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Journal of Nuclear Medicine : Official... Jun 2023α-particle emitters have recently been explored as valuable therapeutic radionuclides. Yet, toxicity to healthy organs and cancer radioresistance limit the efficacy of...
Signaling Network Response to α-Particle-Targeted Therapy with the Ac-Labeled Minigastrin Analog Ac-PP-F11N Reveals the Radiosensitizing Potential of Histone Deacetylase Inhibitors.
α-particle emitters have recently been explored as valuable therapeutic radionuclides. Yet, toxicity to healthy organs and cancer radioresistance limit the efficacy of targeted α-particle therapy (TAT). Identification of the radiation-activated mechanisms that drive cancer cell survival provides opportunities to develop new points for therapeutic interference to improve the efficacy and safety of TAT. Quantitative phosphoproteomics and matching proteomics followed by the bioinformatics analysis were used to identify alterations in the signaling networks in response to TAT with the Ac-labeled minigastrin analog Ac-PP-F11N (DOTA-(dGlu)-Ala-Tyr-Gly-Trp-Nle-Asp-Phe) in A431 cells, which overexpress cholecystokinin B receptor (CCKBR). Western blot analysis and microscopy verified the activation of the selected signaling pathways. Small-molecule inhibitors were used to validate the potential of the radiosensitizing combinatory treatments both in vitro and in A431/CCKBR tumor-bearing nude mice. TAT-induced alterations were involved in DNA damage response, cell cycle regulation, and signal transduction, as well as RNA transcription and processing, cell morphology, and transport. Western blot analysis and microscopy confirmed increased phosphorylations of the key proteins involved in DNA damage response and carcinogenesis, including p53, p53 binding protein 1 (p53BP1), histone deacetylases (HDACs), and H2AX. Inhibition of HDAC class II, ataxia-telangiectasia mutated (ATM), and p38 kinases by TMP269, AZD1390, and SB202190, respectively, sensitized A431/CCKBR cells to Ac-PP-F11N. As compared with the control and monotherapies, the combination of Ac-PP-F11N with the HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) significantly reduced the viability and increased the DNA damage of A431/CCKBR cells, led to the most pronounced tumor growth inhibition, and extended the mean survival of A431/CCKBR xenografted nude mice. Our study revealed the cellular responses to TAT and demonstrated the radiosensitizing potential of HDAC inhibitors to Ac-PP-F11N in CCKBR-positive tumors. This proof-of-concept study recommends development of novel radiosensitizing strategies by targeting TAT-activated and survival-promoting signaling pathways.
Topics: Animals; Mice; Histone Deacetylase Inhibitors; Mice, Nude; Tumor Suppressor Protein p53; Cell Line, Tumor; Vorinostat; Signal Transduction; Hydroxamic Acids
PubMed: 36732057
DOI: 10.2967/jnumed.122.264597 -
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 -
Research in Pharmaceutical Sciences Jun 2021In mammalian cells, several distinct surveillance systems, named cell cycle checkpoints, can interrupt normal cell-cycle progression. The cyclin-dependent kinases are...
BACKGROUND AND PURPOSE
In mammalian cells, several distinct surveillance systems, named cell cycle checkpoints, can interrupt normal cell-cycle progression. The cyclin-dependent kinases are negatively regulated by proteins of cyclin-dependent kinases inhibitors comprising INK4 and Cip/Kip families. Histone deacetylation induced by histone deacetylases (HDACs) inactivates the INK4 and Cip/Kip families lead to cancer induction. HDAC inhibitors (HDACIs) have been indicated to be potent inducers of differentiation, growth arrest, and apoptotic induction. Vorinostat (suberoylanilide hydroxamic acid, SAHA), as an HDACI, is reported to be useful in various cancers. Previously, we reported the effect of trichostatin A on hepatocellular carcinoma and also vorinostat on colon cancer cell lines. The current study was aimed to investigate the effect of vorinostat on p16INK4a, p14ARF, p15INK4b, and class I HDACs 1, 2, and 3 gene expression, cell growth inhibition, and apoptosis induction in pancreatic cancer AsPC-1 and hepatocellular carcinoma LCL-PI 11 cell lines.
EXPERIMENTAL APPROACH
The AsPC-1 and LCL-PI 11 cell lines were cultured and treated with vorinostat. To determine, viability, apoptosis, and the relative expression level of p16INK4a, p14ARF, p15INK4b, class I HDACs 1, 2, and 3 genes, MTT assay, cell apoptosis assay, and RT-qPCR were performed, respectively.
FINDINGS/RESULTS
Vorinostat significantly inhibited cell growth, induced apoptosis, increased p16INK4a, p14ARF, p15INK4b, and decreased class I HDACs 1, 2, and 3 gene expression.
CONCLUSION AND IMPLICATIONS
Vorinostat can reactivate the INK4 family through inhibition of class I HDACs 1, 2, and 3 genes activity.
PubMed: 34221059
DOI: 10.4103/1735-5362.314824 -
Canadian Respiratory Journal 2020This study aims to explore the role of erythromycin-regulated histone deacetylase-2 in benign tracheal stenosis.
OBJECTIVE
This study aims to explore the role of erythromycin-regulated histone deacetylase-2 in benign tracheal stenosis.
METHODS
The rabbit model of tracheal stenosis was established. The rabbits were randomly divided into 8 groups. Histone deacetylase-2 (HDAC2) expression was detected by immunofluorescence. The expression of type I collagen and type III collagen was detected by immunohistochemical method. The expression of TGF-1, VEGF and IL-8 in serum and alveolar lavage fluid was detected by ELISA. The expression of HDAC2, TGF-1, VEGF and IL-8 in serum and alveolar lavage fluid was detected by ELISA. The expression of HDAC2, TGF.
RESULTS
In Erythromycin (ERY) group, ERY + Budesonide group, ERY + Vorinostat group and ERY + Budesonide + Vorinostat group, the degree of bronchial stenosis was alleviated, and the mucosal epithelium was still slightly proliferated. The effect of ERY combined with other drugs was more obvious. The HDAC2 protein expression increased significantly in ERY group, ERY + Budesonide group and ERY + Budesonide + Vorinostat group and decreased significantly in Vorinostat group, the expression of collagen I and III decreased significantly in ERY group, ERY + Budesonide group and ERY + Budesonide + Vorinostat group ( < 0.05). The TGF-1, VEGF and IL-8 in serum and alveolar lavage fluid was detected by ELISA. The expression of HDAC2, TGF- < 0.05). The TGF.
CONCLUSIONS
Erythromycin inhibited inflammation and excessive proliferation of granulation tissue after tracheobronchial mucosal injury by up-regulating the expression of HDAC2, it promoted wound healing and alleviated tracheobronchial stenosis. When combined with budesonide, penicillin and other glucocorticoids and antibiotics, it had a good synergistic effect. However, vorinostat could attenuate erythromycin's effect by down-regulating the expression of HDAC2. It may have good clinical application prospects in the treatment of tracheal stenosis.
Topics: Animals; Bronchoalveolar Lavage Fluid; Budesonide; Erythromycin; Glucocorticoids; Granulation Tissue; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Immunohistochemistry; Protein Synthesis Inhibitors; Rabbits; Respiratory Mucosa; Tracheal Stenosis; Transforming Growth Factor beta1; Treatment Outcome; Up-Regulation; Vorinostat
PubMed: 32051729
DOI: 10.1155/2020/4213807 -
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 -
Current Research in Translational... 2023Cutaneous T cell lymphomas (CTCLs) are a heterogenous group of skin-involved T-cell non-Hodgkin lymphoma which Mycosis Fungoides and Sezary Syndrome are the most common... (Review)
Review
Cutaneous T cell lymphomas (CTCLs) are a heterogenous group of skin-involved T-cell non-Hodgkin lymphoma which Mycosis Fungoides and Sezary Syndrome are the most common variants. Despite considerable progress in distinguishing the pathophysiology, the treatment options are still limited for advanced-stage disease. Recent approval of novel agents such as vorinostat, brentuximab vedotin and mogamulizumab paved a way. Allogeneic hematopoietic stem cell transplantation has been shown to be a feasible option in selected advanced-stage CTCL patients. Chimeric antigen receptor (CAR) T cells have been promising for the treatment of B-cell tumors and have been approved for second-line treatment in non-Hodgkin's lymphoma. Although several obstacles still need to be addressed, CAR T cell treatment for CTCLs seems not far off. This review discusses new discoveries in pathophysiology, the state of cellular therapies in current practice, challenges for cellular treatment in advanced CTCL, and how to overcome these challenges.
Topics: Humans; Skin Neoplasms; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides; Sezary Syndrome; Vorinostat
PubMed: 37062252
DOI: 10.1016/j.retram.2023.103390 -
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 -
Biomedicines Jan 2020Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and... (Review)
Review
Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and enzalutamide. Histone deacetylase (HDAC) inhibitors showed promising results in hematological malignancies, but they failed in solid tumors such as prostate cancer, despite the overexpression of HDACs in CRPC. Four HDAC inhibitors, vorinostat, pracinostat, panobinostat and romidepsin, underwent phase II clinical trials for prostate cancers; however, phase III trials were not recommended due to a majority of patients exhibiting either toxicity or disease progression. In this review, the pharmacodynamic reasons for the failure of HDAC inhibitors were assessed and placed in the context of the advancements in the understanding of CRPCs, HDACs and resistance mechanisms. The review focuses on three themes: evolution of androgen receptor-negative prostate cancers, development of resistance mechanisms and differential effects of HDACs. In conclusion, advancements can be made in this field by characterizing HDACs in prostate tumors more extensively, as this will allow more specific drugs catering to the specific HDAC subtypes to be designed.
PubMed: 32019149
DOI: 10.3390/biomedicines8020022 -
Medical Oncology (Northwood, London,... Jul 2022Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. TNBC lacks targeted therapy receptors, rendering endocrine and...
BACKGROUND
Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. TNBC lacks targeted therapy receptors, rendering endocrine and HER2-targeted therapies ineffective. TNBC is typically treated with cytotoxic chemotherapy followed by surgery. Targeting epigenetic modifications could potentially be a new effective TNBC target therapy. The aim of this study is to examine the effects of epigenetic drugs, decitabine as DNA methyltransferase inhibitor (DNMTI) and vorinostat as histone deacetylase inhibitor (HDACI), and the ERβ agonist DPN on ERα and ERβ re-expressions in the MDA-MB-231 cells as a model of TNBC.
METHODS
Using MTT assay, the IC of decitabine, vorinostat, and DPN on MDA-MB-231 cells were determined. The effects of all drugs alone or in combinations on MDA-MB-231 cells were evaluated. qRT-PCR was used to determine ERα & ERβ gene expression. Caspase-3 activity and the protein expression levels of VEGF, Cyclin D1, and IGF-1 were assessed.
RESULTS
Both ERα and ERβ mRNA were re-expressed in different high levels in all treated groups, especially in the triple therapy group compared with control. Significantly, the triple drugs therapy showed the lowest levels of VEGF, Cyclin D1, and IGF-1 and the highest level of Caspase-3 activity, indicating a possible antitumor effect of ERβ activation through decreasing proliferation and angiogenesis and increasing apoptosis in MDA-MB-231 cells.
CONCLUSIONS
The antiproliferative effect of ERβ could be retained when co-expressed with Erα using a powerful epigenetic combination of Decitabine and vorinostat with DPN.
Topics: Humans; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Decitabine; Epigenesis, Genetic; Estrogen Receptor alpha; Estrogen Receptor beta; Insulin-Like Growth Factor I; Nitriles; Propionates; Triple Negative Breast Neoplasms; Vascular Endothelial Growth Factor A; Vorinostat
PubMed: 35843988
DOI: 10.1007/s12032-022-01765-1