Search Results (22)

Background: Histone deacetylases (HDACs) are critical epigenetic modulators involved in regulating various molecular mechanisms essential for cell development and growth. Alterations in HDAC activity have been linked to the progression of numerous cancers, including lymphoma. Over the past decade, the FDA has approved several HDAC inhibitors for lymphoma treatment, leading to heightened interest in this emerging class of drugs. Methods: In our research, we developed a novel HDAC inhibitor that exhibits high selectivity for class I HDACs. Results: Our in vitro findings indicate that treating lymphoma/leukemia cells with this inhibitor results in a marked suppression of cell growth and promotes apoptosis, while leaving the cell cycle unaffected. Conclusions: We propose that our new inhibitor, named eimbinostat, holds significant promise as a potential therapeutic agent for the treatment of hematologic malignancies such as lymphoma or leukemia. Full article

Histone deacetylase inhibitors (HDACis) are being recognized as a potentially effective treatment approach for peripheral T-cell lymphomas (PTCLs), a heterogeneous group of aggressive malignancies with an unfavorable prognosis. Recent evidence has shown that HDACis are effective in treating PTCL, especially in cases where the disease has relapsed or is resistant to conventional treatments. Several clinical trials have demonstrated that HDACis, such as romidepsin and belinostat, can elicit long-lasting positive outcomes in individuals with PTCLs, either when used alone or in conjunction with conventional chemotherapy. They exert their anti-tumor effects by regulating gene expression through the inhibition of histone deacetylases, which leads to cell cycle arrest, induction of programmed cell death, and,the transformation of cancerous T cells, as demonstrated by gene expression profile studies. Importantly, besides clinical trials, real-world evidence indicated that the utilization of HDACis presents a significant and beneficial treatment choice for PTCLs. However, although HDACis showed potential effectiveness, they could not cure most patients. Therefore, new combinations with conventional drugs as well as new targeted agents are under investigation. Full article

T cells are essential tumor suppressors in cancer immunology, but their dysfunction induced by cancer cells can result in T cell exhaustion. Exhausted T cells (Tex) significantly influence the tumor immune environment, and thus, there is a need for their thorough investigation across different types of cancer. Here, we address the role of Tex cells in pan-cancer, focusing on the expression, mutations, methylation, immune infiltration, and drug sensitivity of a molecular signature comprising of the genes HAVCR2, CXCL13, LAG3, LAYN, TIGIT, and PDCD1across multiple cancer types, using bioinformatics analysis of TCGA data. Our analysis revealed that the Tex signature genes are differentially expressed across 14 cancer types, being correlated with patient survival outcomes, with distinct survival trends. Pathway analysis indicated that the Tex genes influence key cancer-related pathways, such as apoptosis, EMT, and DNA damage pathways. Immune infiltration analysis highlighted a positive correlation between Tex gene expression and immune cell infiltration in bladder cancer, while mutations in these genes were associated with specific immune cell enrichments in UCEC and SKCM. CNVs in Tex genes were widespread across cancers. We also highlight high LAYN methylation in most tumors and a negative correlation between methylation levels and immune cell infiltration in various cancers. Drug sensitivity analysis identified numerous correlations, with CXCL13 and HAVCR2 expressions influencing sensitivity to several drugs, including Apitolisib, Belinostat, and Docetaxel. Overall, these findings highlight the importance of reviving exhausted T cells to enhance the treatment efficacy to significantly boost anti-tumor immunity and achieve better clinical outcomes. Full article

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. Full article

Histone deacetylase inhibitors (HDACis) are drugs that target the epigenetic state of cells by modifying the compaction of chromatin through effects on histone acetylation. Gliomas often harbor a mutation of isocitrate dehydrogenase (IDH) 1 or 2 that leads to changes in their epigenetic state presenting a hypermethylator phenotype. We postulated that glioma cells with IDH mutation, due to the presence of epigenetic changes, will show increased sensitivity to HDACis. This hypothesis was tested by expressing mutant IDH1 with a point alteration—converting arginine 132 to histidine—within glioma cell lines that contain wild-type IDH1. Glioma cells engineered to express mutant IDH1 produced D-2-hydroxyglutarate as expected. When assessed for response to the pan-HDACi drug belinostat, mutant IDH1-expressing glioma cells were subjected to more potent inhibition of growth than the corresponding control cells. Increased sensitivity to belinostat correlated with the increased induction of apoptosis. Finally, a phase I trial assessing the addition of belinostat to standard-of-care therapy for newly diagnosed glioblastoma patients included one patient with a mutant IDH1 tumor. This mutant IDH1 tumor appeared to display greater sensitivity to the addition of belinostat than the other cases with wild-type IDH tumors based on both standard magnetic resonance imaging (MRI) and advanced spectroscopic MRI criteria. These data together suggest that IDH mutation status within gliomas may serve as a biomarker of response to HDACis. Full article

Background: The mechanism of action of romidepsin and other histone deacetylase inhibitors is still not fully explained. Our goal was to gain a mechanistic understanding of the RAS-linked phenotype associated with romidepsin sensitivity. Methods: The NCI60 dataset was screened for molecular clues to romidepsin sensitivity. Histone acetylation, DNA damage, ROS production, metabolic state (real-time measurement and metabolomics), and gene expression alterations (transcriptomics) were determined in KRAS-WT versus KRAS-mutant cell groups. The search for biomarkers in response to HDACi was implemented by supervised machine learning analysis on a 608-cell transcriptomic dataset and validated in a clinical dataset. Results: Romidepsin treatment induced depletion in acetyl-CoA in all tested cell lines, which led to oxidative stress, metabolic stress, and increased death—particularly in KRAS-mutant cell lines. Romidepsin-induced stresses and death were rescued by acetyl-CoA replenishment. Two acetyl-CoA gene expression signatures associated with HDACi sensitivity were derived from machine learning analysis in the CCLE (Cancer Cell Line Encyclopedia) cell panel. Signatures were then validated in the training cohort for seven HDACi, and in an independent 13-patient cohort treated with belinostat. Conclusions: Our study reveals the importance of acetyl-CoA metabolism in HDAC sensitivity, and it highlights acetyl-CoA generation pathways as potential targets to combine with HDACi. Full article

Epigenetic alterations found in all human cancers are promising targets for anticancer therapy. In this sense, histone deacetylase inhibitors (HDACIs) are interesting anticancer agents that play an important role in the epigenetic regulation of cancer cells. Here, we report 15 novel hydroxamic acid-based histone deacetylase inhibitors with quinazolinone core structures. Five compounds exhibited antiproliferative activity with IC₅₀ values of 3.4–37.8 µM. Compound 8 with a 2-mercaptoquinazolinone cap moiety displayed the highest antiproliferative efficacy against MCF-7 cells. For the HDAC6 target selectivity study, compound 8 displayed an IC₅₀ value of 2.3 µM, which is 29.3 times higher than those of HDAC3, HDAC4, HDAC8, and HDAC11. Western blot assay proved that compound 8 strongly inhibited tubulin acetylation, a substrate of HDAC6. Compound 8 also displayed stronger inhibition activity against HDAC11 than the control drug Belinostat. The inhibitory mechanism of action of compound 8 on HDAC enzymes was then explored using molecular docking study. The data revealed a high binding affinity (−7.92 kcal/mol) of compound 8 toward HDAC6. In addition, dock pose analysis also proved that compound 8 might serve as a potent inhibitor of HDAC11. Full article

Glioblastoma (GBM) is highly aggressive and has a poor prognosis. Belinostat is a histone deacetylase inhibitor with blood–brain barrier permeability, anti-GBM activity, and the potential to enhance chemoradiation. The purpose of this clinical trial was to assess the efficacy of combining belinostat with standard-of-care therapy. Thirteen patients were enrolled in each of control and belinostat cohorts. The belinostat cohort was given a belinostat regimen (500–750 mg/m² 1×/day × 5 days) every three weeks (weeks 0, 3, and 6 of RT). All patients received temozolomide and radiation therapy (RT). RT margins of 5–10 mm were added to generate clinical tumor volumes and 3 mm added to create planning target volumes. Median overall survival (OS) was 15.8 months for the control cohort and 18.5 months for the belinostat cohort (p = 0.53). The recurrence volumes (rGTVs) for the control cohort occurred in areas that received higher radiation doses than that in the belinostat cohort. For those belinostat patients who experienced out-of-field recurrence, tumors were detectable by spectroscopic MRI before RT. Recurrence analysis suggests better in-field control with belinostat. This study highlights the potential of belinostat as a synergistic therapeutic agent for GBM. It may be particularly beneficial to combine this radio-sensitizing effect with spectroscopic MRI-guided RT. Full article

The acquired resistance of neuroblastoma (NB) and leukemia cells to anticancer therapy remains the major challenge in the treatment of patients with these diseases. Although targeted therapy, such as receptor tyrosine kinase (RTK) inhibitors, has been introduced into clinical practice, its efficacy is limited to patients harboring mutant kinases. Through the analysis of transcriptomic data of 701 leukemia and NB patient samples and cell lines, we revealed that the expression of RTK, such as KIT, FLT3, AXL, FGFR3, and NTRK1, is linked with HDAC class I. Although HDAC inhibitors have antitumor activity, they also have high whole-body toxicity. We developed a novel belinostat derivative named hydrazostat, which targets HDAC class I with limited off-target effects. We compared the toxicity of these drugs within the panel of leukemia and NB cell lines. Next, we revealed that HDAC inhibition with hydrazostat reactivates NTRK1, FGFR3, ROR2, KIT, and FLT3 expression. Based on this finding, we tested the efficacy of hydrazostat in combination with RTK inhibitor imatinib. Additionally, we show the ability of hydrazostat to enhance venetoclax-induced apoptosis. Thus, we reveal the connection between HDACs and RTK and describe a useful strategy to overcome the complications of single-agent therapies. Full article

Multi-gene assays often include UGT1A1 and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of UGT1A1 polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, UGT1A1*28 was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m², supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m² for UGT1A1*28 homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between UGT1A1 polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of UGT1A1-guided pazopanib dose adjustments. Limited studies have investigated the association between UGT1A1 polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for UGT1A1-guided nilotinib dose adjustments. Full article

Novel treatment options are needed for testicular germ cell tumor (TGCT) patients, particularly important for those showing or developing cisplatin resistance, the major cause of cancer-related deaths. As TGCTs pathobiology is highly related to epigenetic (de)regulation, epidrugs are potentially effective therapies. Hence, we sought to explore, for the first time, the effect of the two most recently FDA-approved HDAC inhibitors (HDACis), belinostat and panobinostat, in (T)GCT cell lines including those resistant to cisplatin. In silico results were validated in 261 patient samples and differential expression of HDACs was also observed across cell lines. Belinostat and panobinostat reduced cell viability in both cisplatin-sensitive cells (NCCIT-P, 2102Ep-P, and NT2-P) and, importantly, also in matched cisplatin-resistant subclones (NCCIT-R, 2102Ep-R, and NT2-R), with IC50s in the low nanomolar range for all cell lines. Treatment of NCCIT-R with both drugs increased acetylation, induced cell cycle arrest, reduced proliferation, decreased Ki67 index, and increased p21, while increasing cell death by apoptosis, with upregulation of cleaved caspase 3. These findings support the effectiveness of HDACis for treating TGCT patients in general, including those developing cisplatin resistance. Future studies should explore them as single or combination agents. Full article

Lymph node metastasis is an aggressive condition characterized by poor treatment outcomes and low overall survival. Belinostat is a novel histone deacetylase (HDAC) inhibitor approved by the Food and Drug Administration (FDA) for the treatment of relapsed peripheral T-cell lymphoma (PTCL). However, the major problem is that belinostat has a short half-life of 1.1 h. In this study, we successfully prepared 50 nm liposomal colloids, which showed a controlled release pattern and excellent pharmacokinetics. The results showed that the particle size of liposomes consisting of dioleoylphosphatidylcholine (DOPC) was larger than that of those consisting of dioleoylglycerophosphoserine (DOPS). In terms of release kinetics of belinostat, the free drug was rapidly released and showed lower area under curve (AUC) exposure for in vivo pharmacokinetics. When liposomal formulations were employed, the release pattern was fitted with Hixson–Crowell models and showed sustained release of belinostat. Moreover, HuT-78 cells were able to take up all the liposomes in a concentration-dependent manner. The safety assessment confirmed hemocompatibility, and the platelet count was increased. Furthermore, the liposomes consisting of DOPC or DOPS had different behavior patterns, and their delivery to lymphatic regions should be thoroughly investigated in the future. Full article

Combination antiretroviral therapy (cART) is successful in maintaining undetectable levels of HIV in the blood; however, the persistence of latent HIV reservoirs has become the major barrier for a HIV cure. Substantial efforts are underway in finding the best latency-reversing agents (LRAs) to purge the latent viruses from the reservoirs. We hypothesize that identifying the right combination of LRAs will be the key to accomplishing that goal. In this study, we evaluated the effect of combinations of three protein kinase C activators (prostratin, (-)-indolactam V, and TPPB) with four histone deacetylase inhibitors (AR-42, PCI-24781, givinostat, and belinostat) on reversing HIV latency in different cell lines including in a primary CD4+ T-cell model. Combinations including indolactam and TPPB with AR-42 and PCI produced a strong synergistic effect in reactivating latent virus as indicated by higher p24 production and envelope gp120 expression. Furthermore, treatment with TPPB and indolactam greatly downregulated the cellular receptor CD4. Indolactam/AR-42 combination emerged from this study as the best combination that showed a strong synergistic effect in reactivating latent virus. Although AR-42 alone did not downregulate CD4 expression, indolactam/AR-42 showed the most efficient downregulation. Our results suggest that indolactam/AR-42 is the most effective combination, showing a strong synergistic effect in reversing HIV latency combined with the most efficient CD4 downregulation. Full article

ZL277 is a prodrug of belinostat with enhanced bioavailability and efficacy as a pan histone deacetylase (HDAC) inhibitor. In this study, we investigated the metabolism and pharmacokinetics of ZL277 in liver S9 fractions, liver microsomes, liver cytosol, and in mice. Metabolic products were identified and quantified by a combination of liquid chromatography and tandem mass spectrometry. The in vitro metabolic profile of ZL277 includes ZL277-B(OH)₂-452, the major oxidative metabolite ZL277-OH-424, the active ingredient belinostat, belinostat amide, belinostat acid, and methylated belinostat in liver S9 fractions. Both ZL277-OH-424 and belinostat underwent further glucuronidation in liver microsome, whereas only ZL277-OH-424, but not belinostat, underwent some level of sulfation in rat liver cytosols. These metabolites were examined in plasma and in a breast tumor model in vivo. They were also examined in urine and feces from mice treated with ZL277. The pharmacokinetic study of ZL277 showed the parameters of active drug belinostat with a half-life (t_1/2) of 10.7 h, an area under curve value (AUC) of 1506.9 ng/mL*h, and a maximum plasma concentration (C_max) of 172 ng/mL, reached 3 h after a single dose of 10 mg/kg. The hydrolysis product of the prodrug, ZL277-B(OH)₂-452 showed an AUC of 8306 ng/mL*h and C_max of 931 ng/mL 3 h after drug administration. Full article

Acetylation is an important post translational modification of histone that plays a role in regulation of physiological and pathological process in the body. We have recently shown that the inhibition of histone deacetylases (HDAC) by low concentrations of HDAC inhibitors (HDACis), belinostat (up to 0.25 µM) and panobinostat (up to 0.04 µM) promote histone acetylation (e.g., AcH4) and neutrophil extracellular trap formation (NETosis). Clinical use of belinostat and panobinostat often leads to neutropenia and the in vivo concentrations vary with time and tissue locations. However, the effects of different concentrations of these HDACis on neutrophil death are not fully understood. We considered that increasing concentrations of belinostat and panobinostat could alter the type of neutrophil death. To test this hypothesis, we treated human neutrophils with belinostat and panobinostat in the presence or absence of agonists that promote NOX-dependent NETosis (phorbol myristate acetate or lipopolysaccharide from Escherichia coli 0128) and NOX-independent NETosis (calcium ionophores A23187 or ionomycin from Streptomyces conglobatus). Increasing concentrations of HDACis induced histone acetylation in a dose-dependent manner. ROS analyses showed that increasing concentrations of HDACis, increased the degree of NOX-derived ROS production. Higher levels (>1 µM belinostat and >0.2 µM panobinostat) of AcH4 resulted in a significant inhibition of spontaneous as well as the NOX-dependent and -independent NETosis. By contrast, the degree of neutrophil apoptosis significantly increased, particularly in non-activated cells. Collectively, this study establishes that increasing concentrations of belinostat and panobinostat initially increases NETosis but subsequently reduces NETosis or switches the form of cell death to apoptosis. This new information indicates that belinostat and panobinostat can induce different types of neutrophil death and may induce neutropenia and regulate inflammation at different concentrations. Full article