The Bioequivalence of Abexinostat (CRA-024781) Tosylate Tablet (20 mg) in Chinese Healthy Subjects Under Fasting Conditions.

This study aimed to investigate the pharmacokinetic parameters of single oral administration of postchange and prechange abexinostat (CRA-024781) tosylate tablets in Chinese healthy subjects under fasting conditions, and assess the bioequivalence (BE) of the 2 formulations (Test [T1] and Reference [T2]). This study was a randomized, open-label, 2-formulation, fasting administration, single-dose, 2-sequence, 2-cycle, crossover BE study. Thirty-six subjects were enrolled in the study and 33 subjects completed 2 cycles. The plasma concentrations were determined by liquid chromatography-tandem mass spectrometry. The 90% confidence intervals (CIs) for the Cmax, AUC0-t, and AUC0-∞ of CRA-024781 and its 2 major metabolites (PCI-27789 and PCI-27887, both metabolites are pharmacologically inactive on HDAC1) fell within the acceptable range of 80%-125%. The results suggest that the CRA-024781 test preparation (Test [T1]) is bioequivalent to the reference preparation (Reference [T2]) in healthy Chinese subjects under fasting conditions.

Reversal of cognitive deficits in FUSR521G amyotrophic lateral sclerosis mice by arimoclomol and a class I histone deacetylase inhibitor independent of heat shock protein induction.

Protein misfolding and mislocalization are common to both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Maintaining proteostasis through induction of heat shock proteins (HSP) to increase chaperoning capacity is a rational therapeutic strategy in the treatment of ALS. However, the threshold for upregulating stress-inducible HSPs remains high in neurons, presenting a therapeutic obstacle. This study used mouse models expressing the ALS variants FUSR521G or SOD1G93A to follow up on previous work in cultured motor neurons showing varied effects of the HSP co-inducer, arimoclomol, and class I histone deacetylase (HDAC) inhibitors on HSP expression depending on the ALS variant being expressed. As in cultured neurons, neither expression of the transgene nor drug treatments induced expression of HSPs in cortex, spinal cord or muscle of FUSR521G mice, indicating suppression of the heat shock response. Nonetheless, arimoclomol, and RGFP963, restored performance on cognitive tests and improved cortical dendritic spine densities. In SOD1G93A mice, multiple HSPs were upregulated in hindlimb skeletal muscle, but not in lumbar spinal cord with the exception of HSPB1 associated with astrocytosis. Drug treatments improved contractile force but reduced the increase in HSPs in muscle rather than facilitating their expression. The data point to mechanisms other than amplification of the heat shock response underlying recovery of cognitive function in ALS-FUS mice by arimoclomol and class I HDAC inhibition and suggest potential benefits in counteracting cognitive impairment in ALS, frontotemporal dementia and related disorders.

Exploring the anti-EBV potential of suberoylanilide hydroxamic acid: Induction of apoptosis in infected cells through suppressing BART gene expression and inducing lytic infection.

Epstein-Barr virus (EBV) is linked to lymphoma and epithelioma but lacks drugs specifically targeting EBV-positive tumors. BamHI A Rightward Transcript (BART) miRNAs are expressed in all EBV-positive tumors, suppressing both lytic infection and host cell apoptosis. We identified suberoylanilide hydroxamic acid (SAHA), an inhibitor of histone deacetylase enzymes, as an agent that suppresses BART promoter activity and transcription of BART miRNAs. SAHA treatment demonstrated a more pronounced inhibition of cell proliferation in EBV-positive cells compared to EBV-negative cells, affecting both p53 wild-type and mutant gastric epithelial cells. SAHA treatment enhanced lytic infection in wild-type EBV-infected cells, while also enhancing cell death in BZLF1-deficient EBV-infected cells. It reduced BART gene expression by 85% and increased the expression of proapoptotic factors targeted by BART miRNAs. These findings suggest that SAHA not only induces lytic infection but also leads to cell death by suppressing BART miRNA transcription and promoting the apoptotic program.

Structure-Based Identification of Novel Histone Deacetylase 4 (HDAC4) Inhibitors.

Histone deacetylases (HDACs) are important cancer drug targets. Existing FDA-approved drugs target the catalytic pocket of HDACs, which is conserved across subfamilies (classes) of HDAC. However, engineering specificity is an important goal. Herein, we use molecular modeling approaches to identify and target potential novel pockets specific to Class IIA HDAC-HDAC4 at the interface between HDAC4 and the transcriptional corepressor component protein NCoR. These pockets were screened using an ensemble docking approach combined with consensus scoring to identify compounds with a different binding mechanism than the currently known HDAC modulators. Binding was compared in experimental assays between HDAC4 and HDAC3, which belong to a different family of HDACs. HDAC4 was significantly inhibited by compound 88402 but not HDAC3. Two other compounds (67436 and 134199) had IC50 values in the low micromolar range for both HDACs, which is comparable to the known inhibitor of HDAC4, SAHA (Vorinostat). However, both of these compounds were significantly weaker inhibitors of HDAC3 than SAHA and thus more selective, albeit to a limited extent. Five compounds exhibited activity on human breast carcinoma and/or urothelial carcinoma cell lines. The present result suggests potential mechanistic and chemical approaches for developing selective HDAC4 modulators.

Targeting histone deacetylase in cardiac diseases.

Histone deacetylases (HDAC) catalyze the removal of acetylation modifications on histones and non-histone proteins, which regulates gene expression and other cellular processes. HDAC inhibitors (HDACi), approved anti-cancer agents, emerge as a potential new therapy for heart diseases. Cardioprotective effects of HDACi are observed in many preclinical animal models of heart diseases. Genetic mouse models have been developed to understand the role of each HDAC in cardiac functions. Some of the findings are controversial. Here, we provide an overview of how HDACi and HDAC impact cardiac functions under physiological or pathological conditions. We focus on in vivo studies of zinc-dependent classical HDACs, emphasizing disease conditions involving cardiac hypertrophy, myocardial infarction (MI), ischemic reperfusion (I/R) injury, and heart failure. In particular, we review how non-biased omics studies can help our understanding of the mechanisms underlying the cardiac effects of HDACi and HDAC.

Combination of HDAC and FYN inhibitors in synovial sarcoma treatment.

The SS18-SSX fusion protein is an oncogenic driver in synovial sarcoma. At the molecular level, SS18-SSX functions as both an activator and a repressor to coordinate transcription of different genes responsible for tumorigenesis. Here, we identify the proto-oncogene FYN as a new SS18-SSX target gene and examine its relation to synovial sarcoma therapy. FYN is a tyrosine kinase that promotes cancer growth, metastasis and therapeutic resistance, but SS18-SSX appears to negatively regulate FYN expression in synovial sarcoma cells. Using both genetic and histone deacetylase inhibitor (HDACi)-based pharmacologic approaches, we show that suppression of SS18-SSX leads to FYN reactivation. In support of this notion, we find that blockade of FYN activity synergistically enhances HDACi action to reduce synovial sarcoma cell proliferation and migration. Our results support a role for FYN in attenuation of anti-cancer activity upon inhibition of SS18-SSX function and demonstrate the feasibility of targeting FYN to improve the effectiveness of HDACi treatment against synovial sarcoma.

Combination Therapy with Immune Checkpoint Inhibitors and Histone Deacetylase Inhibitors or Alkylating Agents.

Purpose: Immune checkpoint inhibitors (CPIs) have been widely adopted in a number of early and advanced malignancies. Histone deacetylase inhibitors (HDACis) and alkylating agents (AAs) have been suggested to potentiate the actions of CPIs on tumor cells. We conducted a comprehensive literature review to explore the potential synergistic activity between CPIs, AAs, and HDACis. Patients and Methods: Clinical and non-clinical studies describing outcomes in patients with cancer receiving CPIs and either concomitant or sequential (pre- or post-CPI) AAs or HDACis were identified in PubMed using pre-defined search strings. Manual searches of key oncology congresses were similarly performed. All relevant articles and abstracts were manually screened for relevance, classified according to the specific anticancer agents used (CPIs, AAs, or HDACis), tumor entity, and whether treatment was concomitant or sequential. Results: Overall, 227 unique clinical studies across a range of tumor types, both solid tumors and hematological malignancies, were identified. One hundred and fifty-nine publications on Phase I and II clinical studies together with 41 publications on Phase III studies were examined. The most commonly investigated tumor types were melanoma, triple-negative breast cancer, non-small cell lung cancer, and Hodgkin lymphoma. The randomized clinical studies identified, all of which reported on the combination of a CPI with an AA, demonstrated superior outcomes in the combination arm compared with CPI or AA monotherapy. Similarly, combination therapy with CPIs and HDACis demonstrated promising activity. Conclusion: Sequential or concomitant administration of a CPI with an AA or an HDACi may improve outcomes for patients with a range of tumor types. There is a rationale to support further investigation into the potential for synergy between CPIs, alkylating agents and/or HDACis in both the non-clinical and clinical settings.

People being treated for cancer will often receive more than one drug at a time, and the concept of combining cancer drugs is frequently investigated as a potential opportunity to improve outcomes for patients. We reviewed the published literature for clinical trials and work undertaken in laboratories to explore whether combining targeted agents that stop cancer cells from multiplying (known as checkpoint inhibitors) with traditional chemotherapy that kills cancer cells could be a useful approach. We looked at evidence in publications where checkpoint inhibitors were used at the same time as chemotherapy, or given immediately before or after chemotherapy. The most important evidence came from clinical trials where outcomes for patients receiving combinations of treatment were directly compared with those from patients receiving a single treatment. These studies showed superior outcomes for patients who were treated with a combination of cancer drugs compared with patients receiving monotherapy. We also found evidence that adding another class of cancer drug, called histone deacetylase inhibitors, might sensitize tumors to checkpoint inhibitors. These findings provide a rationale for examining alkylating agents and/or histone deacetylase inhibitors combined with checkpoint inhibitors.

Advances in targeting histone deacetylase for treatment of solid tumors.

Histone deacetylase (HDAC) serves as a critical molecular regulator in the pathobiology of various malignancies and have garnered attention as a viable target for therapeutic intervention. A variety of HDAC inhibitors (HDACis) have been developed to target HDACs. Many preclinical studies have conclusively demonstrated the antitumor effects of HDACis, whether used as monotherapy or in combination treatments. On this basis, researchers have conducted various clinical studies to evaluate the potential of selective and pan-HDACis in clinical settings. In our work, we extensively summarized and organized current clinical trials, providing a comprehensive overview of the current clinical advancements in targeting HDAC therapy. Furthermore, we engaged in discussions about several clinical trials that did not yield positive outcomes, analyzing the factors that led to their lack of anticipated therapeutic effectiveness. Apart from the experimental design factors, issues such as toxicological side effects, tumor heterogeneity, and unexpected off-target effects also contributed to these less-than-expected results. These challenges have naturally become significant barriers to the application of HDACis. Despite these challenges, we believe that advancements in HDACi research and improvements in combination therapies will pave the way or lead to a broad and hopeful future in the treatment of solid tumors.

[Histone deacetylase and histone acetyltransferase inhibitors as antischistosomal agents: a review].

Schistosomiasis is a neglected zoonotic parasitic disease. Currently, praziquantel is the drug of choice for the treatment of schistosomiasis, and is the only effective chemical for treatment of schistosomiasis japonica. Since its introduction in the 1970s, praziquantel has been used for large-scale chemotherapy of schistosomiasis for over 40 years. However, there have been reports pertaining to the resistance to praziquantel in schistosomes. Therefore, development of novel antischistosomal agents as alternatives of praziquantel, is of great need. Histone deacetylases and histone acetyltransferases have been recently reported to play critical roles in the growth, development and reproduction of schistosomes, and are considered as potential drug targets for the treatment of schistosomiasis. This review summarizes the latest advances of histone deacetylase and histone acetyltransferase inhibitors in the research on antischistosomal drugs, so as to provide insights into research and development of novelantischistosomal agents.

Panobinostat, a Histone Deacetylase Inhibitor, Reduces LPS-Induced Expression of Inducible Nitric Oxide Synthase in Rat Immortalized Microglia HAPI Cells.

Microglia, resident immune cells in the central nervous system (CNS), play a critical role in maintaining CNS homeostasis. However, microglia activated in response to brain injury produce various inflammatory mediators, including nitric oxide (NO) and proinflammatory cytokines, leading to considerable neuronal damage. NO generated by inducible NO synthase (iNOS) rapidly reacts with superoxide to form a highly toxic product, peroxynitrite. Therefore, iNOS is considered to be a putative therapeutic target for cerebral ischemia. Here, we examined the effects of panobinostat (Pano), a histone deacetylase inhibitor, on lipopolysaccharide (LPS)-induced iNOS expression using rat immortalized microglia HAPI cells. Pano inhibited LPS-induced expression of iNOS mRNA and NO production in a dose-dependent manner; however, it had little effect on the LPS-induced activation of c-Jun N-terminal kinase (JNK) and p38 or nuclear translocation of nuclear factor-κB (NF-κB). The interferon-ß (IFN-ß)/signal transducer and activator of transcription (STAT) pathway is essential for LPS-induced iNOS expression in macrophages/microglia. We also examined the effects of Pano on LPS-induced IFN-ß signaling. Pano markedly inhibited LPS-induced IFN-ß expression and subsequent tyrosine phosphorylation of STAT1. However, the addition of IFN-ß restored the decreased STAT1 phosphorylation but not the decreased iNOS expression. In addition, Pano inhibited the LPS-increased expression of octamer binding protein-2 and interferon regulatory factor 9 responsible for iNOS expression, but IFN-ß addition also failed to restore the decreased expression of these factors. Thus, we conclude that the inhibitory effects of Pano are due not only to the inhibition of the IFN-ß/STAT axis but also to the downregulation of other factors not involved in this axis.

Novel Histone Deacetylase (HDAC) Inhibitor Induces Apoptosis and Suppresses Invasion via E-Cadherin Upregulation in Pancreatic Ductal Adenocarcinoma (PDAC).

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal form of pancreatic cancer characterized by therapy resistance and early metastasis, resulting in a low survival rate. Histone deacetylase (HDAC) inhibitors showed potential for the treatment of hematological malignancies. In PDAC, the overexpression of HDAC 2 is associated with the epithelial-mesenchymal transition (EMT), principally accompanied by the downregulation of the epithelial marker E-cadherin and increased metastatic capacity. The effector cytokine transforming growth factor-ß (TGF ß) is known to be a major inducer of the EMT in PDAC, leading to high metastatic and invasive potential. In addition, the overexpression of HDAC 6 in PDAC is associated with reduced apoptosis. Here, we have demonstrated that a novel HDAC 2/6 inhibitor not only significantly increased E-cadherin expression in PANC-1 cells (5.5-fold) and in 3D PDAC co-culture spheroids (2.5-fold) but was also able to reverse the TGF-ß-induced downregulation of E-cadherin expression. Moreover, our study indicates that the HDAC inhibitor mediated re-differentiation resulting in a significant inhibition of tumor cell invasion by approximately 60% compared to control. In particular, we have shown that the HDAC inhibitor induces both apoptosis (2-fold) and cell cycle arrest. In conclusion, the HDAC 2/6 inhibitor acts by suppressing invasion via upregulating E-cadherin mediated by HDAC 2 blockade and by inducing cell cycle arrest leading to apoptosis via HDAC 6 inhibition. These results suggest that the HDAC 2/6 inhibitor might represent a novel therapeutic strategy for the treatment of PDAC tumorigenesis and metastasis.

Histone deacetylase inhibition mitigates cognitive deficits and astrocyte dysfunction induced by amyloid-ß (Aß) oligomers.

BACKGROUND AND PURPOSE: Inhibitors of histone deacetylases (iHDACs) are promising drugs for neurodegenerative diseases. We have evaluated the therapeutic potential of the new iHDAC LASSBio-1911 in Aß oligomer (AßO) toxicity models and astrocytes, key players in neuroinflammation and Alzheimer's disease (AD). EXPERIMENTAL APPROACH: Astrocyte phenotype and synapse density were evaluated by flow cytometry, Western blotting, immunofluorescence and qPCR, in vitro and in mice. Cognitive function was evaluated by behavioural assays using a mouse model of intracerebroventricular infusion of AßO. KEY RESULTS: LASSBio-1911 modulates reactivity and synaptogenic potential of cultured astrocytes and improves synaptic markers in cultured neurons and in mice. It prevents AßO-triggered astrocytic reactivity in mice and enhances the neuroprotective potential of astrocytes. LASSBio-1911 improves behavioural performance and rescues synaptic and memory function in AßO-infused mice. CONCLUSION AND IMPLICATIONS: These results contribute to unveiling the mechanisms underlying astrocyte role in AD and provide the rationale for using astrocytes as targets to new drugs for AD.

Histone deacetylase as emerging pharmacological therapeutic target for neuropathic pain: From epigenetic to selective drugs.

BACKGROUND: Neuropathic pain remains a formidable challenge for modern medicine. The first-line pharmacological therapies exhibit limited efficacy and unfavorable side effect profiles, highlighting an unmet need for effective therapeutic medications. The past decades have witnessed an explosion in efforts to translate epigenetic concepts into pain therapy and shed light on epigenetics as a promising avenue for pain research. Recently, the aberrant activity of histone deacetylase (HDAC) has emerged as a key mechanism contributing to the development and maintenance of neuropathic pain. AIMS: In this review, we highlight the distinctive role of specific HDAC subtypes in a cell-specific manner in pain nociception, and outline the recent experimental evidence supporting the therapeutic potential of HDACi in neuropathic pain. METHODS: We have summarized studies of HDAC in neuropathic pain in Pubmed. RESULTS: HDACs, widely distributed in the neuronal and non-neuronal cells of the dorsal root ganglion and spinal cord, regulate gene expression by deacetylation of histone or non-histone proteins and involving in increased neuronal excitability and neuroinflammation, thus promoting peripheral and central sensitization. Importantly, pharmacological manipulation of aberrant acetylation using HDAC-targeted inhibitors (HDACi) has shown promising pain-relieving properties in various preclinical models of neuropathic pain. Yet, many of which exhibit low-specificity that may induce off-target toxicities, underscoring the necessity for the development of isoform-selective HDACi in pain management. CONCLUSIONS: Abnormally elevated HDACs promote neuronal excitability and neuroinflammation by epigenetically modulating pivotal gene expression in neuronal and immune cells, contributing to peripheral and central sensitization in the progression of neuropathic pain, and HDACi showed significant efficacy and great potential for alleviating neuropathic pain.

Characterization of the dehydrogenase-reductase DHRS2 and its involvement in histone deacetylase inhibition in urological malignancies.

BACKGROUND: Being implicated during tumor migration, invasion, clonogenicity, and proliferation, the nicotinamide adenine dinucleotide (NAD)/-phosphate (NADP)-dependent dehydrogenase/reductase member 2 (DHRS2) has been considered to be induced upon inhibition of histone deacetylases (HDACi). In this study, we evaluated the current knowledge on the underlying mechanisms of the (epi)genetic regulation of DHRS2, as well as its function during tumor progression. METHODS: DHRS2 expression was evaluated on mRNA- and protein-level upon treatment with HDACi by means of qRT-PCR and western blot analyses, respectively. Re-analysis of RNA-sequencing data gained insight into expression of specific DHRS2 isoforms, while re-analysis of ATAC-sequencing data shed light on the chromatin accessibility at the DHRS2 locus. Further examination of the energy and lipid metabolism of HDACi-treated urologic tumor cells was performed using liquid chromatography-mass spectrometry. RESULTS: Enhanced DHRS2 expression levels upon HDACi treatment were directly linked to an enhanced chromatin accessibility at the DHRS2 locus. Particularly the DHRS2 ENST00000250383.11 protein-coding isoform was increased upon HDACi treatment. Application of the HDACi quisinostat only mildly influenced the energy metabolism of urologic tumor cells, though, the analysis of the lipid metabolism showed diminished sphingosine levels, as well as decreased S1P levels. Also the ratios of S1P/sphingosine and S1P/ceramides were reduced in all four quisinostat-treated urologic tumor cells. CONCLUSIONS: With the emphasis on urologic malignancies (testicular germ cell tumors, urothelial, prostate, and renal cell carcinoma), this study concluded that elevated DHRS2 levels are indicative of a successful HDACi treatment and, thereby offering a novel putative predictive biomarker.

Impact of histone deacetylase inhibition and arimoclomol on heat shock protein expression and disease biomarkers in primary culture models of familial ALS.

Protein misfolding and mislocalization are common themes in neurodegenerative disorders, including motor neuron disease, and amyotrophic lateral sclerosis (ALS). Maintaining proteostasis is a crosscutting therapeutic target, including the upregulation of heat shock proteins (HSP) to increase chaperoning capacity. Motor neurons have a high threshold for upregulating stress-inducible HSPA1A, but constitutively express high levels of HSPA8. This study compared the expression of these HSPs in cultured motor neurons expressing three variants linked to familial ALS: TAR DNA binding protein 43 kDa (TDP-43)G348C, fused in sarcoma (FUS)R521G, or superoxide dismutase I (SOD1)G93A. All variants were poor inducers of Hspa1a, and reduced levels of Hspa8 mRNA and protein, indicating multiple compromises in chaperoning capacity. To promote HSP expression, cultures were treated with the putative HSP coinducer, arimoclomol, and class I histone deacetylase inhibitors, to promote active chromatin for transcription, and with the combination. Treatments had variable, often different effects on the expression of Hspa1a and Hspa8, depending on the ALS variant expressed, mRNA distribution (somata and dendrites), and biomarker of toxicity measured (histone acetylation, maintaining nuclear TDP-43 and the neuronal Brm/Brg-associated factor chromatin remodeling complex component Brg1, mitochondrial transport, FUS aggregation). Overall, histone deacetylase inhibition alone was effective on more measures than arimoclomol. As in the FUS model, arimoclomol failed to induce HSPA1A or preserve Hspa8 mRNA in the TDP-43 model, despite preserving nuclear TDP-43 and Brg1, indicating neuroprotective properties other than HSP induction. The data speak to the complexity of drug mechanisms against multiple biomarkers of ALS pathogenesis, as well as to the importance of HSPA8 for neuronal proteostasis in both somata and dendrites.

Neuroinflammation and the role of epigenetic-based therapies for Huntington's disease management: the new paradigm.

Huntington's disease (HD) is an inherited, autosomal, neurodegenerative ailment that affects the striatum of the brain. Despite its debilitating effect on its patients, there is no proven cure for HD management as of yet. Neuroinflammation, excitotoxicity, and environmental factors have been reported to influence the regulation of gene expression by modifying epigenetic mechanisms. Aside focusing on the etiology, changes in epigenetic mechanisms have become a crucial factor influencing the interaction between HTT protein and epigenetically transcribed genes involved in neuroinflammation and HD. This review presents relevant literature on epigenetics with special emphasis on neuroinflammation and HD. It summarizes pertinent research on the role of neuroinflammation and post-translational modifications of chromatin, including DNA methylation, histone modification, and miRNAs. To achieve this about 1500 articles were reviewed via databases like PubMed, ScienceDirect, Google Scholar, and Web of Science. They were reduced to 534 using MeSH words like 'epigenetics, neuroinflammation, and HD' coupled with Boolean operators. Results indicated that major contributing factors to the development of HD such as mitochondrial dysfunction, excitotoxicity, neuroinflammation, and apoptosis are affected by epigenetic alterations. However, the association between neuroinflammation-altered epigenetics and the reported transcriptional changes in HD is unknown. Also, the link between epigenetically dysregulated genomic regions and specific DNA sequences suggests the likelihood that transcription factors, chromatin-remodeling proteins, and enzymes that affect gene expression are all disrupted simultaneously. Hence, therapies that target pathogenic pathways in HD, including neuroinflammation, transcriptional dysregulation, triplet instability, vesicle trafficking dysfunction, and protein degradation, need to be developed.

Trichostatin C Synergistically Interacts with DNMT Inhibitor to Induce Antineoplastic Effect via Inhibition of Axl in Bladder and Lung Cancer Cells.

Aberrant epigenetic modifications are fundamental contributors to the pathogenesis of various cancers. Consequently, targeting these aberrations with small molecules, such as histone deacetylase (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors, presents a viable strategy for cancer therapy. The objective of this study is to assess the anti-cancer efficacy of trichostatin C (TSC), an analogue of trichostatin A sourced from the fermentation of Streptomyces sp. CPCC 203909. Our investigations reveal that TSC demonstrates potent activity against both human lung cancer and urothelial bladder cancer cell lines, with IC50 values in the low micromolar range. Moreover, TSC induces apoptosis mediated by caspase 3/7 and arrests the cell cycle at the G2/M phase. When combined with the DNMT inhibitor decitabine, TSC exhibits a synergistic anti-cancer effect. Additionally, protein analysis elucidates a significant reduction in the expression of the tyrosine kinase receptor Axl. Notably, elevated concentrations of TSC correlate with the up-regulation of the transcription factor forkhead box class O1 (FoxO1) and increased levels of the proapoptotic proteins Bim and p21. In conclusion, our findings suggest TSC as a promising anti-cancer agent with HDAC inhibitory activity. Furthermore, our results highlight the potential utility of TSC in combination with DNMT inhibitors for cancer treatment.

A real-world pharmacovigilance study investigating the toxicities of histone deacetylase inhibitors.

Histone deacetylase (HDAC) inhibitors are emerging as promising treatments for hematological malignancies, with potential applications extending to solid tumors in the future. Given their wide-ranging biological effects, there is a pressing need for a thorough understanding of the toxicities linked to HDAC inhibition. In this study, a pharmacovigilance analysis was conducted using the FDA Adverse Event Reporting System database. Suspected adverse events linked to HDAC inhibitors were detected through various statistical methodologies, including reporting odds ratio, proportional reporting ratio, information component, and Empirical Bayes Geometric Mean. Our study findings have illuminated that, among the total reported cases examined, gastrointestinal disorders accounted for 13% patients of the cohort, while lymphatic system disorders comprised 8% cases of the cohort, all of which manifested as adverse events induced by HDAC inhibitors. Importantly, the usage of HDAC inhibitors was found to be associated with incidents of atrial fibrillation, heart failure, respiratory failure, hepatic dysfunction, and acute kidney injury. Romidepsin and belinostat demonstrated more pronounced signals of adverse events compared to panobinostat and vorinostat, emphasizing the need for vigilant monitoring of adverse events in this particular population. Furthermore, atrial fibrillation (clinical priority score of 7 points) emerged as the paramount medical event warranting utmost clinical attention. Eventually, multiple adverse events were observe to emerge within the initial and second months following the initiation of treatment. Vigilant monitoring and supportive care strategies are critical in addressing the toxicities associated with HDAC inhibitors, particularly those concerning cardiotoxicity, respiratory toxicity, renal toxicity, and hepatotoxicity.

The Utility of Spectroscopic MRI in Stereotactic Biopsy and Radiotherapy Guidance in Newly Diagnosed Glioblastoma.

Current diagnostic and therapeutic approaches for gliomas have limitations hindering survival outcomes. We propose spectroscopic magnetic resonance imaging as an adjunct to standard MRI to bridge these gaps. Spectroscopic MRI is a volumetric MRI technique capable of identifying tumor infiltration based on its elevated choline (Cho) and decreased N-acetylaspartate (NAA). We present the clinical translatability of spectroscopic imaging with a Cho/NAA ≥ 5x threshold for delineating a biopsy target in a patient diagnosed with non-enhancing glioma. Then, we describe the relationship between the undertreated tumor detected with metabolite imaging and overall survival (OS) from a pilot study of newly diagnosed GBM patients treated with belinostat and chemoradiation. Each cohort (control and belinostat) were split into subgroups using the median difference between pre-radiotherapy Cho/NAA ≥ 2x and the treated T1-weighted contrast-enhanced (T1w-CE) volume. We used the Kaplan-Meier estimator to calculate median OS for each subgroup. The median OS was 14.4 months when the difference between Cho/NAA ≥ 2x and T1w-CE volumes was higher than the median compared with 34.3 months when this difference was lower than the median. The T1w-CE volumes were similar in both subgroups. We find that patients who had lower volumes of undertreated tumors detected via spectroscopy had better survival outcomes.

Butyrate's (a short-chain fatty acid) microbial synthesis, absorption, and preventive roles against colorectal and lung cancer.

Butyrate, a short-chain fatty acid (SCFA) produced by bacterial fermentation of fiber in the colon, is a source of energy for colonocytes. Butyrate is essential for improving gastrointestinal (GI) health since it helps colonocyte function, reduces inflammation, preserves the gut barrier, and fosters a balanced microbiome. Human colonic butyrate producers are Gram-positive firmicutes, which are phylogenetically varied. The two most prevalent subgroups are associated with Eubacterium rectale/Roseburia spp. and Faecalibacterium prausnitzii. Now, the mechanism for the production of butyrate from microbes is a very vital topic to know. In the present study, we discuss the genes encoding the core of the butyrate synthesis pathway and also discuss the butyryl-CoA:acetate CoA-transferase, instead of butyrate kinase, which usually appears to be the enzyme that completes the process. Recently, butyrate-producing microbes have been genetically modified by researchers to increase butyrate synthesis from microbes. The activity of butyrate as a histone deacetylase inhibitor (HDACi) has led to several clinical trials to assess its effectiveness as a potential cancer treatment. Among various significant roles, butyrate is the main energy source for intestinal epithelial cells, which helps maintain colonic homeostasis. Moreover, people with non-small-cell lung cancer (NSCLC) have distinct gut microbiota from healthy adults and frequently have dysbiosis of the butyrate-producing bacteria in their guts. So, with an emphasis on colon and lung cancer, this review also discusses how the microbiome is crucial in preventing the progression of certain cancers through butyrate production. Further studies should be performed to investigate the underlying mechanisms of how these specific butyrate-producing bacteria can control both colon and lung cancer progression and prognosis.