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Antiviral Research Oct 2018While combination antiretroviral therapy (cART) has successfully converted HIV to a chronic but manageable infection in many parts of the world, HIV continues to persist... (Review)
Review
While combination antiretroviral therapy (cART) has successfully converted HIV to a chronic but manageable infection in many parts of the world, HIV continues to persist within latent cellular reservoirs, which can become reactivated at any time to produce infectious virus. New therapies are therefore needed not only for HIV suppression but also for containing or eliminating HIV reservoirs. Compounds derived from plant, marine, and other natural products have been found to combat HIV infection and/or target HIV reservoirs, and these discoveries have substantially guided current HIV therapy-based studies. Here we summarize the role of natural product-derived compounds in current HIV suppression, remission, and cure strategies.
Topics: Anti-HIV Agents; Biological Products; Bryostatins; Depsipeptides; Disease Reservoirs; Diterpenes; Drug Discovery; Gene Products, tat; HIV Infections; HIV-1; Histone Deacetylase Inhibitors; Humans; Phorbol Esters; Virus Latency; Vorinostat; rev Gene Products, Human Immunodeficiency Virus
PubMed: 30063970
DOI: 10.1016/j.antiviral.2018.07.016 -
Journal of Inorganic Biochemistry May 2020Vorinostat (suberoylanilide hydroxamic acid; SAHA) and Belinostat are two hydroxamate-based histone deacetylase inhibitors that are used clinically as potent anti-cancer...
Vorinostat (suberoylanilide hydroxamic acid; SAHA) and Belinostat are two hydroxamate-based histone deacetylase inhibitors that are used clinically as potent anti-cancer agents. Their metabolic breakdown into inactive metabolites such as carboxylic acid and glucuronic derivatives results in them having short half-lives, which can negatively impact their pharmacokinetic profiles. Herein we report the potential of both Vorinostat and Belinostat to also act as nitric oxide donors under both chemical and biological ex vivo experimental conditions. More specifically, using ruthenium(III) as an effective NO scavenger, we were able to establish, in the first instance, that both Vorinostat and Belinostat had the capacity to release NO under chemical conditions. Both Vorinostat and Belinostat were then shown to cause vascular relaxation of rat aorta via NO-mediated activation of the haem-containing guanylate cyclase enzyme. A summary of our findings is reported herein.
Topics: Animals; Antineoplastic Agents; Aorta; Guanylate Cyclase; Hydroxamic Acids; Nitric Oxide Donors; Rats; Ruthenium; Sulfonamides; Vasodilation; Vasodilator Agents; Vorinostat
PubMed: 32088592
DOI: 10.1016/j.jinorgbio.2019.110981 -
Cancer Medicine Jan 2018Oxaliplatin-based systemic chemotherapy has been proposed to have efficacy in hepatocellular carcinoma (HCC). We investigated the combination of vorinostat and...
Oxaliplatin-based systemic chemotherapy has been proposed to have efficacy in hepatocellular carcinoma (HCC). We investigated the combination of vorinostat and oxaliplatin for possible synergism in HCC cells. SMMC7721, BEL7402, and HepG2 cells were treated with vorinostat and oxaliplatin. Cytotoxicity assay, tumorigenicity assay in vitro, cell cycle analysis, apoptosis analysis, western blot analysis, animal model study, immunohistochemistry, and quantitative PCR were performed. We found that vorinostat and oxaliplatin inhibited the proliferation of SMMC7721, BEL7402, and HepG2 cells. The combination index (CI) values were all <1, and the dose-reduction index values were all greater than 1 in the three cell lines, indicating a synergistic effect of combination of the two agents. Coadministration of vorinostat and oxaliplatin induced G2/M phase arrest, triggered caspase-dependent apoptosis, and decreased tumorigenicity both in vitro and in vivo. Vorinostat suppressed the expression of BRCA1 induced by oxaliplatin. In conclusion, cotreatment with vorinostat and oxaliplatin exhibited synergism in HCC cells. The combination inhibited cell proliferation and tumorigenicity both in vitro and in vivo through induction of cell cycle arrest and apoptosis. Our results predict that a combination of vorinostat and oxaliplatin may be useful in the treatment of advanced HCC.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinogenesis; Carcinoma, Hepatocellular; Cell Cycle Checkpoints; Cell Proliferation; Drug Synergism; Hep G2 Cells; Humans; Liver Neoplasms; Mice; Oxaliplatin; Treatment Outcome; Vorinostat; Xenograft Model Antitumor Assays
PubMed: 29239146
DOI: 10.1002/cam4.1278 -
Head & Neck Feb 2023Associations between peripheral blood biomarkers and oncologic outcomes were explored in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HN) and...
Neutrophil to lymphocyte ratio and peripheral blood biomarkers correlate with survival outcomes but not response among head and neck and salivary cancer treated with pembrolizumab and vorinostat.
BACKGROUND
Associations between peripheral blood biomarkers and oncologic outcomes were explored in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HN) and salivary gland cancer (SGC) treated with pembrolizumab and vorinostat on a phase II trial (NCT02538510).
EXPERIMENTAL DESIGN
Twenty-five HN and 25 SGCs were treated with pembrolizumab and vorinostat. Baseline peripheral blood was available in 21 HN and 20 SGCs and evaluated for associations with grade ≥3 adverse events (G ≥ 3AE) by CTCAEv4, objective response rate (ORR), overall survival (OS), and progression-free survival (PFS).
RESULTS
Higher pretreatment neutrophil-to-lymphocyte ratio (NLR) and neutrophils, as well as lower pretreatment lymphocytes and T helper cells correlated with worse OS and PFS. Higher NLR further predicted increased rates of G ≥ 3AEs. No correlations with ORR were observed.
CONCLUSIONS
In a prospectively evaluated cohort of HN and SGCs treated with pembrolizumab and vorinostat, we observed novel associations between peripheral blood biomarkers and oncologic outcomes and toxicities.
Topics: Humans; Biomarkers; Head and Neck Neoplasms; Lymphocytes; Neoplasm Recurrence, Local; Neutrophils; Prognosis; Squamous Cell Carcinoma of Head and Neck; Vorinostat
PubMed: 36412064
DOI: 10.1002/hed.27252 -
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 -
International Journal of Molecular... Apr 2023Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL) and is characterized by epidermotrophism of malignant CD4+ T-lymphocytes. When MF...
Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL) and is characterized by epidermotrophism of malignant CD4+ T-lymphocytes. When MF advances to a recurrent stage, patients require treatment with systemic therapies such as vorinostat, a histone deacetylase inhibitor. While vorinostat has been shown to exhibit anti-tumor activity in MF, its exact molecular mechanism has yet to be fully discerned. In the present study, we examined the transcriptomic and proteomic profiles of vorinostat treatment in two MF cell lines, Myla 2059 and HH. We find that vorinostat downregulates CTLA-4, CXCR4, and CCR7 in both cell lines, but its effect on several key pathways differs between the two MF cell lines. For example, vorinostat upregulates CCL5, CCR5, and CXCL10 expression in Myla cells but downregulates CCL5 and CXCL10 expression in HH cells. Furthermore, vorinostat upregulates IFN-γ and IL-23 signaling and downregulates IL-6, IL-7, and IL-15 signaling in Myla cells but does not affect these pathways in HH cells. Although Myla and HH represent established MF cell lines, their distinct tumor origin from separate patients demonstrates that inherent phenotypic variations within the disease persist, underscoring the importance of using a variety of MF cells in the preclinical development of MF therapeutics.
Topics: Humans; Vorinostat; Proteomics; Mycosis Fungoides; Lymphoma, T-Cell, Cutaneous; Skin Neoplasms
PubMed: 37175780
DOI: 10.3390/ijms24098075 -
Current Topics in Medicinal Chemistry 2023Quantitative Structure-activity Relationship (QSAR) studies gained a foothold in the mid-1960s to rationalise the biological activity of medicinally important compounds.... (Review)
Review
Quantitative Structure-activity Relationship (QSAR) studies gained a foothold in the mid-1960s to rationalise the biological activity of medicinally important compounds. Since then, the advancements in computer hardware and software added many new techniques and areas to this field of study. Molecular dynamics (MD) simulations are one such technique in direct drug design approaches. MD simulations have a special place in drug design studies because they decode the dynamics of intermolecular interactions between a biological target and its potential ligands/inhibitors. The trajectories from MD simulations provide different non-bonding interaction parameters to assess the compatibility of the protein-ligand complex and thereby facilitate the design of prospective compounds prior to their wet-lab exploration. Histone deacetylases (HDACs) play a key role in epigenetics and they are promising drug targets for cancer and various other diseases. This review attempts to shed some light on the modelling studies of HDAC inhibitors as anticancer agents. In view of the advantages of MD simulations in direct drug design, this review also discusses the fragment-based approach in designing new inhibitors of HDAC8 and HDAC2, starting from the interaction energies of ligand fragments obtained from the MD simulations of respective protein-ligand complexes. Here, the design of new anticancer compounds from largazole thiol, trichostatin A, vorinostat, and several other prototype compounds are reviewed. These studies may stimulate the interest of medicinal chemists in MD simulations as a direct drug design approach for new drug development.
Topics: Molecular Dynamics Simulation; Ligands; Prospective Studies; Vorinostat; Histone Deacetylases; Histone Deacetylase Inhibitors; Quantitative Structure-Activity Relationship; Drug Design; Molecular Docking Simulation
PubMed: 37779411
DOI: 10.2174/0115680266250924230920042845 -
BMC Microbiology Feb 2020Invasive aspergillosis is a fungal infection that occurs mainly in immunocompromised patients. It is responsible for a high degree of mortality and is invariably...
BACKGROUND
Invasive aspergillosis is a fungal infection that occurs mainly in immunocompromised patients. It is responsible for a high degree of mortality and is invariably unresponsive to conventional antifungal treatments. Histone deacetylase inhibitors can affect the cell cycle, apoptosis and differentiation. The histone deacetylase inhibitor vorinostat (SAHA) has recently received approval for the treatment of cutaneous T cell lymphoma. Here, we investigated the interactions of SAHA and itraconazole, voriconazole, and posaconazole against Aspergillus spp. in vitro using both planktonic cells and biofilms.
RESULTS
We investigated 20 clinical strains using broth microdilution checkerboard methods. The results showed synergy between SAHA and itraconazole, voriconazole, and posaconazole against 60, 40, and 25% of tested isolates of planktonic Aspergillus spp., respectively. Similar synergy was also observed against Aspergillus biofilms. The expression of the azole-associated multidrug efflux pumps MDR1, MDR2, MDR3 and MDR4, as well as that of HSP90, was measured by RT-PCR. The results indicated that the molecular mechanism of the observed synergistic effects in Aspergillus fumigatus may be partly associated with dampened expression of the efflux pump genes and, furthermore, that HSP90 suppression may be a major contributor to the observed synergistic effects of the drugs.
CONCLUSIONS
SAHA has potential as a secondary treatment to enhance the effects of azoles against both biofilm and planktonic cells of Aspergillus spp. in vitro. This effect occurs mostly by inhibition of HSP90 expression.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Aspergillus; Azoles; Biofilms; Drug Synergism; Gene Expression Regulation; HSP90 Heat-Shock Proteins; Itraconazole; Microbial Sensitivity Tests; Plankton; Triazoles; Voriconazole; Vorinostat; ATP-Binding Cassette Sub-Family B Member 4
PubMed: 32028887
DOI: 10.1186/s12866-020-1718-x -
Cell Cycle (Georgetown, Tex.) Jun 2022We examined the apoptotic response of two glioblastoma cells, p53 wild type U87 and p53 mutated T98G, to doxorubicin, bortezomib, and vorinostat, which respectively...
We examined the apoptotic response of two glioblastoma cells, p53 wild type U87 and p53 mutated T98G, to doxorubicin, bortezomib, and vorinostat, which respectively target DNA, 26S proteasome and histone deacetylase, to clarify p53's function in apoptosis. We demonstrated that doxorubicin induced apoptosis in U87 cells but not in T98G cells. The level of p53 was definitively correlated to the extent of DNA damage and apoptosis initiation. Dominant-negative p53 reduced p21 expression, but did not affect doxorubicin-induced apoptosis, so the transcriptional activity of p53 seemed not to participate in doxorubicin-induced apoptosis. However, p53 concentrated into the nucleus during heavy apoptosis. Bortezomib could induce apoptosis in U87 with high sensitivity and T98G cells with low sensitivity. In contrast, vorinostat promoted apoptosis in both U87 and T98G cells and reduced the basal level of p53 in U87 cells, indicating that p53 played no role in the vorinostat-induced apoptosis. To clearly define the role of p53 in bortezomib- and doxorubicin-induced apoptosis, we combined doxorubicin with bortezomib to treat U87 cells to assess this combination's effect on apoptosis and p53 status. Interestingly, the combination of doxorubicin with bortezomib engendered compound stress, resulting in a synergistic outcome for apoptosis in U87 cells. However, the amounts of p53 in the total count and in the nucleus were much lower with the combination than with doxorubicin alone, suggesting that p53 played no role in either the compound stress, doxorubicin-only or bortezomib-induced apoptosis.
Topics: Apoptosis; Bortezomib; Cell Line, Tumor; Doxorubicin; Glioblastoma; Humans; Tumor Suppressor Protein p53; Vorinostat
PubMed: 35311459
DOI: 10.1080/15384101.2022.2041954 -
Bioorganic Chemistry Oct 2021Reviewed herein are key research accomplishments of Professor Ronald Charles D. Breslow (1931-2017) throughout his more than 60 year research career. These... (Review)
Review
Reviewed herein are key research accomplishments of Professor Ronald Charles D. Breslow (1931-2017) throughout his more than 60 year research career. These accomplishments span a wide range of topics, most notably physical organic chemistry, medicinal chemistry, and bioorganic chemistry. These topics are reviewed, as are topics of molecular electronics and origin of chirality, which combine to make up the bulk of this review. Also reviewed briefly are Breslow's contributions to the broader chemistry profession, including his work for the American Chemical Society and his work promoting gender equity. Throughout the article, efforts are made to put Breslow's accomplishments in the context of other work being done at the time, as well as to include subsequent iterations and elaborations of the research.
Topics: Amino Acids; Catalysis; Chemistry, Pharmaceutical; Cyclodextrins; History, 20th Century; Humans; Stereoisomerism; Thiamine; Vorinostat
PubMed: 34523507
DOI: 10.1016/j.bioorg.2021.104868