Marizomib in the therapy of brain tumors—how far did we go and where do we stand?

Sep 23, 2026

Uploaded by Franzy

Glioblastoma (GBM), a highly malignant central nervous system tumor, has limited effective treatments and therefore poor survival outcomes. The review examines proteasome inhibitors (PIs), noting that benefits from hematological malignancies do not transfer easily to brain tumors due to blood-brain barrier impermeability and low brain bioavailability. Marizomib (MZB), an irreversible second-generation PI that can penetrate the BBB, shows promise, yet has not been adopted into ready-to-use GBM chemotherapy. The work summarizes preclinical and clinical findings, explains possible causes of MZB therapy failure, and outlines future research directions.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Abstract

Introduction

Glioblastoma features and therapeutic challenges

Standard of care and limitations

Keywords and abbreviations

Pharmacological Reports (2025) 77:1177–1195 [https://doi.org/10.1007/s43440-025-00739-0](https://doi.org/10.1007/s43440-025-00739-0) REVIEW Marizomib in the therapy of brain tumors—how far did we go and where do we stand? Magdalena Kusaczuk1 · Wiktoria Monika Piskorz1 · Julia Domasik1 Received: 29 March 2025 / Revised: 9 May 2025 / Accepted: 19 May 2025 / Published online: 29 May 2025 © The Author(s) 2025, corrected publication 2025 Abstract Out of several types of tumors of the central nervous system (CNS), glioblastoma (GBM) represents one of the most frequent and malignant forms of brain neoplasms. To date, GBM holds very limited therapeutic options leaving patients with poor prognosis of survival. As such, novel treatment approaches are constantly quested. One of these strategies is based on the utilization of proteasome inhibitors (PIs) . However, although several PIs have been approved as therapy for patients with hematological malignancies, these treatment benefits cannot not be easily extrapolated to brain tumors. This is mostly due to the blood-brain barrier (BBB) impermeability of the majority of PIs, which is then followed by their low brain bioavailability. Marizomib (MZB) is a unique, irreversible, second-generation proteasome inhibitor, which unlike other PIs can penetrate through the BBB, making it a promising therapeutic tool in brain tumors. Despite an indisputable therapeutic potential of MZB, it has yet failed to be successfully introduced to the clinics as a ready-to-use chemotherapy for GBM-suffering patients. Therefore, in this work we describe the potential of PIs as candidates for neuro-oncological drugs, present results of preclinical and clinical investigations concerning MZB in brain tumors, discuss possible reasons of failure of MZB-based therapies and delineate future directions of MZB-related studies. Keywords Apoptosis · ER stress · Glioblastoma · Marizomib · Proteasome inhibitors Abbreviations Atf4 Atf6α Atg5 BBB Bcl2 CHOP C-L cl-Casp3 cl-PARPCNS CT-L Cyt CDR5 FDA Activating transcription factor 4 Activating transcription factor 6α Autophagy protein 5 The blood–brain barrier B–cell leukemia/lymphoma 2 protein C/EBP homologus protein caspase–like cleaved caspase 3 cleaved PARP The central nervous system chymotrypsin–like Cytochrome c Death receptor 5 Food and Drug Administration 􀀍 Magdalena Kusaczuk [magdalena.kusaczuk@umb.edu.pl](magdalena.kusaczuk@umb.edu.pl); [mkusaczuk@wp.pl](mkusaczuk@wp.pl) 1 Department of Pharmaceutical Biochemistry, Medical University of Bialystok, Mickiewicza 2A, Białystok 15-222, Poland GBM GRP78 GSCs IC50 IRE1α MCL MGMT MZB NAC NAD+ PAN p-EIF2α PERK PI PIs PLGA p-SAPK/JNK ROS Glioblastoma Glucose regulated protein 78 Glioma stem-like cells Half–maximal inhibitory concentration Inositol–requiring transmembrane kinaseendoribonuclease–1α Mantle cell lymphoma O6–Methylguanine–DNA–methyltransferase Marizomib N–acetyl cysteine Nicotinamide adenine dinucleotide Panobinostat phosphorylated eukaryotic translation initiation factor 2α Protein kinase RNA–like ER kinase Proteasome inhibitor Proteasome inhibitors Polylactic–co–glycolic acid phosphorylatedstress–activated protein kinase Reactive oxygen species Published online: 29 May 2025 1 3 RT Radiotherapy T-L trypsin–like TMZ Temozolomide UPR Unfolded protein response UPS Ubiquitin–proteasome system γH2AX phosphorylated histone H2AX Introduction Brain cancers, also referred to as central nervous system (CNS) cancers, are a group of several types of tumors originating mostly from glial and neuronal precursor cells [1] . The most common histological types of primary CNS tumors in adults are gliomas. Gliomas constitute a group of malignant brain tumors, including low-grade gliomas (astrocytoma, oligodendroglioma) and high-grade glioma or glioblastoma (GBM) [1] . GBM is considered one of the most frequent and agg

FAQs

Why are proteasome inhibitors difficult to apply to brain tumors like glioblastoma?

Most proteasome inhibitors have poor blood-brain barrier penetration, leading to low brain bioavailability, which limits their effectiveness in brain tumors.

What distinguishes marizomib from other proteasome inhibitors?

Marizomib is an irreversible, second-generation proteasome inhibitor designed to penetrate the blood-brain barrier, potentially improving delivery to brain tumors.

What does the review cover regarding marizomib-based therapy?

It summarizes preclinical and clinical investigations, discusses reasons marizomib therapies have not succeeded in clinical introduction for GBM, and proposes future study directions.

Sep 23, 2026

Uploaded by Franzy