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Health Science Reports Nov 2023Nonsmall cell lung cancer accounts for over 85% of lung cancer incidences worldwide, and often has a poor prognosis. Proteasome inhibitors, such as bortezomib, have...
BACKGROUND AND AIMS
Nonsmall cell lung cancer accounts for over 85% of lung cancer incidences worldwide, and often has a poor prognosis. Proteasome inhibitors, such as bortezomib, have previously demonstrated evidence in preclinical and clinical models in the treatment of NSCLC both alone and as part of chemotherapeutic regimens.
METHODS
Five databases were searched from inception to February 2023 to identify published clinical trial data and ongoing clinical trials on the use of proteasome inhibitors in treatment of NSCLC with a comprehensive search strategy.
RESULTS
This review examines the clinical evidence from 21 completed and published phase I and II trials studying the use of bortezomib monotherapy and combination therapy in the treatment of NSCLC. Bortezomib/docetaxel combination resulted in longer median time-to-progression (TTP), median duration of response, median duration of disease control and median progression-free survival (PFS) than bortezomib monotherapy, with concurrent administration having greater 6-month PFS and median overall survival (OS) than sequential administration. Bortezomib/vorinostat with chemotherapy was well tolerated and effective. Bortezomib/gemcitabine/carboplatin, bortezomib/bevacizumab/carboplatin and bortezomib/paclitaxel/carboplatin combinations showed promising results and were of further investigational value.
CONCLUSION
Bortezomib showed some clinical promise in combination therapy but not monotherapy. It also demonstrated a manageable side effect profile. Combination regimens are of further investigation value in Phase II trials.
PubMed: 38028684
DOI: 10.1002/hsr2.1443 -
BioRxiv : the Preprint Server For... Nov 2023Dravet syndrome (DS) is a severe genetic epilepsy primarily caused by mutations in a voltage-activated sodium channel gene (SCN1A). Patients face life-threatening...
Dravet syndrome (DS) is a severe genetic epilepsy primarily caused by mutations in a voltage-activated sodium channel gene (SCN1A). Patients face life-threatening seizures that are largely resistant to available anti-seizure medications (ASM). Preclinical DS animal models are a valuable tool to identify candidate ASMs for these patients. Among these, mutant zebrafish exhibiting spontaneous seizure-like activity are particularly amenable to large-scale drug screening. Prior screening in a mutant zebrafish line generated using N-ethyl-Nnitrosourea (ENU) identified valproate, stiripentol, and fenfluramine e.g., Federal Drug Administration (FDA) approved drugs with clinical application in the DS population. Successful phenotypic screening in mutant zebrafish consists of two stages: (i) a locomotion-based assay measuring high-velocity convulsive swim behavior and (ii) an electrophysiology-based assay, using local field potential (LFP) recordings, to quantify electrographic seizure-like events. Using this strategy more than 3000 drug candidates have been screened in zebrafish mutants. Here, we curated a list of nine additional anti-seizure drug candidates recently identified in preclinical models: 1-EBIO, AA43279, chlorzoxazone, donepezil, lisuride, mifepristone, pargyline, soticlestat and vorinostat. First-stage locomotion-based assays in mutant zebrafish identified only 1-EBIO, chlorzoxazone and lisuride. However, second-stage LFP recording assays did not show significant suppression of spontaneous electrographic seizure activity for any of the nine anti-seizure drug candidates. Surprisingly, soticlestat induced frank electrographic seizure-like discharges in wild-type control zebrafish. Taken together, our results failed to replicate clear anti-seizure efficacy for these drug candidates highlighting a necessity for strict scientific standards in preclinical identification of ASMs.
PubMed: 38014342
DOI: 10.1101/2023.11.11.566723 -
Clinical and Translational Radiation... Jan 2024Neoadjuvant radiotherapy is successfully used in rectal cancer to improve overall survival. However, treatment response is both unpredictable and variable. There is...
INTRODUCTION
Neoadjuvant radiotherapy is successfully used in rectal cancer to improve overall survival. However, treatment response is both unpredictable and variable. There is strong evidence to show that the phenomenon of tumour hypoxia is associated with radioresistance, however the mechanism(s) behind this are poorly understood. Consequently, there have only been a small number of studies evaluating methods targeting hypoxia-induced radioresistance. The purpose of this systematic review is to evaluate the potential effectiveness of targeting hypoxia-induced radioresistance in rectal cancer and provide recommendations for future research in this area.
METHODS
A comprehensive literature search was performed following the PRISMA guidelines. This study was registered on the Prospero database (CRD42023441983).
RESULTS
Eight articles met the inclusion criteria. All studies identified were or studies, there were no clinical trials. Of the 8 studies identified, 5 assessed the efficacy of drugs which directly or indirectly targeted hypoxia and three that identified potential targets. There was conflicting evidence for the use of metformin to overcome hypoxia induced radioresistance. Vorinostat, atovaquone, and evofosfamide showed promising preclinical evidence that they can overcome hypoxia-induced radioresistance.
DISCUSSION
The importance of investigating hypoxia-induced radioresistance in rectal cancer is crucial. However, to date, only a small number of preclinical studies exist evaluating this phenomenon. This systematic review highlights the importance of further research to fully understand the mechanism behind this radioresistance. There are promising targets identified in this systematic review however, substantially more pre-clinical and clinical research as a priority for future research is needed.
PubMed: 37961749
DOI: 10.1016/j.ctro.2023.100695 -
International Journal of Molecular... Nov 2023CARD9, a scaffolding protein, has been implicated in the pathogenesis of metabolic diseases, including obesity and diabetes. We recently reported novel roles for CARD9...
CARD9, a scaffolding protein, has been implicated in the pathogenesis of metabolic diseases, including obesity and diabetes. We recently reported novel roles for CARD9 in islet β-cell dysregulation under duress of gluco (HG)- and glucolipotoxic (GLT) stress. CARD9 expression was also increased in β-cells following exposure to HG and GLT stress. The current study is aimed at understanding the putative roles of histone deacetylation in HG- and GLT-induced expression of CARD9. Using two structurally distinct inhibitors of histone deacetylases (HDACs), namely trichostatin (TSA) and suberoylanilide hydroxamic acid (SAHA), we provide the first evidence to suggest that the increased expression of CARD9 seen under duress of HG and GLT stress is under the regulatory control of histone deacetylation. Interestingly, the expression of protein kinase Cδ (PKCδ), a known upstream regulator of CARD9 activation, is also increased under conditions of metabolic stress. However, it is resistant to TSA and SAHA, suggesting that it is not regulated via histone deacetylation. Based on these data, we propose that targeting the appropriate HDACs, which mediate the expression (and function) of CARD9, might be the next step to further enhance our current understanding of the roles of CARD9 in islet dysfunction under metabolic stress and diabetes.
Topics: Humans; Histone Deacetylase Inhibitors; Histones; Hydroxamic Acids; Caspase Activation and Recruitment Domain; Vorinostat; Histone Deacetylases; Stress, Physiological; Diabetes Mellitus; CARD Signaling Adaptor Proteins
PubMed: 37958977
DOI: 10.3390/ijms242115994 -
Clinical Cancer Research : An Official... Apr 2024Patients with aggressive thyroid cancer are frequently failed by the central therapy of ablative radioiodide (RAI) uptake, due to reduced plasma membrane (PM)...
PURPOSE
Patients with aggressive thyroid cancer are frequently failed by the central therapy of ablative radioiodide (RAI) uptake, due to reduced plasma membrane (PM) localization of the sodium/iodide symporter (NIS). We aimed to understand how NIS is endocytosed away from the PM of human thyroid cancer cells, and whether this was druggable in vivo.
EXPERIMENTAL DESIGN
Informed by analysis of endocytic gene expression in patients with aggressive thyroid cancer, we used mutagenesis, NanoBiT interaction assays, cell surface biotinylation assays, RAI uptake, and NanoBRET to understand the mechanisms of NIS endocytosis in transformed cell lines and patient-derived human primary thyroid cells. Systemic drug responses were monitored via 99mTc pertechnetate gamma counting and gene expression in BALB/c mice.
RESULTS
We identified an acidic dipeptide within the NIS C-terminus that mediates binding to the σ2 subunit of the Adaptor Protein 2 (AP2) heterotetramer. We discovered that the FDA-approved drug chloroquine (CQ) modulates NIS accumulation at the PM in a functional manner that is AP2 dependent. In vivo, CQ treatment of BALB/c mice significantly enhanced thyroidal uptake of 99mTc pertechnetate in combination with the histone deacetylase (HDAC) inhibitor vorinostat/SAHA, accompanied by increased thyroidal NIS mRNA. Bioinformatic analyses validated the clinical relevance of AP2 genes with disease-free survival in RAI-treated DTC, enabling construction of an AP2 gene-related risk score classifier for predicting recurrence.
CONCLUSIONS
NIS internalization is specifically druggable in vivo. Our data, therefore, provide new translatable potential for improving RAI therapy using FDA-approved drugs in patients with aggressive thyroid cancer. See related commentary by Lechner and Brent, p. 1220.
Topics: Mice; Animals; Humans; Vorinostat; Sodium Pertechnetate Tc 99m; Iodine Radioisotopes; Thyroid Neoplasms; Symporters; Histone Deacetylase Inhibitors; Cell Line, Tumor
PubMed: 37921808
DOI: 10.1158/1078-0432.CCR-23-2043 -
Scientific Reports Oct 2023'Kick and kill' cure strategies aim to induce HIV protein expression in latently infected cells (kick), and thus trigger their elimination by cytolytic T cells (kill)....
'Kick and kill' cure strategies aim to induce HIV protein expression in latently infected cells (kick), and thus trigger their elimination by cytolytic T cells (kill). In the Research in Viral Eradication of HIV Reservoirs trial (NCT02336074), people diagnosed with primary HIV infection received immediate antiretroviral therapy (ART) and were randomised 24 weeks later to either a latency-reversing agent, vorinostat, together with ChAdV63.HIVconsv and MVA.HIVconsv vaccines, or ART alone. This intervention conferred no reduction in HIV-1 reservoir size over ART alone, despite boosting virus-specific CD4+ and CD8+ T cells. The effects of the intervention were examined at the cellular level in the two trial arms using unbiased computational analysis of polyfunctional scores. This showed that the frequency and polyfunctionality of virus-specific CD4+ and CD8+ T cell populations were significantly increased over 12 weeks post-vaccination, compared to the ART-only arm. HIV-specific IL-2-secreting CD8+ T cells also expanded significantly in the intervention arm and were correlated with antiviral activity against heterologous HIV in vitro. Therapeutic vaccination during ART commenced in primary infection can induce functional T cell responses that are phenotypically similar to those of HIV controllers. Analytical therapy interruption may help determine their ability to control HIV in vivo.
Topics: Humans; HIV Infections; HIV-1; Anti-Retroviral Agents; HIV Seropositivity; CD8-Positive T-Lymphocytes; Vaccination; CD4-Positive T-Lymphocytes; Virus Latency
PubMed: 37821472
DOI: 10.1038/s41598-023-42888-3 -
Genomics & Informatics Sep 2023Multiple myeloma (MM) is a hematological malignancy. It is widely believed that genetic factors play a significant role in the development of MM, as investigated in...
Multiple myeloma (MM) is a hematological malignancy. It is widely believed that genetic factors play a significant role in the development of MM, as investigated in numerous studies. However, the application of genomic information for clinical purposes, including diagnostic and prognostic biomarkers, remains largely confined to research. In this study, we utilized genetic information from the Genomic-Driven Clinical Implementation for Multiple Myeloma database, which is dedicated to clinical trial studies on MM. This genetic information was sourced from the genome-wide association studies catalog database. We prioritized genes with the potential to cause MM based on established annotations, as well as biological risk genes for MM, as potential drug target candidates. The DrugBank database was employed to identify drug candidates targeting these genes. Our research led to the discovery of 14 MM biological risk genes and the identification of 10 drugs that target three of these genes. Notably, only one of these 10 drugs, panobinostat, has been approved for use in MM. The two most promising genes, calcium signal-modulating cyclophilin ligand (CAMLG) and histone deacetylase 2 (HDAC2), were targeted by four drugs (cyclosporine, belinostat, vorinostat, and romidepsin), all of which have clinical evidence supporting their use in the treatment of MM. Interestingly, five of the 10 drugs have been approved for other indications than MM, but they may also be effective in treating MM. Therefore, this study aimed to clarify the genomic variants involved in the pathogenesis of MM and highlight the potential benefits of these genomic variants in drug discovery.
PubMed: 37813627
DOI: 10.5808/gi.23011 -
Nature Communications Oct 2023The phenyl ring is a basic structural element in chemistry. Here, we show the design, synthesis, and validation of its new saturated bioisostere with improved...
The phenyl ring is a basic structural element in chemistry. Here, we show the design, synthesis, and validation of its new saturated bioisostere with improved physicochemical properties - 2-oxabicyclo[2.2.2]octane. The design of the structure is based on the analysis of the advantages and disadvantages of the previously used bioisosteres: bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, and cubane. The key synthesis step is the iodocyclization of cyclohexane-containing alkenyl alcohols with molecular iodine in acetonitrile. 2-Oxabicyclo[2.2.2]octane core is incorporated into the structure of Imatinib and Vorinostat (SAHA) drugs instead of the phenyl ring. In Imatinib, such replacement leads to improvement of physicochemical properties: increased water solubility, enhanced metabolic stability, and reduced lipophilicity. In Vorinostat, such replacement results in a new bioactive analog of the drug. This study enhances the repertoire of available saturated bioisosteres of (hetero)aromatic rings for the use in drug discovery projects.
PubMed: 37783681
DOI: 10.1038/s41467-023-41298-3 -
International Journal of Biological... 2023Heat stress, clinically known as hyperthermia, is a promising adjunctive modality in cancer treatment. However, the efficacy of hyperthermia as a monotherapy is limited...
Heat stress, clinically known as hyperthermia, is a promising adjunctive modality in cancer treatment. However, the efficacy of hyperthermia as a monotherapy is limited and the underlying mechanism remains poorly understood. Targeting histone modifications is an emerging strategy for cancer therapy, but little is known regarding the role of heat stress in altering these modifications. Here, we report that heat shock inhibits H3K9 acetylation (H3K9ac) via histone deacetylase 6 (HDAC6) regulation. Heat shock inhibits the interaction between HDAC6 and heat shock protein 90 (HSP90), enhances nuclear localization of HDAC6, and promotes HDAC6 phosphorylation, which is regulated by protein phosphatase 2A (PP2A). Combining hyperthermia with HDAC inhibitors vorinostat or panobinostat leads to better anti-cancer effects compared to monotherapy. and as genes affected by heat-induced inhibition of H3K9ac, and combining them with hyperthermia can better induce apoptosis in tumor cells. This study reveals previously unknown mechanisms of H3K9ac decreased by heat shock in cancer cells and highlights a potential combinational therapy involving hyperthermia and targeting of these new mechanisms.
Topics: Kelch-Like ECH-Associated Protein 1; Histone Deacetylases; Acetylation; Hydroxamic Acids; NF-E2-Related Factor 2; Heat-Shock Response; Hyperthermia, Induced; Neoplasms
PubMed: 37781518
DOI: 10.7150/ijbs.86384 -
RSC Advances Sep 2023Herein, a series of 4-(benzofuran-6-yloxy)quinazoline derivatives as VEGFR-2/HDAC dual inhibitors were designed and synthesized based on fruquintinib and vorinostat....
Herein, a series of 4-(benzofuran-6-yloxy)quinazoline derivatives as VEGFR-2/HDAC dual inhibitors were designed and synthesized based on fruquintinib and vorinostat. Among them, compound 13 exhibited potent inhibitory activity against VEGFR-2 and HDAC1 with IC values of 57.83 nM and 9.82 nM, and displayed moderate to significant antiproliferative activity against MCF-7, A549, HeLa and HUVEC. The cellular mechanism studies revealed that compound 13 arrested the cell cycle at the S and G2 phases, and induced significant apoptosis in HeLa cells. Tube formation assay in HUVECs demonstrated that 13 had a significant anti-angiogenic effect. Additionally, a molecular docking study supported the initial design strategy. These results highlighted that 13 was a valuable VEGFR-2/HDAC dual inhibitor and deserved further study for cancer therapy.
PubMed: 37771923
DOI: 10.1039/d3ra05542f