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Triple-negative breast cancer (TNBC) is considered the most aggressive form of breast cancer owing to the negative expression of targetable bioreceptors. Epithelial to mesenchymal transition (EMT) associated with metastatic abilities is its critical feature. As an attempt to target TNBC, nanotechnology was utilised to augment the effects of drug repurposing. Concerning that, a combination therapeutic module was structured with one of the aspects being a repurposed antihistamine, promethazine hydrochloride loaded PLGA nanoparticles. The as-synthesized nanoparticles were 217 nm in size and fluoresced at 522 nm, rendering them suitable for theranostic applications too. The second feature of the module was a common histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), used as a form of pre-treatment. Experimental studies demonstrated efficient cellular internalisation and significant innate anti-proliferative potential. The use of SAHA sensitised the cells to the drug loaded nanoparticle treatment. Mechanistic studies showed increase in ROS generation, mitochondrial dysfunction followed by apoptosis. Investigations into protein expression also revealed reduction of mesenchymal proteins like vimentin by 1.90 fold; while increase in epithelial marker like E-Cadherin by 1.42 fold, thus indicating an altered EMT dynamics. Further findings also provided better insight into the benefits of SAHA potentiated targeting of tumor spheroids that mimic solid tumors of TNBC. Thus, this study paves the avenue to a more rational translational validation of combining nanotherapeutics with drug repurposing. [ABSTRACT FROM AUTHOR]

Chimeric Antigen Receptor (CAR) T‐cell therapy is a promising cancer treatment method. However, its application in bladder cancer (BC) remains limited, partially because of the absence of appropriate target molecules. Sialylated cancer‐derived IgG (SIA‐CIgG) is highly expressed in BC and is closely associated with malignant biological behavior. However, its potential as a target for CAR‐T cell therapy to treat BC is yet to be established. Here, it is found that SIA‐CIgG is highly expressed in most BC samples but displayed limited expression in normal tissues. CAR‐T cells specifically targeting SIA‐CIgG can effectively lyse BC cells and the cytotoxicity depends on SIA‐CIgG expression. Furthermore, SIA‐CIgG CAR‐T cells demonstrate milder tumor cell lysis and enhanced persistence compared with human epidermal growth factor receptor 2 (HER2) CAR‐T cells, which have undergone extensive clinical trials. After repeated tumor antigen challenges, SIA‐CIgG CAR‐T cells display substantial alterations in both the transcriptome and chromatin accessibility. When combining SIA‐CIgG CAR‐T cell therapy with FDA‐approved drugs to treat BC, the histone deacetylase inhibitor (HDACi), vorinostat, is found to enhance the ablility of CAR‐T cells for tumor cell lysis. Therefore, the combination of SIA‐CIgG CAR‐T cells and vorinostat is promising for BC treatment. [ABSTRACT FROM AUTHOR]

The clinical use of many potent anticancer agents is limited by their non‐selective toxicity to healthy tissue. One of these examples is vorinostat (SAHA), a pan histone deacetylase inhibitor, which shows high cytotoxicity with limited discrimination for cancerous over healthy cells. In an attempt to improve tumor selectivity, we exploited the properties of cobalt(III) as a redox‐active metal center through stabilization with cyclen and cyclam tetraazamacrocycles, masking the anticancer activity of SAHA and other hydroxamic acid derivatives to allow for the complex to reach the hypoxic microenvironment of the tumor. Biological assays demonstrated the desired low in vitro anticancer activity of the complexes, suggesting effective masking of the activity of SAHA. Once in the tumor, the bioactive moiety may be released through the reduction of the CoIII center. Investigations revealed long‐term stability of the complexes, with cyclic voltammetry and chemical reduction experiments supporting the design hypothesis of SAHA release through the reduction of the CoIII prodrug. The results highlight the potential for further developing this complex class as novel anticancer agents by masking the high cytotoxicity of a given drug, however, the cellular uptake needs to be improved. [ABSTRACT FROM AUTHOR]

Histone deacetylase inhibitors (HDACi) show high antineoplastic potential in preclinical studies in various solid tumors, including gastric carcinoma; however, their use in clinical studies has not yet yielded convincing efficacies. Thus, further studies on cellular/molecular effects of HDACi are needed, for improving clinical efficacy and identifying suitable combination partners. Here, we investigated the role of oxidative stress in gastric cancer cells upon treatment with HDACi. A particular focus was laid on the role of the Nrf2 pathway, which can mediate resistance to cell-inhibitory effects of reactive oxidative species (ROS). Using fluorescence-based ROS sensors, oxidative stress was measured in human gastric cancer cell lines. Activation of the Nrf2 pathway was monitored in luciferase reporter assays as well as by mRNA and proteomic expression analyses of Nrf2 regulators and Nrf2-induced genes. Furthermore, the effects of ROS scavenger N-acetyl-L-cysteine (NAC) and Nrf2-knockdown on HDACi-dependent antiproliferative effects were investigated in colorimetric formazan-based and clonogenic survival assays. HDACi treatment led to increased oxidative stress levels and consequently, treatment with NAC reduced cytotoxicity of HDACi. In addition, vorinostat treatment stimulated expression of a luciferase reporter under the control of an antioxidative response element, indicating activation of the Nrf2 system. This Nrf2 activation was only partially reversible by treatment with NAC, suggesting ROS independent pathways to contribute to HDACi-promoted Nrf2 activation. In line with its cytoprotective role, Nrf2 knockdown led to a sensitization against HDACi. Accordingly, the expression of antioxidant and detoxifying Nrf2 target genes was upregulated upon HDACi treatment. In conclusion, oxidative stress induction upon HDAC inhibition contributes to the antitumor effects of HDAC inhibitors, and activation of Nrf2 represents a potentially important adaptive response of gastric cancer cells in this context. [ABSTRACT FROM AUTHOR]

Purpose: To develop new histone deacetylase (HDAC) inhibitors with thiadiazole moiety as a zinc-binding group. Methods: Maestro software was utilized to design new HDAC inhibitors. The organic synthesis of compounds VIa-VIc was started with the Williamson reaction between benzylic halide derivatives and methyl 4-hydroxybenzoate to form ethers IIIa-IIIb. The resultant ethers were subjected to ester hydrolysis, followed by an amide reaction with 1,2,4-thiadiazol-5-amine to produce the final compound VIa-VIc. The structures of synthesized compounds were characterized using NMR and FTIR spectroscopic techniques. Anti-proliferative activity on colon cancer cells (HRT) was evaluated using MTT assay. Results: Docking study revealed that compounds VIa-VIc had in silico binding affinity for HDAC enzymes, while MTT assay showed that the IC50 values of VIa and VIc (1.00 and 1.44 µM, respectively) were comparable to IC50 of 3.00 µM for the reference compound, vorinostat used in this study. Conclusion: New potential HDAC inhibitors with a thiadiazole moiety as a possible zinc-binding group have been successfully designed, synthesized and characterized. Results from preliminary cytotoxicity evaluation were highly promising. These findings may be useful for developing novel therapeutic agents. [ABSTRACT FROM AUTHOR]

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(1) Background: Niemann–Pick type C1 (NP-C1) is a lysosomal storage disorder that results in the defective trafficking of cholesterol and other cellular lipids in the endosomal–lysosomal pathway. This rare autosomal recessive disorder presents in three forms based on the age of onset. The adult form presents in patients greater than 15 years of age but is rarely seen after the age of 30. Common symptoms of the late adult-onset category of NP-C1 include progressive cognitive impairment and ataxia, with psychiatric and movement disorders presenting less frequently than in other forms of NP-C1. Dystonic movement disorders present most frequently, along with chorea, myoclonus, and parkinsonism. Herein, we present a rare case of NP-C1, diagnosed at age 35 with an initial symptom of supranuclear palsy. The goal of the presented case is to highlight the importance of the neurological examination and an inclusive differential diagnosis in patients with new-onset supranuclear palsy. (2) Methods: A single case report. (3) Results: A 46-year-old male with a past medical history of NP-C1 was admitted to the hospital for respiratory distress. He was noted to have a supranuclear gaze palsy with partially preserved voluntary saccades to the right. His mother revealed that he first had difficulty moving his eyes at the age of 34. After multiple consultations and genetic testing one year later, he was diagnosed with NP-C1. (4) Conclusions: Because NP-C1 affects many regions of the brain responsible for eye movements, neurological eye assessments can be a useful tool in diagnoses. Furthermore, eye movement abnormalities may be the initial presenting symptom of NP-C1, predisposing patients to misdiagnosis with progressive supranuclear palsy and other conditions that may mimic early-stage NP-C1. Definitive diagnosis is achieved through genetic testing. Filipin staining test was the gold standard in the past. The NP-C Suspicion Index was developed to assist in diagnoses, but its efficacy is unclear with late adult-onset NP-C1. Although no cure exists, early identification can facilitate an improved symptom management course for patients. Miglustat, a glucosylceramide synthase (GCS) inhibitor, is the approved therapy in Europe specific to NP-C1 for slowing and preventing the neurological manifestations of NP-C1. Delays between symptom onset and treatment initiation are likely to result in poorer outcomes and a progression of neurological symptoms. High doses may present tolerance concerns, especially in cases of delayed treatment and advanced neurological deficit. [ABSTRACT FROM AUTHOR]

Abstract Chimeric Antigen Receptor (CAR) T‐cell therapy is a promising cancer treatment method. However, its application in bladder cancer (BC) remains limited, partially because of the absence of appropriate target molecules. Sialylated cancer‐derived IgG (SIA‐CIgG) is highly expressed in BC and is closely associated with malignant biological behavior. However, its potential as a target for CAR‐T cell therapy to treat BC is yet to be established. Here, it is found that SIA‐CIgG is highly expressed in most BC samples but displayed limited expression in normal tissues. CAR‐T cells specifically targeting SIA‐CIgG can effectively lyse BC cells and the cytotoxicity depends on SIA‐CIgG expression. Furthermore, SIA‐CIgG CAR‐T cells demonstrate milder tumor cell lysis and enhanced persistence compared with human epidermal growth factor receptor 2 (HER2) CAR‐T cells, which have undergone extensive clinical trials. After repeated tumor antigen challenges, SIA‐CIgG CAR‐T cells display substantial alterations in both the transcriptome and chromatin accessibility. When combining SIA‐CIgG CAR‐T cell therapy with FDA‐approved drugs to treat BC, the histone deacetylase inhibitor (HDACi), vorinostat, is found to enhance the ablility of CAR‐T cells for tumor cell lysis. Therefore, the combination of SIA‐CIgG CAR‐T cells and vorinostat is promising for BC treatment.