1. Novel Acetamide-Based HO-1 Inhibitor Counteracts Glioblastoma Progression by Interfering with the Hypoxic-Angiogenic Pathway.
- Author
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D'Amico AG, Maugeri G, Vanella L, Consoli V, Sorrenti V, Bruno F, Federico C, Fallica AN, Pittalà V, and D'Agata V
- Subjects
- Humans, Cell Line, Tumor, Brain Neoplasms metabolism, Brain Neoplasms drug therapy, Brain Neoplasms pathology, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic metabolism, Cell Proliferation drug effects, Disease Progression, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Gene Expression Regulation, Neoplastic drug effects, Cell Hypoxia drug effects, Glioblastoma metabolism, Glioblastoma drug therapy, Glioblastoma pathology, Heme Oxygenase-1 metabolism, Acetamides pharmacology, Vascular Endothelial Growth Factor A metabolism, Signal Transduction drug effects
- Abstract
Glioblastoma multiforme (GBM) represents the deadliest tumor among brain cancers. It is a solid tumor characterized by uncontrolled cell proliferation generating the hypoxic niches in the cancer core. By inducing the transcription of hypoxic inducible factor (HIF), hypoxia triggers many signaling cascades responsible for cancer progression and aggressiveness, including enhanced expression of vascular endothelial growth factor (VEGF) or antioxidant enzymes, such as heme oxygenase-1 (HO-1). The present work aimed to investigate the link between HO-1 expression and the hypoxic microenvironment of GBM by culturing two human glioblastoma cell lines (U87MG and A172) in the presence of a hypoxic mimetic agent, deferoxamine (DFX). By targeting hypoxia-induced HO-1, we have tested the effect of a novel acetamide-based HO-1 inhibitor (VP18/58) on GBM progression. Results have demonstrated that hypoxic conditions induced upregulation and nuclear expression of HO-1 in a cell-dependent manner related to malignant phenotype. Moreover, our data demonstrated that the HO-1 inhibitor counteracted GBM progression by modulating the HIFα/HO-1/VEGF signaling cascade in cancer cells bearing more malignant phenotypes.
- Published
- 2024
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