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Molecular Therapy. Oncology Mar 2024The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic...
The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic stress by targeting protein degradation with proteasome inhibitors (PIs) has revolutionized the treatment of MM. However, resistance to PIs is inevitable and represents an ongoing clinical challenge. Our first-in-human study of the selective inhibitor of RNA polymerase I transcription of ribosomal RNA genes, CX-5461, has demonstrated a potential signal for anti-tumor activity in three of six heavily pre-treated MM patients. Here, we show that CX-5461 has potent anti-myeloma activity in PI-resistant MM preclinical models and . In addition to inhibiting ribosome biogenesis, CX-5461 causes topoisomerase II trapping and replication-dependent DNA damage, leading to G2/M cell-cycle arrest and apoptotic cell death. Combining CX-5461 with PI does not further enhance the anti-myeloma activity of CX-5461 . In contrast, CX-5461 shows synergistic interaction with the histone deacetylase inhibitor panobinostat in both the Vk∗MYC and the 5T33-KaLwRij mouse models of MM by targeting ribosome biogenesis and protein synthesis through distinct mechanisms. Our findings thus provide strong evidence to facilitate the clinical development of targeting the ribosome to treat relapsed and refractory MM.
PubMed: 38596309
DOI: 10.1016/j.omton.2024.200771 -
Clinical & Translational Immunology 2024The rapid recognition of epigenetic manipulation's potential in restricting cancer cell capabilities spurred translational initiatives, including histone deacetylase...
OBJECTIVES
The rapid recognition of epigenetic manipulation's potential in restricting cancer cell capabilities spurred translational initiatives, including histone deacetylase inhibitors (HDACis). Clinical trials on multiple myeloma (MM) demonstrated substantial benefits of HDACis, coupled with promising outcomes from cytokine-induced killer cell (CIK) immunotherapy. Intriguingly, the unexplored synergy of HDACis and CIK cell immunotherapy in MM prompted our study.
METHODS
We examined clinically relevant HDACis (panobinostat/LBH589 and romidepsin) alongside CIK cells derived from peripheral blood mononuclear cells across diverse MM cell lines (U266, RPMI8226, OPM-2 and NCI-H929). Utilising various methodologies, we investigated how HDACis enhance CIK cell lysis of myeloma cells through NKG2D/NKG2D ligand interactions.
RESULTS
The results of our analysis indicated several key findings. (1) Enhanced cytotoxicity of CIK cells in MM cells when combined with HDACis. (2) Significant increase in apoptosis, suggesting HDACis and CIK may together enhance apoptotic effects in specific MM cell lines. (3) Elevated IFN-γ secretion and alterations in granzyme B secretion because of the independent activity of HDACis. (4) Notably, HDACis increased the expression of MICA/B and ULBP2, crucial for inducing antitumor cytotoxicity of NKT cells. Validation through NKG2D receptor blocking in CIK cells with a purified mouse antihuman NKG2D antibody further supported our findings.
CONCLUSIONS
Our analyses provide sufficient evidence to consider this clinically forgotten instance (HDACis-CIK cell combination) as a therapeutic priority for MM treatment. Furthermore, we suggest that NKG2D/NKG2D-ligand interactions activating NK/NKT cells may contribute to enhanced myeloma cell lysis in response to HDACis treatment by CIK cells.
PubMed: 38529413
DOI: 10.1002/cti2.1500 -
Frontiers in Oncology 2024Acute lymphocytic leukemia is a hematological malignancy that primarily affects children. Long-term chemotherapy is effective, but always causes different toxic side... (Review)
Review
Acute lymphocytic leukemia is a hematological malignancy that primarily affects children. Long-term chemotherapy is effective, but always causes different toxic side effects. With the application of a chemotherapy-free treatment strategy, we intend to demonstrate the most recent results of using one type of epigenetic drug, histone deacetylase inhibitors, in ALL and to provide preclinical evidence for further clinical trials. In this review, we found that panobinostat (LBH589) showed positive outcomes as a monotherapy, whereas vorinostat (SAHA) was a better choice for combinatorial use. Preclinical research has identified chidamide as a potential agent for investigation in more clinical trials in the future. In conclusion, histone deacetylase inhibitors play a significant role in the chemotherapy-free landscape in cancer treatment, particularly in acute lymphocytic leukemia.
PubMed: 38450195
DOI: 10.3389/fonc.2024.1324859 -
The Journal of Pharmacology and... Feb 2024Panobinostat is a potent pan-HDAC inhibitor that has been tested in multiple studies for the treatment of brain tumors. There have been contrasting views surrounding its...
Panobinostat is a potent pan-HDAC inhibitor that has been tested in multiple studies for the treatment of brain tumors. There have been contrasting views surrounding its efficacy for the treatment of tumors in the CNS following systemic administration when examined in different models or species. We conducted experiments using three different mouse strains or genotypes to have a more comprehensive understanding of the systemic as well as the CNS distributional kinetics of panobinostat. Our study found that panobinostat experienced rapid degradation in FVB mouse matrices and a faster degradation rate was observed at 37{degree sign}C compared with room temperature and 4{degree sign}C, suggesting that the instability of panobinostat was due to enzymatic metabolism. Panobinostat also showed inter-strain and inter-species differences in the plasma stability; and was stable in human plasma. The objective of this study was to examine the metabolic stability of panobinostat in different matrices and assess the influence of that metabolic stability on the pharmacokinetics and CNS delivery of panobinostat. Importantly, the plasma stability in various mouse strains was not reflected in the systemic pharmacokinetic behavior of panobinostat. Several hypotheses arise from this finding, including: the binding of panobinostat to red blood cells, the existence of competing endogenous compounds to enzyme(s), the distribution into tissues with a lower level of enzymatic activity or the metabolism occurring in the plasma is a small fraction of the total metabolism Panobinostat showed different degradation in plasma from different mouse strains and genotypes. However, despite the differences surrounding plasma stability, panobinostat showed similar pharmacokinetic behavior in different mouse models. This suggests that the inter-strain difference in enzymatic activity did not affect the pharmacokinetic behavior of panobinostat and its CNS distribution in mice. This lack of translation between metabolism assays and disposition can confound drug development.
PubMed: 38409112
DOI: 10.1124/jpet.123.002051 -
Pharmaceuticals (Basel, Switzerland) Feb 2024Triple-negative breast cancer (TNBC) poses a therapeutic challenge due to its aggressive nature and lack of targeted therapies. Epigenetic modifications contribute to...
Triple-negative breast cancer (TNBC) poses a therapeutic challenge due to its aggressive nature and lack of targeted therapies. Epigenetic modifications contribute to TNBC tumorigenesis and drug resistance, offering potential therapeutic targets. Recent advancements in three-dimensional (3D) organoid cultures, enabling precise drug screening, hold immense promise for identifying novel compounds targeting TNBC. In this study, we established two patient-derived TNBC organoids and implemented a high-throughput drug screening system using these organoids and two TNBC cell lines. Screening a library of 169 epigenetic compounds, we found that organoid-based systems offer remarkable precision in drug response assessment compared to cell-based models. The top 30 compounds showing the highest drug sensitivity in the initial screening were further assessed in a secondary screen. Four compounds, panobinostat, pacritinib, TAK-901, and JIB-04, targeting histone deacetylase, JAK/STAT, histone demethylases, and aurora kinase pathways, respectively, exhibited potent anti-tumor activity in TNBC organoids, surpassing the effect of paclitaxel. Our study highlights the potential of these novel epigenetic drugs as effective therapeutic agents for TNBC and demonstrates the valuable role of patient-derived organoids in advancing drug discovery.
PubMed: 38399440
DOI: 10.3390/ph17020225 -
Cell Feb 2024CD4 T cells with latent HIV-1 infection persist despite treatment with antiretroviral agents and represent the main barrier to a cure of HIV-1 infection.... (Randomized Controlled Trial)
Randomized Controlled Trial
CD4 T cells with latent HIV-1 infection persist despite treatment with antiretroviral agents and represent the main barrier to a cure of HIV-1 infection. Pharmacological disruption of viral latency may expose HIV-1-infected cells to host immune activity, but the clinical efficacy of latency-reversing agents for reducing HIV-1 persistence remains to be proven. Here, we show in a randomized-controlled human clinical trial that the histone deacetylase inhibitor panobinostat, when administered in combination with pegylated interferon-α2a, induces a structural transformation of the HIV-1 reservoir cell pool, characterized by a disproportionate overrepresentation of HIV-1 proviruses integrated in ZNF genes and in chromatin regions with reduced H3K27ac marks, the molecular target sites for panobinostat. By contrast, proviruses near H3K27ac marks were actively selected against, likely due to increased susceptibility to panobinostat. These data suggest that latency-reversing treatment can increase the immunological vulnerability of HIV-1 reservoir cells and accelerate the selection of epigenetically privileged HIV-1 proviruses.
Topics: Humans; HIV Infections; HIV-1; Panobinostat; Proviruses; Virus Latency; Histone Deacetylase Inhibitors; Interferon-alpha
PubMed: 38367616
DOI: 10.1016/j.cell.2024.01.037 -
Heart, Lung & Circulation May 2024Increased cancer survivorship represents a remarkable achievement for modern medicine. Unfortunately, cancer treatments have inadvertently contributed to cardiovascular...
BACKGROUND
Increased cancer survivorship represents a remarkable achievement for modern medicine. Unfortunately, cancer treatments have inadvertently contributed to cardiovascular (CV) damage, significantly threatening the health and quality of life of patients living with, through and beyond cancer. Without understanding the mechanisms, including whether the cardiotoxicity is due to the direct or indirect effects on cardiomyocytes, prevention and management of cardiotoxicity can pose challenges in many patients. To date, the cardiotoxicity profiles of most of the chemotherapy drugs are still poorly understood.
AIM
To conduct a pilot study to investigate the direct effects of a range of cancer therapies on cardiomyocyte viability.
METHODS
Primary human cardiomyocytes (HCM) were cultured and seeded into 96-well culture plates. A total of 35 different Food and Drug Administration-approved anti-cancer drugs were added to the HCM cells with a concentration of 1uM for 72 hours. The viability of HCMs was determined using CellTitre-Glo. The experiments were repeated at least three times for each drug with HCMs of different passages.
RESULTS
We identified 15 anti-cancer agents that significantly reduced HCM viability. These drugs were: (1) anthracyclines (daunorubicin [HCM viability, mean %±standard error, 13.7±3.2%], epirubicin [47.6±5.3%]), (2) antimetabolite (azacitidine [67.1±2.4%]), (3) taxanes (paclitaxel [60.2±3.0%]), (4) protein kinase inhibitors (lapatinib [49.8±7.0%], ponatinib [42.4±9.0%], pemigatinib [68.1±2.3%], sorafenib [52.9±10.6%], nilotinib [64.4±4.5%], dasatinib [38.5±3.6%]), (5) proteasome inhibitors (ixazomib citrate [65.4±7.2%]), (6) non-selective histone-deacetylase inhibitor (panobinostat [19.1±4.1%]), poly adenosine diphosphate-ribose polymerase inhibitor (olaparib [68.2±1.7%]) and (7) vinca alkaloids (vincristine [44.6±7.4%], vinblastine [31.2±3.9%]).
CONCLUSIONS
In total, 15 of the 35 commercially available anti-cancer drugs have direct cardiotoxic effects on HCM. Some of those, have not been associated with clinical cardiotoxicity, while others, known to be cardiotoxic do not appear to mediate it via direct effects on cardiomyocytes. More detailed investigations of the effects of cancer therapies on various cardiovascular cells should be performed to comprehensively determine the mechanisms of cardiotoxicity.
Topics: Humans; Myocytes, Cardiac; Antineoplastic Agents; Cell Survival; Cardiotoxicity; Neoplasms; Cells, Cultured; Pilot Projects; Female
PubMed: 38365500
DOI: 10.1016/j.hlc.2024.01.013 -
Cells Jan 2024Isocitrate Dehydrogenase-1 (IDH1) is commonly mutated in lower-grade diffuse gliomas. The IDH1R132H mutation is an important diagnostic tool for tumor diagnosis and...
Isocitrate Dehydrogenase-1 (IDH1) is commonly mutated in lower-grade diffuse gliomas. The IDH1R132H mutation is an important diagnostic tool for tumor diagnosis and prognosis; however, its role in glioma development, and its impact on response to therapy, is not fully understood. We developed a murine model of proneural IDH1R132H-mutated glioma that shows elevated production of 2-hydroxyglutarate (2-HG) and increased trimethylation of lysine residue K27 on histone H3 (H3K27me3) compared to IDH1 wild-type tumors. We found that using Tazemetostat to inhibit the methyltransferase for H3K27, Enhancer of Zeste 2 (EZH2), reduced H3K27me3 levels and increased acetylation on H3K27. We also found that, although the histone deacetylase inhibitor (HDACi) Panobinostat was less cytotoxic in IDH1R132H-mutated cells (either isolated from murine glioma or oligodendrocyte progenitor cells infected in vitro with a retrovirus expressing IDH1R132H) compared to IDH1-wild-type cells, combination treatment with Tazemetostat is synergistic in both mutant and wild-type models. These findings indicate a novel therapeutic strategy for IDH1-mutated gliomas that targets the specific epigenetic alteration in these tumors.
Topics: Animals; Mice; Histone Deacetylase Inhibitors; Histones; Glioma; Benzamides; Biphenyl Compounds; Morpholines; Pyridones
PubMed: 38334611
DOI: 10.3390/cells13030219 -
Archives of Iranian Medicine Sep 2023Several studies have revealed that the aberrant expressions of forkhead box (FOX) genes are associated with carcinogenesis. However, the crucial biological functions of...
BACKGROUND
Several studies have revealed that the aberrant expressions of forkhead box (FOX) genes are associated with carcinogenesis. However, the crucial biological functions of the FOX gene in colon adenocarcinoma (COAD) remain unknown.
METHODS
The TCGA-COAD dataset (n=328) was utilized for determining the deregulated FOX genes and their association with functional enrichment, protein-protein interaction (PPI), survival prognosis, anti-tumor immunity, cancer-associated pathways, and biological processes in COAD. In addition, we used GSE166427 (GPL13667) as a validation cohort (n=196). Molecular docking studies were applied to perform the drug interactions.
RESULTS
The FOX genes are deregulated in the COAD (Log FC>0.50, <0.05), and the PPI network of FOX members is substantially related to the enrichment of cancerous signaling, immune responses, and cellular development (FDR<0.05). A worse prognosis for overall survival in COAD individuals is connected with the subgroup of FOX transcripts (≤0.05). , , and were identified as predictive variables in the univariate and multivariate Cox regression models (≤0.05). and are substantially linked to the deregulated immunity in COAD (R>0.20, <0.01). Furthermore, expression regulates cancer-associated pathways and biological processes (<0.05). Moreover, , , and are genetically altered and showed diagnostic efficacy in COAD. We revealed that , , and are consistently deregulated in GSE166427 (<0.05). Finally, molecular docking revealed that interacted with various drugs, including belinostat, entinostat, and panobinostat.
CONCLUSION
The FOX genes have a strong correlation with the poor prognosis for survival, tumor immunity, cancer-associated pathways, and biochemical processes that cause the pathogenesis of COAD.
Topics: Humans; Colonic Neoplasms; Adenocarcinoma; Molecular Docking Simulation; Prognosis; Carcinogenesis; Forkhead Transcription Factors
PubMed: 38310407
DOI: 10.34172/aim.2023.77 -
Genome Research Feb 2024Histone acetylation is a dynamic modification regulated by the opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Deacetylation of...
Histone acetylation is a dynamic modification regulated by the opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Deacetylation of histone tails results in chromatin tightening, and therefore, HDACs are generally regarded as transcriptional repressors. Counterintuitively, simultaneous deletion of and in embryonic stem cells (ESCs) reduces expression of the pluripotency-associated transcription factors , , and (PSN). By shaping global histone acetylation patterns, HDACs indirectly regulate the activity of acetyl-lysine readers, such as the transcriptional activator BRD4. Here, we use inhibitors of HDACs and BRD4 (LBH589 and JQ1, respectively) in combination with precision nuclear run-on and sequencing (PRO-seq) to examine their roles in defining the ESC transcriptome. Both LBH589 and JQ1 cause a marked reduction in the pluripotent gene network. However, although JQ1 treatment induces widespread transcriptional pausing, HDAC inhibition causes a reduction in both paused and elongating polymerase, suggesting an overall reduction in polymerase recruitment. Using enhancer RNA (eRNA) expression to measure enhancer activity, we find that LBH589-sensitive eRNAs are preferentially associated with superenhancers and PSN binding sites. These findings suggest that HDAC activity is required to maintain pluripotency by regulating the PSN enhancer network via the recruitment of RNA polymerase II.
Topics: Histones; Transcription Factors; RNA Polymerase II; Nuclear Proteins; Histone Deacetylases; Gene Regulatory Networks; Panobinostat; Histone Acetyltransferases; Acetylation; Histone Deacetylase Inhibitors
PubMed: 38290976
DOI: 10.1101/gr.278050.123