Ferroptosis is a programmed cell death characterized by excessive, iron-dependent accumulation of membrane lipid peroxides due to insufficient glutathione-dependent antioxidant defense. It is influenced by the metabolism of amino acids, lipids, and iron, and occurs in conditions of decreased glutathione peroxidase 4 (GPX4) activity. The increased polyunsaturated fatty acid (PUFA) content in membrane phospholipids is associated with cellular hypersusceptibility to ferroptosis. In contrast, incorporation of monounsaturated fatty acids may protect cells against ferroptotic cell death. Cellular sensitivity to ferroptosis is additionally influenced by glutamine catabolism and the xc–system-mediated import of cystine, which modulate glutathione production, and by elevated iron levels, which lead to the buildup of reactive oxygen species (ROS) that attack membrane-localized PUFAs. This review focuses on recent findings of perturbed metabolic processes in cancer that create a high iron demand and an altered lipid composition, thereby predisposing cells to ferroptosis. We analyze the therapeutic potential of pharmacological agents that can selectively trigger ferroptosis in tumor cells.
Mirjana Macvanin, D. Spasić, S. Gluščević et al.· Archives of Medical Science· 0 citations
Hematological malignancies are highly heterogeneous diseases characterized by dysregulated signaling pathways and limited durable therapeutic responses. Calcium homeostasis has emerged as a critical regulator of cancer cell fate, yet the role of the sodium/calcium exchanger 1 (NCX1/SLC8A1) in leukemogenesis remains poorly defined. In this study, we comprehensively investigated the biological significance and therapeutic potential of NCX1 across major hematological malignancies by integrating transcriptomic analyses, protein-protein interaction networks, experimental validation, and in silico drug repurposing strategies. NCX1 was highly expressed in HL-60, K-562, and Jurkat cells compared to HaCaT controls. Network analyses revealed that NCX1 interacts with key regulators of calcium signaling, immune response, and signal transduction. In AML and CML patient datasets, a strong positive correlation was observed between NCX1 expression and immune-related pathways, while a negative correlation was observed with translation-related processes. Molecular docking analyses demonstrated that several clinically approved compounds, particularly imatinib and nilotinib, interact with NCX1. Molecular dynamics simulation was performed to evaluate the binding stability and safety of imatinib. Remarkably, the comprehensive analysis showed that imatinib exhibited a stable molecular dynamics profile. All these findings have demonstrated NCX1 as a biologically informative marker of myeloid differentiation and a promising therapeutic weak point within calcium signaling networks in hematological malignancies, providing a rationale for future functional and single-cell validation studies.
Sema Mısır, S. Yaman, Nina Petrović et al.· Biochemical and Biophysical...· 0 citations
