Metabolism, HDACs, and HDAC Inhibitors: A Systems Biology Perspective

King, Jacob; Patel, Maya; Chandrasekaran, Sriram

doi:10.3390/metabo11110792

Cited by 35 publications

(28 citation statements)

References 66 publications

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“…In agreement with previous reports, the present study observed that LSC-like cell lines and primary CD34 + AML progenitor cells were moderately susceptible to the cytotoxicity of chidamide. Recent studies found that HDACs might have important roles outside of transcriptional modulation, such as impacting the metabolic process [ 24 , 25 ]. Moreover, the pharmacological blocking of HDAC activity impacts various metabolic processes [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Chidamide and apatinib are therapeutically synergistic in acute myeloid leukemia stem and progenitor cells

et al. 2022

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Background Leukemia stem cells (LSCs) are responsible for the initiation and perpetuation of acute myeloid leukemia (AML), and also represent leukemia relapse reservoirs with limited therapeutic approaches. Thus, additional treatment strategies are medical unmet needs to eliminate LSCs. Methods Cell counting kit-8 and Annexin-V-FITC/PI assays were used to examine the interaction of chidamide and apatinib on LSC-like cell lines (CD34+CD38− KG1α and Kasumi-1 cells) and primary CD34+ AML cells. AML patient-derived xenografts were established to investigate the in vivo efficacy of the combined regimen. RNA sequencing, Glutamine uptake assay, oxygen consumption assay, and western blotting were employed to explore the molecule mechanism for the cytotoxicity of chidamide with or without apatinib against LSC-like cell lines and/or primary CD34+ AML cells. Results In this study, chidamide and apatinib were synergisitc to diminish cell viability and induce apoptosis in CD34+CD38− KG1α and Kasumi-1 cells and in CD34+ primary AML cells. Importantly, chidamide combined with apatinib had more powerful in reducing leukemia burden and improving prognosis than single drug alone in an AML PDX model without significant adverse effects. Chidamide cytotoxicity was associated with decreasing glutamine uptake. The therapeutic synergy of chidamide and apatinib correlated with reprogramming of energy metabolic pathways. In addition, inactivating the VEGFR function and reducing the anti-apoptotic ability of the Bcl2 family contributed to the synergism of chidamide and apatinib in CD34+CD38− KG1α cells and CD34+ primary AML cells. Conclusion Chidamide in combination with apatinib might be a promising therapeutic strategy to get rid of the population of AML stem and progenitor cells, and thus provide a potentially curative option in the treatment of patients with AML, although further clinical evaluations are required to substantiate the conclusion.

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Section: Discussionmentioning

confidence: 99%

Chidamide and apatinib are therapeutically synergistic in acute myeloid leukemia stem and progenitor cells

et al. 2022

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“…HDACs disturb energy metabolism by regulating epigenome modifiers [ 33 ]. Inhibition of HDAC can improve metabolically disturbed adipose, liver, muscle, and cardiac tissue [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

In Vivo Two-Photon Imaging Analysis of Dynamic Degradation of Hepatic Lipid Droplets in MS-275-Treated Mouse Liver

Lee

Park

et al. 2022

IJMS

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The accumulation of hepatic lipid droplets (LDs) is a hallmark of non-alcoholic fatty liver disease (NAFLD). Appropriate degradation of hepatic LDs and oxidation of complete free fatty acids (FFAs) are important for preventing the development of NAFLD. Histone deacetylase (HDAC) is involved in the impaired lipid metabolism seen in high-fat diet (HFD)-induced obese mice. Here, we evaluated the effect of MS-275, an inhibitor of HDAC1/3, on the degradation of hepatic LDs and FFA oxidation in HFD-induced NAFLD mice. To assess the dynamic degradation of hepatic LDs and FFA oxidation in fatty livers of MS-275-treated HFD C57BL/6J mice, an intravital two-photon imaging system was used and biochemical analysis was performed. The MS-275 improved hepatic metabolic alterations in HFD-induced fatty liver by increasing the dynamic degradation of hepatic LDs and the interaction between LDs and lysozyme in the fatty liver. Numerous peri-droplet mitochondria, lipolysis, and lipophagy were observed in the MS-275-treated mouse fatty liver. Biochemical analysis revealed that the lipolysis and autophagy pathways were activated in MS-275 treated mouse liver. In addition, MS-275 reduced the de novo lipogenesis, but increased the mitochondrial oxidation and the expression levels of oxidation-related genes, such as PPARa, MCAD, CPT1b, and FGF21. Taken together, these results suggest that MS-275 stimulates the degradation of hepatic LDs and mitochondrial free fatty acid oxidation, thus protecting against HFD-induced NAFLD.

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“…Certain postbiotics exert antitumor activity, including selective cytotoxicity against tumor cells suggesting their therapeutic potential (Figure 1 )[ 5 ]. For example, SCFAs are well-known inhibitors of epigenetic enzymes histone deacetylases, which play a central role in gene regulation; thus, SCFAs have the ability to induce cell cycle arrest, and/or apoptosis in many cancer cell lines[ 37 ]. Cell-free supernatants (CFS) of different Lactobacillus and Bifidobacterium strains have been shown to induce apoptosis or inhibit proliferation of CRC cell lines[ 38 - 40 ].…”

Section: Postbioticsmentioning

confidence: 99%

Probiotics and postbiotics in colorectal cancer: Prevention and complementary therapy

Kvaková¹,

Kamlárová²,

Štofilová³

et al. 2022

WJG

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Colorectal cancer (CRC) is a leading cause of human mortality worldwide. As conventional anticancer therapy not always being effective, there is growing interest in innovative “drug-free” cancer treatments or interventions that improve the efficacy of established therapy. CRC is associated with microbiome alterations, a process known as dysbiosis that involves depletion and/or enrichment of particular gut bacterial species and their metabolic functions. Supplementing patient treatment with traditional probiotics (with or without prebiotics), next-generation probiotics (NGP), or postbiotics represents a potentially effective and accessible complementary anticancer strategy by restoring gut microbiota composition and/or by signaling to the host. In this capacity, restoration of the gut microbiota in cancer patients can stabilize and enhance intestinal barrier function, as well as promote anticarcinogenic, anti-inflammatory, antimutagenic or other biologically important biochemical pathways that show high specificity towards tumor cells. Potential benefits of traditional probiotics, NGP, and postbiotics include modulating gut microbiota composition and function, as well as the host inflammatory response. Their application in CRC prevention is highlighted in this review, where we consider supportive in vitro , animal, and clinical studies. Based on emerging research, NGP and postbiotics hold promise in establishing innovative treatments for CRC by conferring physiological functions via the production of dominant natural products and metabolites that provide new host-microbiota signals to combat CRC. Although favorable results have been reported, further investigations focusing on strain and dose specificity are required to ensure the efficacy and safety of traditional probiotics, NGP, and postbiotics in CRC prevention and treatment.

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Metabolism, HDACs, and HDAC Inhibitors: A Systems Biology Perspective

Cited by 35 publications

References 66 publications

Chidamide and apatinib are therapeutically synergistic in acute myeloid leukemia stem and progenitor cells

Chidamide and apatinib are therapeutically synergistic in acute myeloid leukemia stem and progenitor cells

In Vivo Two-Photon Imaging Analysis of Dynamic Degradation of Hepatic Lipid Droplets in MS-275-Treated Mouse Liver

Probiotics and postbiotics in colorectal cancer: Prevention and complementary therapy

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