Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas.

Abstract

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.

• Authors: Shiyou Wei, Delong Yin, Shengnan Yu, Xiang Lin, Milan R Savani, Kuang Du, Yin Ku, Di Wu, Shasha Li, Hao Liu, Meng Tian, Yaohui Chen, Michelle Bowie, Seethalakshmi Hariharan, Matthew Waitkus, Stephen T Keir, Eric T Sugarman, Rebecca A Deek, Marilyne Labrie, Mustafa Khasraw, Yiling Lu, Gordon B Mills, Meenhard Herlyn, Kongming Wu, Lunxu Liu, Zhi Wei, Keith T Flaherty, Kalil Abdullah, Gao Zhang, David M Ashley
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 28 Issue 10 Pg. 2180-2195 (05 13 2022) ISSN: 1557-3265 [Electronic] United States
• PMID: 35247901 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Temozolomide

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Brain Neoplasms (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Glioma (drug therapy, genetics, metabolism)
• Humans
• Mice
• Mitochondria (metabolism)
• Temozolomide (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays