Panobinostat penetrates the blood–brain barrier and achieves effective brain concentrations in a murine model

Homan, Morgan J; Franson, Andrea; Ravi, Karthik; Roberts, Holly; Pai, Manjunath P.; Liu, Cai; He, Miao; Matvekas, Aleksas; Koschmann, Carl; Marini, Bernard L.

doi:10.1007/s00280-021-04313-2

Cited by 18 publications

(9 citation statements)

References 46 publications

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“…S6A). Collectively, our current data demonstrated that EB had an acceptable oral bioavailability to achieve therapeutic levels as well as blood-brain barrier penetrance ability, which is similar to other small-molecule CNS drugs ( 29 – 31 ).…”

Section: Resultssupporting

confidence: 64%

Neuroinflammation inhibition by small-molecule targeting USP7 noncatalytic domain for neurodegenerative disease therapy

et al. 2022

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Neuroinflammation is a fundamental contributor to progressive neuronal damage, which arouses a heightened interest in neurodegenerative disease therapy. Ubiquitin-specific protease 7 (USP7) has a crucial role in regulating protein stability in multiple biological processes; however, the potential role of USP7 in neurodegenerative progression is poorly understood. Here, we discover the natural small molecule eupalinolide B (EB), which targets USP7 to inhibit microglia activation. Cocrystal structure reveals a previously undisclosed covalent allosteric site, Cys 576 , in a unique noncatalytic HUBL domain. By selectively modifying Cys 576 , EB allosterically inhibits USP7 to cause a ubiquitination-dependent degradation of Keap1. Keap1 function loss further results in an Nrf2-dependent transcription activation of anti-neuroinflammation genes in microglia. In vivo, pharmacological USP7 inhibition attenuates microglia activation and resultant neuron injury, thereby notably improving behavioral deficits in dementia and Parkinson’s disease mouse models. Collectively, our findings provide an attractive future direction for neurodegenerative disease therapy by inhibiting microglia-mediated neuroinflammation by targeting USP7.

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Section: Resultssupporting

confidence: 64%

Neuroinflammation inhibition by small-molecule targeting USP7 noncatalytic domain for neurodegenerative disease therapy

et al. 2022

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“…Although the potentiation of anticancer effects by the combination of panobinostat and marizomib has been reported previously [20], little attention has been directed toward understanding mechanisms of resistance to this class of inhibitors [28], which is of vital importance given the propensity of these tumors to rapidly fail initial therapies. We selected panobinostat and marizomib over vorinostat and bortezomib for our in vitro and in vivo studies because of their superior blood–brain barrier penetrance [25,93]. Here, we identified and characterized a critical resistance mechanism to this combination of agents, with the goal of leveraging the insights obtained from this study to develop strategies for counteracting this process.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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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.

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“…In the infection group, most of the mice developed severe vitreous, subretinal fluid, posterior vitreous detachment and disorder of retinal structure ( Chen et al., 2016 ; Brandao-de-Resende et al., 2020 ; Ksiaa et al., 2022 ), while the symptoms were relatively mild with LBH589 treatment. In addition, we set a drug dose gradient of 1 to 3 ng/μl based on the previous study about pharmacokinetics of LBH589 to avoid the toxicity of drugs to the retina ( Van Veggel et al., 2018 ; Karol et al., 2020 ; Homan et al., 2021 ). Though the OCT results found that when the drug concentration was greater than 1 ng, vitreous opacity occurred in the eyes of mice, which was easily confused with the symptoms caused by infection, but the retinal results were not significantly abnormal.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo anti−Toxoplasma activities of HDAC inhibitor Panobinostat on experimental acute ocular toxoplasmosis

Zhang¹,

Li²,

Huang³

et al. 2022

Front. Cell. Infect. Microbiol.

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Ocular toxoplasmosis (OT) is retinochoroiditis caused by Toxoplasma gondii infection, which poses a huge threat to vision. However, most traditional oral drugs for this disease have multiple side effects and have difficulty crossing the blood-retinal barrier, so the new alternative strategy is required to be developed urgently. Histone deacetylases (HDAC) inhibitors, initially applied to cancer, have attracted considerable attention as potential anti-Toxoplasma gondii drugs. Here, the efficacy of a novel HDAC inhibitor, Panobinostat (LBH589), against T. gondii has been investigated. In vitro, LBH589 inhibited the proliferation and activity of T. gondii in a dose-dependent manner with low toxicity to retinal pigment epithelial (RPE) cells. In vivo, optical coherence tomography (OCT) examination and histopathological studies showed that the inflammatory cell infiltration and the damage to retinal architecture were drastically reduced in C57BL/6 mice upon treatment with intravitreal injection of LBH589. Furthermore, we have found the mRNA expression levels of inflammatory cytokines were significantly decreased in LBH589–treated group. Collectively, our study demonstrates that LBH589 holds great promise as a preclinical candidate for control and cure of ocular toxoplasmosis.

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Panobinostat penetrates the blood–brain barrier and achieves effective brain concentrations in a murine model

Cited by 18 publications

References 46 publications

Neuroinflammation inhibition by small-molecule targeting USP7 noncatalytic domain for neurodegenerative disease therapy

Neuroinflammation inhibition by small-molecule targeting USP7 noncatalytic domain for neurodegenerative disease therapy

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

In vitro and in vivo anti−Toxoplasma activities of HDAC inhibitor Panobinostat on experimental acute ocular toxoplasmosis

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