation and induced cell apoptosis and death in 17 primary glioma cell lines, 6 TMZ-resistant glioma cell lines, 4 neurospheres, and 3 PDOs. Importantly, Gamitrinib significantly delayed the tumor growth and improved survival of mice in both CDX and PDX models in which tumors were either subcutaneously or intracranially implanted. Integrated computational analyses of RNAseq and RPPA data revealed that Gamitrinib exhibited its antitumor activity via (i) suppressing mitochondrial biogenesis, OXPHOS, and cell-cycle progression and (ii) activating the energy-sensing AMP-activated kinase, DNA damage, and stress response.
Conclusions:
These preclinical findings established the therapeutic role of Gamitrinib in gliomas and revealed the inhibition of mitochondrial biogenesis and tumor bioenergetics as the primary antitumor mechanisms in gliomas.
Insights
Gamitrinib, a mitochondrial HSP90 inhibitor, shows significant antitumor activity in glioma models by suppressing mitochondrial function and activating stress responses. This establishes its therapeutic potential for glioma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Glioblastoma (GBM) remains a challenging brain tumor with limited treatment options.
- Mitochondrial dysfunction is increasingly recognized as a therapeutic target in cancer.
Purpose of the Study:
- To evaluate the antitumor efficacy of Gamitrinib, a mitochondrial-localized HSP90 inhibitor, in diverse glioma models.
- To elucidate the molecular mechanisms underlying Gamitrinib's antitumor effects in gliomas.
Main Methods:
- Screening of multiple human glioma cell lines (primary and temozolomide-resistant) using viability and apoptosis assays.
- Assessment of mitochondrial respiration via Seahorse assays.
- Integrated RNA sequencing (RNAseq) and reverse phase protein array (RPPA) analyses.
- Evaluation in preclinical models including neurospheres, organoids, and xenografts (CDX and PDX).
Main Results:
- Gamitrinib demonstrated potent inhibition of proliferation and induction of apoptosis across various glioma cell lines and models.
- Significant tumor growth delay and improved survival were observed in mice bearing CDX and PDX tumors.
- Mechanistic studies revealed suppression of mitochondrial biogenesis, oxidative phosphorylation (OXPHOS), and cell-cycle progression, alongside activation of AMP-activated kinase, DNA damage, and stress response pathways.
Conclusions:
- Gamitrinib exhibits significant preclinical antitumor activity in multiple glioma models.
- Inhibition of mitochondrial biogenesis and tumor bioenergetics are key antitumor mechanisms of Gamitrinib in gliomas.
