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HDAC6 INHIBITOR ACY-738 INDUCES FERRITINOPHAGY-MEDIATED FERROPTOSIS IN LEUKEMIA (ePoster area) - Feb 14, 2024 - Abstract #EBMT2024EBMT_1648;
Mechanistically, ACY-738 induces ferroptosis through promotes NCOA4-mediated ferritinophagy and regulated the SLC7A11-GPX4 axis. ACY-738, identified as a novel ferroptosis inducer, may be effective chemosensitizer that can expand the efficacy and range of chemotherapeutic agents.
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Effects of HDAC6 Inhibition in ALS mouse models (Event Halle, Messe Basel, Ground Floor) - Nov 7, 2023 - Abstract #ALSMND2023ALS_MND_486;
The potential effects of ACY-738 on axonal degeneration and global proteome are currently being further evaluated in the TDP-43 models. Fariha.Kabir@utas.edu.au
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Preclinical, Journal: HDAC-6 inhibition ameliorates the early neuropathology in a mouse model of Krabbe disease. (Pubmed Central) - Aug 17, 2023
ACY-738 was effective in rescuing neuronal defects of Twitcher neurons, stabilizing microtubule dynamics and increasing the axonal transport of mitochondria. Overall, our results support that ACY-738 has a neuroprotective effect in KD and should be considered as an add-on therapy combined with strategies targeting metabolic correction.
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Preclinical, Journal, Epigenetic controller: Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis. (Pubmed Central) - Dec 17, 2021
Recently, histone deacetylase (HDAC) inhibition using ACY-738 has been shown to restore metabolic alterations in the spinal cord of a FUS mouse model of ALS, which was accompanied by a beneficial effect on the motor phenotype and survival...Strikingly, HDAC inhibition mitigated lipid homeostasis defects by selectively targeting glycerophospholipid metabolism and reducing cholesteryl esters accumulation. Therefore, our data suggest that HDAC inhibition is a potential new therapeutic strategy to modulate lipid metabolism defects in ALS and potentially other neurodegenerative diseases.
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Journal: HDAC6 Signaling at Primary Cilia Promotes Proliferation and Restricts Differentiation of Glioma Cells. (Pubmed Central) - May 1, 2021
Surprisingly, overexpressing HDAC6 did not reduce cilia length or the frequency of ciliated glioma cells, suggesting other factors are required to control HDAC6-mediated cilia disassembly in glioma cells. Collectively, our findings suggest that HDAC6 promotes the proliferation of glioma cells through primary cilia.
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Journal: Selective Histone Deacetylase 6 Inhibition Normalizes B Cell Activation and Germinal Center Formation in a Model of Systemic Lupus Erythematosus. (Pubmed Central) - Nov 4, 2020
We treated NZB/W lupus mice with the selective HDAC6 inhibitor, ACY-738, for 4 weeks beginning at 20 weeks-of age...Pathway analysis suggested alterations in cellular metabolism might contribute to the normalization of lupus mouse spleen genomic signatures, and this was confirmed by direct measurement of the impact of the HDAC6 inhibitor on metabolic activities of murine spleen cells. Taken together, these studies show HDAC6 inhibition decreases B cell activation signaling pathways and reduces PC differentiation in SLE and suggest that a critical event might be modulation of cellular metabolism.
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Preclinical, Journal: HDAC6-selective inhibitors decrease nerve-injury and inflammation-associated mechanical hypersensitivity in mice. (Pubmed Central) - Oct 24, 2020
Taken together, these studies show HDAC6 inhibition decreases B cell activation signaling pathways and reduces PC differentiation in SLE and suggest that a critical event might be modulation of cellular metabolism. Overall, our findings suggest that inhibition of HDAC6 provides a promising therapeutic avenue for the alleviation of mechanical allodynia associated with peripheral nerve injury and peripheral inflammation.
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Preclinical, Journal: Restoration of histone acetylation ameliorates disease and metabolic abnormalities in a FUS mouse model. (Pubmed Central) - Aug 2, 2020
At the molecular level, ACY-738 restored global histone acetylation and metabolic gene expression, thereby re-establishing metabolite levels in the spinal cord. Taken together, our findings link epigenetic alterations to metabolic dysregulation in ALS pathology, and highlight ACY-738 as a potential therapeutic strategy to treat this devastating disease.
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Journal: Silencing of HDAC6 as a therapeutic target in chronic lymphocytic leukemia. (Pubmed Central) - Sep 22, 2019
Furthermore, coadministration of ACY738 and ibrutinib displayed synergistic cell kill against CLL cell lines and improved overall survival compared with either single agent in vivo. These results demonstrate for the first time the therapeutic efficacy of selective HDAC6 inhibition in preclinical CLL models and suggest a rationale for the clinical development of HDAC6 inhibitors for CLL treatment, either alone or in combination with Bruton tyrosine kinase inhibition.
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Preclinical, Journal: The Selective HDAC6 Inhibitor ACY-738 Impacts Memory and Disease Regulation in an Animal Model of Multiple Sclerosis. (Pubmed Central) - Jul 19, 2019
Because ACY-738 increases short-term memory only with lower amounts of EAE-inducing reagents, we hypothesize that the inflammatory-demyelinating environment induced by higher amount of EAE-inducing reagents overpowers (at day 10 post-immunization) the synaptic molecules targeted by ACY-738. These studies pave the way for developing ACY-738-like compounds for MS patients and for using ACY-738 as a probe to elucidate disease-sensitive changes at the synapses occurring early in the disease course.
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