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Marizomib sensitizes primary glioma cells to apoptosis induced by a latest-generation TRAIL receptor agonist

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posted on 19.01.2022, 17:44 by Chiara Boccellato, Emily Kolbe, Nathalie Peters, Viktorija JuricViktorija Juric, Gavin Fullstone, Maïté Verreault, Ahmed Idbaih, Martine LM Lamfers, Brona MurphyBrona Murphy, Markus RehmMarkus Rehm
Due to the absence of curative treatments for glioblastoma (GBM), we assessed the efficacy of single and combination treatments with a translationally relevant 2nd generation TRAIL-receptor agonist (IZI1551) and the blood–brain barrier (BBB) permeant proteasome inhibitor marizomib in a panel of patient-derived glioblastoma cell lines. These cells were cultured using protocols that maintain the characteristics of primary tumor cells. IZI1551+marizomib combination treatments synergistically induced apoptotic cell death in the majority of cases, both in 2D, as well as in 3D spheroid cultures. In contrast, single-drug treatments largely failed to induce noticeable amounts of cell death. Kinetic analyses suggested that time-shifted drug exposure might further increase responsiveness, with marizomib pre-treatments indeed strongly enhancing cell death. Cell death responses upon the addition of IZI1551 could also be observed in GBM cells that were kept in a medium collected from the basolateral side of a human hCMEC/D3 BBB model that had been exposed to marizomib. Interestingly, the subset of GBM cell lines resistant to IZI1551+marizomib treatments expressed lower surface amounts of TRAIL death receptors, substantially lower amounts of procaspase-8, and increased amounts of cFLIP, suggesting that apoptosis initiation was likely too weak to initiate downstream apoptosis execution. Indeed, experiments in which the mitochondrial apoptosis threshold was lowered by antagonizing Mcl-1 re-established sensitivity to IZI1551+marizomib in otherwise resistant cells. Overall, our study demonstrates a high efficacy of combination treatments with a latest-generation TRAIL receptor agonist and the BBB permeant proteasome inhibitor marizomib in relevant GBM cell models, as well as strategies to further enhance responsiveness and to sensitize subgroups of otherwise resistant GBM cases.

Funding

European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (#766069 (GLIO-TRAIN)

German Research Foundation (DFG FOR2036 MO 3226/1-1; EXC 2075 390740016; MO 3226/4- 1)

Projekt DEAL

History

Comments

The original article is available at https://www.nature.com/

Published Citation

Boccellato C. et al. Marizomib sensitizes primary glioma cells to apoptosis induced by a latest-generation TRAIL receptor agonist. Cell Death Dis. 2021;12(7):647

Publication Date

24 June 2021

PubMed ID

34168123

Department/Unit

  • Physiology and Medical Physics

Research Area

  • Cancer

Publisher

Springer Nature

Version

  • Published Version (Version of Record)