Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
13 05 2022
13 05 2022
Historique:
received:
04
03
2021
revised:
31
08
2021
accepted:
01
03
2022
pubmed:
6
3
2022
medline:
18
5
2022
entrez:
5
3
2022
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 35247901
pii: 682043
doi: 10.1158/1078-0432.CCR-21-0833
pmc: PMC9757132
mid: NIHMS1853635
doi:
Substances chimiques
Antineoplastic Agents
0
Temozolomide
YF1K15M17Y
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2180-2195Subventions
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Informations de copyright
©2022 American Association for Cancer Research.
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