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Journal of Nanobiotechnology Apr 2024Vasculogenic mimicry (VM), when microvascular channels are formed by cancer cells independent of endothelial cells, often occurs in deep hypoxic areas of tumors and...
LIFU/MMP-2 dual-responsive release of repurposed drug disulfiram from nanodroplets for inhibiting vasculogenic mimicry and lung metastasis in triple-negative breast cancer.
BACKGROUND
Vasculogenic mimicry (VM), when microvascular channels are formed by cancer cells independent of endothelial cells, often occurs in deep hypoxic areas of tumors and contributes to the aggressiveness and metastasis of triple-negative breast cancer (TNBC) cells. However, well-developed VM inhibitors exhibit inadequate efficacy due to their low drug utilization rate and limited deep penetration. Thus, a cost-effective VM inhibition strategy needs to be designed for TNBC treatment.
RESULTS
Herein, we designed a low-intensity focused ultrasound (LIFU) and matrix metalloproteinase-2 (MMP-2) dual-responsive nanoplatform termed PFP@PDM-PEG for the cost-effective and efficient utilization of the drug disulfiram (DSF) as a VM inhibitor. The PFP@PDM-PEG nanodroplets effectively penetrated tumors and exhibited substantial accumulation facilitated by PEG deshielding in a LIFU-mediated and MMP-2-sensitive manner. Furthermore, upon exposure to LIFU irradiation, DSF was released controllably under ultrasound imaging guidance. This secure and controllable dual-response DSF delivery platform reduced VM formation by inhibiting COL1/pro-MMP-2 activity, thereby significantly inhibiting tumor progression and metastasis.
CONCLUSIONS
Considering the safety of the raw materials, controlled treatment process, and reliable repurposing of DSF, this dual-responsive nanoplatform represents a novel and effective VM-based therapeutic strategy for TNBC in clinical settings.
Topics: Disulfiram; Triple Negative Breast Neoplasms; Matrix Metalloproteinase 2; Animals; Female; Humans; Mice; Cell Line, Tumor; Lung Neoplasms; Nanoparticles; Neovascularization, Pathologic; Mice, Inbred BALB C; Mice, Nude; Drug Repositioning; Ultrasonic Waves; Antineoplastic Agents
PubMed: 38664830
DOI: 10.1186/s12951-024-02492-7 -
International Immunopharmacology May 2024Cuproptosis has recently been identified as a novel regulatory mechanism of cell death. It is characterized by the accumulation of copper in mitochondria and its binding... (Review)
Review
Cuproptosis has recently been identified as a novel regulatory mechanism of cell death. It is characterized by the accumulation of copper in mitochondria and its binding to acylated proteins. These characteristics lead to the downregulation of iron-sulfur cluster proteins and protein toxicity stress, ultimately resulting in cell death. Cuproptosis is distinct from other types of cell death, including necrosis, apoptosis, ferroptosis, and pyroptosis. Cu induces oxidative stress damage, protein acylation, and the oligomerization of acylated TCA cycle proteins. These processes lead to the downregulation of iron-sulfur cluster proteins and protein toxicity stress, disrupting cellular Cu homeostasis, and causing cell death. Cuproptosis plays a significant role in the development and progression of various kidney diseases such as acute kidney injury, chronic kidney disease, diabetic nephropathy, kidney transplantation, and kidney stones. On the one hand, inducers of cuproptosis, such as disulfiram (DSF), chloroquinolone, and elesclomol facilitate cuproptosis by promoting cell oxidative stress. In contrast, inhibitors of Cu chelators, such as tetraethylenepentamine and tetrathiomolybdate, relieve these diseases by inhibiting apoptosis. To summarize, cuproptosis plays a significant role in the pathogenesis of kidney disease. This review comprehensively discusses the molecular mechanisms underlying cuproptosis and its significance in kidney diseases.
Topics: Humans; Copper; Animals; Kidney Diseases; Oxidative Stress; Chelating Agents; Mitochondria
PubMed: 38663316
DOI: 10.1016/j.intimp.2024.112075 -
The Journal of Biological Chemistry Apr 2024The Hippo signaling pathway plays an essential role in organ size control and tumorigenesis. Loss of Hippo signal and hyper-activation of the downstream oncogenic YAP...
The Hippo signaling pathway plays an essential role in organ size control and tumorigenesis. Loss of Hippo signal and hyper-activation of the downstream oncogenic YAP signaling are commonly observed in various types of cancers. We previously identified STRN3-containing PP2A phosphatase as a negative regulator of MST1/2 kinases (i.e., Hippo) in gastric cancer (GC), opening the possibility of selectively targeting the PP2Aa-STRN3-MST1/2 axis to recover Hippo signaling against cancer. Here, we further discovered 1) disulfiram (DSF), an FDA-approved drug, which can similarly block the binding of STRN3 to PP2A core enzyme and 2) CX-6258 (CX), a chemical inhibitor, that can disrupt the interaction between STRN3 and MST1/2, both allowing reactivation of Hippo activity to inhibit GC. More importantly, we found these two compounds, via an MST1/2 kinase-dependent manner, inhibit DNA repair to sensitize GC towards chemotherapy. In addition, we identified thiram, a structural analog of DSF, can function similarly to inhibit cancer cell proliferation or enhance chemotherapy sensitivity. Interestingly, inclusion of copper ion enhanced such effects of DSF and thiram on GC treatment. Overall, this work demonstrated that pharmacological targeting of the PP2Aa-STRN3-MST1/2 axis by drug compounds can potently recover Hippo signal for tumor treatment.
PubMed: 38657866
DOI: 10.1016/j.jbc.2024.107311 -
Blood Apr 2024Thrombotic microangiopathy (TMA) is characterized by immunothrombosis and life-threatening organ failure, but the precise underlying mechanism driving its pathogenesis...
Thrombotic microangiopathy (TMA) is characterized by immunothrombosis and life-threatening organ failure, but the precise underlying mechanism driving its pathogenesis remains elusive. In this study, we hypothesized that gasdermin D (GSDMD), a pore-forming protein serving as the final downstream effector of pyroptosis/interleukin (IL)-1pathway, contributes to TMA and its consequences by amplifying neutrophil maturation and subsequent necrosis. Using a murine model of focal crystalline TMA, we found that Gsdmd-deficiency ameliorated immunothrombosis, acute tissue injury and failure. Gsdmd-/- mice exhibited a decrease in mature IL-1, as well as in neutrophil maturation, 2 integrin activation, and recruitment to TMA lesions, where they formed reduced neutrophil extracellular traps both in arteries and interstitial tissue. The GSDMD inhibitor disulfiram dose-dependently suppressed human neutrophil pyroptosis in response to cholesterol crystals. Experiments with GSDMD-deficient human induced pluripotent stem cell-derived neutrophils confirmed the involvement of GSDMD in neutrophil 2 integrin activation, maturation as well as pyroptosis. Both prophylactic and therapeutic administration of disulfiram protected mice from focal TMA, acute tissue injury and failure. Our data identify GSDMD as a key mediator of focal crystalline TMA and its consequences: ischemic tissue infarction and organ failure. GSDMD could potentially serve as a therapeutic target for systemic forms of TMA.
PubMed: 38657197
DOI: 10.1182/blood.2023021949 -
Oral Diseases Apr 2024Salivary glands are frequently damaged in patients undergoing radiotherapy for head and neck cancer. Whether PANoptosis, which is characterized by pyroptosis, apoptosis,...
OBJECTIVE
Salivary glands are frequently damaged in patients undergoing radiotherapy for head and neck cancer. Whether PANoptosis, which is characterized by pyroptosis, apoptosis, and necroptosis, occurs during radiation injury to the salivary glands and its role remain unclear.
MATERIALS AND METHODS
Radiation-induced injury models of mouse submandibular gland, as well as primary acinar cells and HSG cell lines were established to determine the presence of radiation-induced PANoptosis. Several programmed cell death inhibitors, PFTα, disulfiram, Nec-1 and zVAD, were used to compare the effects of different cell death pathway on radiation injury. The LEGENDplex™ Human Inflammation Panel was used to characterize the inflammatory landscape secreted by salivary gland cells after radiotherapy.
RESULTS
Single 15Gy or 8Gy radiotherapy triggered PANoptosis in mouse submandibular gland or salivary gland cells. Compared to the suppression of pyroptosis, apoptosis, or necroptosis alone, the inhibition of PANoptosis is more effective in preventing radiation injury to the salivary glands (p < 0.0001). The levels of multiple inflammatory cytokines were significantly up-regulated in the supernatants of HSG cells within 48 h after IR. Neutralizing inflammatory cytokines are capable of inhibiting salivary glands PANoptosis.
CONCLUSIONS
Inhibition of PANoptosis induced by inflammatory cytokines can effectively prevent radiation injury of salivary glands.
PubMed: 38655600
DOI: 10.1111/odi.14967 -
RSC Advances Apr 2024Disulfiram (DSF) can target and kill cancer cells by disrupting cellular degradation of extruded proteins and has therefore received particular attention for its tumor...
Disulfiram (DSF) can target and kill cancer cells by disrupting cellular degradation of extruded proteins and has therefore received particular attention for its tumor chemotherapeutic potential. However, the uncontrollable Cu/DSF ratio reduces the efficacy of DSF-mediated chemotherapy. Herein, self-supplying Cu and oxidative stress synergistically enhanced DSF-mediated chemotherapy is proposed for melanoma-based on PVP-coated CuO nanodots (CPNDs). Once ingested, DSF is broken down to diethyldithiocarbamate (DTC), which is delivered into a tumor the circulation. Under the acidic tumor microenvironment, CPNDs produce sufficient Cu and HO. DTC readily chelates Cu ions to generate CuET, which shows antitumor efficacy. CuET-mediated chemotherapy can be enhanced by HO. Sufficient Cu generation can guarantee the maximum efficacy of DSF-mediated chemotherapy. Furthermore, released Cu can be reduced to Cu by glutathione (GSH) and O in tumor cells, and Cu can react with HO to generate toxic hydroxyl radicals (·OH) a Fenton-like reaction, promoting the efficacy of CuET. Therefore, this study hypothesizes that employing CPNDs instead of Cu ions could enhance DSF-mediated melanoma chemotherapy, providing a simple but efficient strategy for achieving chemotherapeutic efficacy.
PubMed: 38655468
DOI: 10.1039/d4ra01075b -
Drug and Alcohol Review Apr 2024We assessed the prevalence of prescribing of certain medications for alcohol dependence and the extent of any inequalities in receiving prescriptions for individuals...
INTRODUCTION
We assessed the prevalence of prescribing of certain medications for alcohol dependence and the extent of any inequalities in receiving prescriptions for individuals with such a diagnosis. Further, we compared the effectiveness of two of the most prescribed medications (acamprosate and disulfiram) for alcohol dependence and assessed whether there is inequality in prescribing either of them.
METHODS
We used a nationwide dataset on prescriptions and hospitalisations in Scotland, UK (N = 19,748). We calculated the percentage of patients receiving alcohol dependence prescriptions after discharge, both overall and by socio-economic groups. Binary logistic regressions were used to assess the odds of receiving any alcohol-dependence prescription and the comparative odds of receiving acamprosate or disulfiram. Comparative effectiveness in avoiding future alcohol-related hospitalisations (N = 11,239) was assessed using Cox modelling with statistical adjustment for potential confounding.
RESULTS
Upto 7% of hospitalised individuals for alcohol use disorder received prescriptions for alcohol dependence after being discharged. Least deprived socio-economic groups had relatively more individuals receiving prescriptions. Inequalities in prescribing for alcohol dependence existed, especially across sex and comorbidities: males had 12% (odds ratio [OR] 0.88, 95% confidence interval [CI] 0.81-0.96) and those with a history of mental health hospitalisations had 10% (OR 0.90, 95% CI 0.82-0.98) lower odds of receiving prescriptions after an alcohol-related hospitalisation. Prescribing disulfiram was superior to prescribing acamprosate in preventing alcohol-related hospitalisations (hazard ratio ranged between 0.60 and 0.81 across analyses). Disulfiram was relatively less likely prescribed to those from more deprived areas.
DISCUSSION AND CONCLUSIONS
Inequalities in prescribing for alcohol dependence exists in Scotland with lower prescribing to men and disulfiram prescribed more to those from least deprived areas.
PubMed: 38653552
DOI: 10.1111/dar.13841 -
Transplant International : Official... 2024Macrophages contribute to post-transplant lung rejection. Disulfiram (DSF), an anti-alcoholic drug, has an anti-inflammatory effect and regulates macrophage chemotactic...
Macrophages contribute to post-transplant lung rejection. Disulfiram (DSF), an anti-alcoholic drug, has an anti-inflammatory effect and regulates macrophage chemotactic activity. Here, we investigated DSF efficacy in suppressing acute rejection post-lung transplantation. Male Lewis rats (280-300 g) received orthotopic left lung transplants from Fisher 344 rats (minor histocompatibility antigen-mismatched transplantation). DSF (0.75 mg/h) monotherapy or co-solvent only (50% hydroxypropyl-β-cyclodextrin) as control was subcutaneously administered for 7 days (n = 10/group). No post-transplant immunosuppressant was administered. Grades of acute rejection, infiltration of immune cells positive for CD68, CD3, or CD79a, and gene expression of monocyte chemoattractant protein and pro-inflammatory cytokines in the grafts were assessed 7 days post-transplantation. The DSF-treated group had significantly milder lymphocytic bronchiolitis than the control group. The infiltration levels of CD68 or CD3 cells to the peribronchial area were significantly lower in the DSF than in the control groups. The normalized expression of chemokine ligand 2 and interleukin-6 mRNA in allografts was lower in the DSF than in the control groups. Validation assay revealed interleukin-6 expression to be significantly lower in the DSF than in the control groups. DSF can alleviate acute rejection post-lung transplantation by reducing macrophage accumulation around peripheral bronchi and suppressing pro-inflammatory cytokine expression.
Topics: Animals; Lung Transplantation; Graft Rejection; Male; Disulfiram; Rats, Inbred Lew; Rats, Inbred F344; Rats; Macrophages; Allografts; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Chemokine CCL2; Lung
PubMed: 38650846
DOI: 10.3389/ti.2024.12556 -
Tijdschrift Voor Psychiatrie 2024In this paper we discuss the case of a 52-year-old man who consulted the emergency department because of confusion. Based on anamnesis, clinical presentation, various...
In this paper we discuss the case of a 52-year-old man who consulted the emergency department because of confusion. Based on anamnesis, clinical presentation, various technical investigations and recovery after discontinuation of disulfiram, the diagnosis of disulfiram encephalopathy is made. This is a less common but serious complication of a frequently used therapy and underscores the importance of early recognition and careful but also controlled prescription of disulfiram. We describe the pathophysiology behind this complication and reflect on some important numbers.
Topics: Humans; Disulfiram; Male; Middle Aged; Alcohol Deterrents; Drug Overdose; Alcoholism
PubMed: 38650532
DOI: No ID Found -
Communications Biology Apr 2024Antibody responses, involving B cells, CD4 + T cells, and macrophages, are implicated in autoimmune diseases and organ transplant rejection. We have previously shown...
Antibody responses, involving B cells, CD4 + T cells, and macrophages, are implicated in autoimmune diseases and organ transplant rejection. We have previously shown that inhibiting FROUNT with disulfiram (DSF) suppresses macrophage activation and migration, effectively treating inflammatory diseases. In this study, we investigated the effectiveness of DSF in antibody-producing reactions. Using a heart transplantation mouse model with antibody-mediated rejection, we administered anti-CD8 antibody to exclude cellular rejection. DSF directly inhibited B cell responses in vitro and significantly reduced plasma donor-specific antibodies and graft antibody deposition in vivo, resulting in prolonged survival of the heart graft. DSF also mediated various effects, including decreased macrophage infiltration and increased Foxp3+ regulatory T-cells in the grafts. Additionally, DSF inhibited pyrimidine metabolism-related gene expression induced by B-cell stimulation. These findings demonstrate that DSF modulates antibody production in the immune response complexity by regulating B-cell and macrophage responses.
Topics: Animals; Disulfiram; Mice; B-Lymphocytes; Macrophage Activation; Pyrimidines; Mice, Inbred C57BL; Heart Transplantation; Male; Macrophages; Antibody Formation; Graft Rejection; Mice, Inbred BALB C
PubMed: 38649462
DOI: 10.1038/s42003-024-06183-9