Current Issue : April-June Volume : 2026 Issue Number : 2 Articles : 5 Articles
Background: Heat shock protein 90 (HSP90) is a molecular chaperone that stabilizes numerous oncogenic proteins and supports tumor survival. Small molecules targeting HSP90 offer a novel approach to overcome drug resistance and immune suppression in breast cancer. Methods: A novel thiazolyl benzodiazepine (TB) containing a hydrazone moiety was evaluated in breast cancer cell lines (ER+ MCF-7, TNBC MDA-MB-231, and HER2+ SK-BR-3). Cytotoxicity was assessed using the CCK-8 assay, followed by PCR sequencing, flow cytometry, RT-qPCR, protein profiling, and HSP90 binding assays. Results: TB showed the strongest activity in MCF-7 cells (IC50 = 7.21 μM) compared to MDA-MB-231 (IC50 = 28.07 μM) and SK-BR-3 (IC50 = 12.8 μM) cells. Mechanistic studies showed that TB binds to HSP90 (Kd = 3.10 μM), leading to disruption of the oncogenic signal. TB induced G2/M cell cycle arrest, promoted apoptosis via Bax and Caspase-3 activation, and suppressed cancer stem cell markers (NANOG, OCT4, SOX2). Additionally, TB activated immune-related pathways via ERK/MAPK signaling and upregulated genes such as SMAD2, SMAD3, and JUN. Conclusions: TB functions as an HSP90 inhibitor with dual anticancer and immunomodulatory properties in Estrogen Receptor-Positive (ER+) breast cancer cells. These findings suggest that TB represents a promising scaffold for the development of multi-targeted breast cancer therapies....
Despite the known antitumor properties of echinacoside (ECH), its specific role and mechanism in hepatocellular carcinoma (HCC) require in-depth exploration. Our study aimed to decipher the mechanism of ECH against HCC through a multi-disciplinary strategy. We first identified tumor protein p53 (TP53) as a key mediator and ferroptosis as a critical process, through network pharmacology and enrichment analyses. The direct interaction between ECH and TP53 was validated by molecular docking and dynamics simulations. In vitro assessments demonstrated that ECH suppresses HCC proliferation by activating ferroptosis, marked by increased intracellular Fe2+, lipid peroxidation (LPO), and malondialdehyde (MDA), alongside reduced glutathione (GSH). The ferroptosis inhibitor ferrostatin-1 notably attenuated ECH’s effects, confirming ferroptosis as the primary mode of cell death. Further mechanistic investigation revealed that ECH acts through the TP53/solute carrier family 7 member 11(SLC7A11)/glutathione peroxidase 4(GPX4) pathway. These results collectively identify ECH as a promising ferroptosis-inducing agent for HCC therapy via TP53 activation....
Background/Objectives: Neuroblastoma is a pediatric embryonal tumor of the autonomic nervous system, characterized by high heterogeneity. Recent research has explored the therapeutic potential of retinoic acid and selenium derivatives as antiproliferative agents. This study aims to assess the antiproliferative effects of sodium selenite and retinoic acid, as well as the conventional chemotherapeutic agents, cyclophosphamide and cisplatin, using the SH-SY5Y neuroblastoma cell line. Methods: Cells were treated with the compounds at concentrations ranging from 0 to 1000 μM for 72 h. The following assays were performed: cell viability, clonogenic assay, cell migration, cell cycle analysis, and gene expression (BCL2 and BAX). Data were analyzed using the Kruskal–Wallis test followed by Dunn’s or the Mann–Whitney test (p < 0.05). IC50 values were obtained from dose–response curves. Results: Sodium selenite (100–1000 μM) significantly reduced cell viability by more than 50% (IC50: 166 μMat 72 h). Retinoic acid (300 μM) reduced viability by 65% (IC50: 198 μMat 72 h), and cisplatin (10 μM) reduced viability by 79% (IC50: 3.4 μM at 72 h). All compounds significantly decreased colony formation. Sodium selenite and retinoic acid induced arrest in the G0/G1 phase of the cell cycle. Gene expression analysis revealed downregulation of the BCL2 gene by all compounds and upregulation of BAX only by sodium selenite at IC50 concentration. Conclusions: Sodium selenite and retinoic acid showed antiproliferative effects on neuroblastoma cells, suggesting their potential as adjuvant therapeutic agents. To reach this goal, we suggest further investigation of their mechanisms of action and evaluation of the combined strategies....
Hydroxychloroquine (HCQ), originally developed as an antimalarial agent, has been associated with hepatotoxic effects in experimental and clinical settings. Our study was designed to evaluate the effects of this agent on liver toxicity and to understand the protective roles of adenosine triphosphate (ATP), Liver-52 (Liv-52), and their combination. MaleWistar rats (250–280 g) were randomly assigned to five groups (n = 6): healthy control (C), HCQ only (H), ATP plus HCQ (AH), Liv-52 plus HCQ (LH), and ATP–Liv-52 plus HCQ (ALH). ATP (4 mg/kg) was administered intraperitoneally once daily, whereas Liv- 52 (20 mg/kg) was administered orally via gavage. One hour later, all groups except C received HCQ (120 mg/kg, orally, twice daily). All treatments were continued for seven consecutive days. At the end of the experiment, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured, and liver tissues were analyzed for malondialdehyde (MDA), total glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities, along with histopathological evaluation. HCQ administration significantly increased oxidative stress, as evidenced by elevated MDA levels (p < 0.01) and reduced antioxidant parameters, including GSH, SOD, and CAT (p < 0.05), accompanied by prominent histopathological damage. Treatment with ATP or Liv-52 markedly ameliorated these alterations by decreasing MDA and restoring antioxidant markers. The combination treatment was observed to exhibit the most pronounced protective effect; it significantly reduced MDA levels, improved GSH, SOD, and CAT levels more effectively, and produced significant decreases in AST and ALT values (p < 0.05)....
Obesity is a foremost risk factor for the development of cardiovascular disease, a hallmark of which is chronic vascular inflammation and overproduction of reactive oxygen species (ROS). NADPH oxidases (NOX) are central mediators of ROS overproduction in the obese vasculature, yet a complete understanding of the mechanism underlying their dysregulation in obesity remains poorly understood. Herein, we investigated the contribution of NOX1 in obesity-associated hypertension and evaluated the therapeutic potential of pharmacologically targeting NOX1 using the novel inhibitor GKT771. In obese db/db mice, NOX1 deletion ameliorated hypertension independent of metabolic improvements such as weight loss or improved glucose handling. Furthermore, NOX1 deletion improved renal sodium handling with no compensatory upregulation of other NOX isoforms. Importantly, treatment with the NOX1-specific inhibitor GKT771 rescued endothelial function in obese mice, restoring microvascular function to levels observed in lean controls. These data highlight the importance of NOX1 as a driver of endothelial dysfunction in obesity and suggest that NOX1 inhibition may offer a novel therapeutic strategy for obesity-associated endothelial dysfunction and its downstream cardiovascular complications....
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