Proteasome Inhibition in Glioblastoma Therapeutics

Glioblastoma is the most common and aggressive primary brain tumour in adults, characterised by rapid proliferation, diffuse infiltration and pronounced resistance to conventional therapies. The ubiquitin-proteasome system governs degradation of misfolded, damaged or regulatory proteins, thereby maintaining proteostasis and enabling tumour cell survival under stress. Inhibition of proteasomal activity disrupts cell cycle regulation, enhances accumulation of pro-apoptotic factors and sensitises malignant cells to DNA damage. First-generation inhibitors such as bortezomib have limited efficacy in glioblastoma owing to poor blood–brain barrier penetrance and dose-limiting toxicities. Second-generation agents like marizomib demonstrate improved central nervous system bioavailability and broader catalytic subunit targeting. Preclinical studies reveal that proteasome inhibition induces endoplasmic reticulum stress and caspase-dependent apoptosis, while combination regimens with histone deacetylase inhibitors or metabolic modulators hold promise for overcoming adaptive resistance. Ongoing efforts focus on optimising drug delivery, identifying predictive biomarkers and integrating proteasome inhibitors into personalised, multi-modal treatment strategies for glioblastoma.

Research from Nature Portfolio

Recent studies have demonstrated that the pan-proteasome inhibitor marizomib induces caspase 9-dependent apoptosis in glioblastoma cell lines and in orthotopic murine models. Unique among its class, this agent crosses the blood–brain barrier to achieve in situ proteasome inhibition, as evidenced by increased levels of cell cycle regulator p27 and enhanced cleavage of apoptotic substrates. Synergistic interactions have been observed when marizomib is combined with histone deacetylase inhibitors, triggering amplified death signalling and suggesting potential biomarkers of response. These foundational insights establish a mechanistic basis for targeting proteasomal degradation in glioblastoma and guide the design of future combination regimens.

Proteasome Inhibition in Glioblastoma Therapeutics publication trend

The graph below shows the total number of articles in proteasome inhibition in glioblastoma therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Proteasome: A multisubunit protease complex that degrades ubiquitin-tagged proteins to regulate cellular protein turnover and homeostasis.

Ubiquitination: A post-translational modification in which ubiquitin molecules are covalently attached to substrate proteins, marking them for proteasomal degradation.

Blood–brain barrier: A specialised endothelial interface that restricts passage of molecules from the circulation into the central nervous system.

Endoplasmic reticulum stress: A cellular condition arising from accumulation of misfolded proteins in the endoplasmic reticulum, triggering adaptive or apoptotic unfolded protein responses.

Apoptosis: A form of programmed cell death characterised by caspase activation, chromatin condensation and formation of apoptotic bodies.

References

1. Marizomib for patients with newly diagnosed glioblastoma: A randomized phase 3 trial. Neuro-Oncology (2024).
2. The Proteasome Inhibitor Marizomib Evokes Endoplasmic Reticulum Stress and Promotes Apoptosis in Human Glioblastoma Cells. Pharmaceuticals (2024).
3. Targeting mitochondrial energetics reverses panobinostat‐ and marizomib‐induced resistance in pediatric and adult high‐grade gliomas. Molecular Oncology (2023).
4. Proteasome Inhibitors against Glioblastoma—Overview of Molecular Mechanisms of Cytotoxicity, Progress in Clinical Trials, and Perspective for Use in Personalized Medicine. Current Oncology (2023).
5. Induction of cell death by the novel proteasome inhibitor marizomib in glioblastoma in vitro and in vivo. Scientific Reports (2016).