Novel Acetamide-Based HO-1 Inhibitor Counteracts Glioblastoma Progression by Interfering with the Hypoxic–Angiogenic Pathway

Sep 22, 2026

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Glioblastoma multiforme (GBM) is the deadliest brain tumor, driven by uncontrolled proliferation that creates hypoxic niches in the tumor core. Hypoxia induces hypoxia-inducible factor (HIF) signaling, enhancing aggressive pathways including vascular endothelial growth factor (VEGF) expression and heme oxygenase-1 (HO-1). This study evaluates the HO-1–hypoxia link by exposing U87MG and A172 glioblastoma cells to the hypoxic mimetic deferoxamine (DFX) and testing a novel acetamide-based HO-1 inhibitor (VP18/58). Results show cell-dependent HO-1 upregulation and nuclear localization under hypoxia, and demonstrate that HO-1 inhibition counteracts GBM progression by modulating the HIFα/HO-1/VEGF cascade, especially in more malignant phenotypes.

LanguageEnglish

CategoryHealthcare

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Pages19

Reading Time48 min

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Introduction

Hypoxic microenvironment and HIF signaling in GBM

HO-1 expression and rationale for targeted inhibition

Article Novel Acetamide-Based HO-1 Inhibitor Counteracts Glioblastoma Progression by Interfering with the Hypoxic–Angiogenic Pathway Agata Grazia D’Amico 1,†, Grazia Maugeri 2,†, Luca Vanella 1, Valeria Consoli 1, Valeria Sorrenti 1, Francesca Bruno 3, Concetta Federico 3, Antonino Nicolò Fallica 1, Valeria Pittalà 1,4 and Velia D’Agata 2, * Citation: D’Amico, A.G.; Maugeri, G.; Vanella, L.; Consoli, V.; Sorrenti, V.; Bruno, F.; Federico, C.; Fallica, A.N.; Pittalà, V.; D’Agata, V. Novel Acetamide-Based HO-1 Inhibitor Counteracts Glioblastoma Progression by Interfering with the Hypoxic– Angiogenic Pathway. Int. J. Mol. Sci. 2024, 25, 5389. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms25105389](10.3390/ijms25105389) Academic Editor: Peter Hau Received: 15 March 2024 Revised: 6 May 2024 Accepted: 8 May 2024 Published: 15 May 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; [agata.damico@unict.it](agata.damico@unict.it) (A.G.D.); [valeria_consoli@yahoo.it](valeria_consoli@yahoo.it) (V.C.); [sorrenti@unict.it](sorrenti@unict.it) (V.S.); valeria.pittala@unict.it (V.P.) 2 Department of Biomedical and Biotechnological Sciences, Section of Anatomy, Histology and Movement Sciences, University of Catania, 95100 Catania, Italy 3 Department of Biological, Geological and Environmental Sciences, Section of Animal Biology, University of Catania, 95123 Catania, Italy; [federico@unict.it](federico@unict.it) (C.F.) 4 Department of Molecular Medicine, College of Medicine and Medical Sciences, Princess Al-Jawhara Centre for Molecular Medicine, Arabian Gulf University, Manama 329, Bahrain * [Correspondence: vdagata@unict.it](Correspondence: vdagata@unict.it); Tel.: +39-095-3782147 † These authors contributed equally to this work. 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 hypoxiainduced 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. Keywords: HO-1 gene; HO-1 inhibitors; glioblastoma multiforme; hypoxia; angiogenesis; vascular endothelial growth factor 1. Introduction Glioblastoma multiforme (GBM) is classified as grade IV astrocytoma and represents the deadliest brain cancer, affecting adults with poor prognosis [1,2] . Based on a histological and molecular approach, the World Health Organization (WHO) has classified this type of glioma as glioblastoma isocitrate dehydrogenase (IDH)-wild type. The median survival of the affected patient is between 14 and 17 months due to cancer relapse. T

FAQs

Why is hypoxia important in glioblastoma progression?

GBM growth generates hypoxic niches that activate hypoxia-inducible factor (HIF) signaling, driving cascades linked to aggressiveness such as VEGF-related pathways.

How was HO-1 targeted in this study?

The research used a novel acetamide-based HO-1 inhibitor (VP18/58) and examined HO-1 behavior under hypoxic conditions induced with the mimetic deferoxamine (DFX) in U87MG and A172 cells.

What did the results show about HO-1 and inhibitor effects?

Hypoxic conditions induced HO-1 upregulation and nuclear expression in a cell-dependent manner, and the HO-1 inhibitor counteracted GBM progression by modulating the HIFα/HO-1/VEGF signaling cascade.

Sep 22, 2026

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