Targeting mitochondrial energetics reverses panobinostat‐ and marizomib‐induced resistance in pediatric and adult high‐grade gliomas

Abstract

In previous studies, we demonstrated that panobinostat, a histone deacetylase inhibitor, and bortezomib, a proteasomal inhibitor, displayed synergistic therapeutic activity against pediatric and adult high‐grade gliomas. Despite the remarkable initial response to this combination, resistance emerged. Here, in this study, we aimed to investigate the molecular mechanisms underlying the anticancer effects of panobinostat and marizomib, a brain‐penetrant proteasomal inhibitor, and the potential for exploitable vulnerabilities associated with acquired resistance. RNA sequencing followed by gene set enrichment analysis (GSEA) was employed to compare the molecular signatures enriched in resistant compared with drug‐naïve cells. The levels of adenosine 5′‐triphosphate (ATP), nicotinamide adenine dinucleotide (NAD)+ content, hexokinase activity, and tricarboxylic acid (TCA) cycle metabolites required for oxidative phosphorylation to meet their bioenergetic needs were analyzed. Here, we report that panobinostat and marizomib significantly depleted ATP and NAD+ content, increased mitochondrial permeability and reactive oxygen species generation, and promoted apoptosis in pediatric and adult glioma cell lines at initial treatment. However, resistant cells exhibited increased levels of TCA cycle metabolites, which required for oxidative phosphorylation to meet their bioenergetic needs. Therefore, we targeted glycolysis and the electron transport chain (ETC) with small molecule inhibitors, which displayed substantial efficacy, suggesting that resistant cell survival is dependent on glycolytic and ETC complexes. To verify these observations in vivo, lonidamine, an inhibitor of glycolysis and mitochondrial function, was chosen. We produced two diffuse intrinsic pontine glioma (DIPG) models, and lonidamine treatment significantly increased median survival in both models, with particularly dramatic effects in panobinostat‐ and marizomib‐resistant cells. These data provide new insights into mechanisms of treatment resistance in gliomas.

Marine-Derived Anticancer Agents Targeting Apoptotic Pathways: Exploring the Depths for Novel Cancer Therapies

“…Subsequent investigation revealed that the highly integrated tricarboxylic (TCA) cycle of Marizomib ® with panobinostat, which upregulated glycolysis and activated the energy metabolism to replenish the supply of ATP for cell growth and survival, was responsible for the observed resistance to the drug in glioma-resistant cells. These findings call for more research on treating glioma-resistant cells by focusing on metabolic vulnerability [ 319 ].…”

Mitochondrial inhibitors: a new horizon in breast cancer therapy

“…Mutations of isocitrate dehydrogenase (IDH) one and 2 impair the decarboxylation of α-KG to isocitrate and enhance the production of 2-hydroxyglutarate (2HG) ( Jane et al, 2023 ). This enzymatic disruption leads to elevated DNA methylation levels, a phenomenon frequently observed in diseases such as acute myeloid leukemia (AML) ( Wilde et al, 2019 ; Pei et al, 2023 ).…”