Endoplasmic reticulum stress‑induced cell death as a potential mechanism for targeted therapy in glioblastoma (Review)

Shi, Pengfei; Zhang, Zhuohang; Xu, Jie; Zhang, Li; Cui, Hongjuan

doi:10.3892/ijo.2021.5240

Cited by 9 publications

(3 citation statements)

References 195 publications

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“…These characteristic of tumor cells can be exploited as a therapeutic strategy by overstimulating ER stress and UPR to induce cancer cell death ( 48 , 49 ). Preclinical studies in glioblastoma models have shown the anticancer efficacy of ER stress inducers that include small molecules and natural compounds ( 50 ). This therapeutic strategy is already being tested in clinical trials, currently, an ongoing study is investigating TN-TC11G (9-tetrahydrocannabinol + CBD) in combination with temozolomide and radiotherapy in patients with newly diagnosed GBM (NCT03529448).…”

Section: Discussionmentioning

confidence: 99%

Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models

Mancini

Colapietro²,

Cristiano³

et al. 2022

Front. Oncol.

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BackgroundGlioblastoma multiforme (GBM) is the most malignant adult brain tumor. Current standard of care treatments have very limited efficacy, being the patients´ overall survival 14 months and the 2-year survival rate less than 10%. Therefore, the treatment of GBM is an urgent unmet clinical need.MethodsThe aim of this study was to investigate in vitro and in vivo the potential of ABTL0812, an oral anticancer compound currently in phase II clinical stage, as a novel therapy for GBM.ResultsWe showed that ABTL0812 inhibits cell proliferation in a wide panel of GBM cell lines and patient-derived glioblastoma stem cells (GSCs) with half maximal inhibitory concentrations (IC50s) ranging from 15.2 µM to 46.9 µM. Additionally, ABTL0812 decreased GSCs neurosphere formation. GBM cells aggressiveness is associated with a trans-differentiation process towards a less differentiated phenotype known as proneural to mesenchymal transition (PMT). ABTL0812 was shown to revert PMT and induce cell differentiation to a less malignant phenotype in GBM cell lines and GSCs, and consequently reduced cell invasion. As previously shown in other cancer types, we demonstrated that the molecular mechanism of action of ABTL0812 in glioblastoma involves the inhibition of Akt/mTORC1 axis by overexpression of TRIB3, and the activation of endoplasmic reticulum (ER) stress/unfolded protein response (UPR). Both actions converge to induce autophagy-mediated cell death. ABTL0812 anticancer efficacy was studied in vivo using subcutaneous and orthotopic intra-brain xenograft tumor models. We demonstrated that ABTL0812 impairs tumor growth and increases disease-free survival and overall survival of mice. Furthermore, the histological analysis of tumors indicated that ABTL0812 decreases angiogenesis. Finally, we investigated the combination of ABTL0812 with the standard of care treatments for GBM radiotherapy and temozolomide in an orthotopic model, detecting that ABTL0812 potentiates the efficacy of both treatments and that the strongest effect is obtained with the triple combination of ABTL0812+radiotherapy+temozolomide.ConclusionsOverall, the present study demonstrated the anticancer efficacy of ABTL0812 as single agent and in combination with the GBM standard of care treatments in models of glioblastoma and supports the clinical investigation of ABTL0812 as a potential novel therapy for this aggressive brain tumor type.

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Section: Discussionmentioning

confidence: 99%

Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models

Mancini

Colapietro²,

Cristiano³

et al. 2022

Front. Oncol.

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“…TMZ resistance in gliomas is caused by exosomal import of MIF, which also activates PI3K/Akt pathways [ 55 ]. Downregulation of ATF4 in GBM enhanced the ability of TMZ to induce cell death [ 56 ]. Many studies have shown that different mechanisms are involved in TMZ sensitivity or resistance.…”

Section: Temozolomide In Chemotherapy: From History To Molecular Mech...mentioning

confidence: 99%

The landscape of circRNAs in gliomas temozolomide resistance: Insights into molecular pathways

Mafi,

Hedayati,

Kahkesh

et al. 2024

Non-coding RNA Research

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“…GBM cell death can be achieved by promoting apoptosis [16]. According to previous studies, GBM apoptosis is influenced by spindle morphology, but also by endomitochondria, endoplasmic reticulum and redox status [17][18][19]. The Bcl-2 family is considered to be one of the most prominent apoptotic pathways because of its association with mitochondrial dysfunction and the release of intermembrane proteins, such as cytochrome c, that activate caspases [20].…”

Section: Open Accessmentioning

confidence: 99%

USP7 inhibition induces apoptosis in glioblastoma by enhancing ubiquitination of ARF4

Pan

et al. 2021

Cancer Cell Int

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Background Glioblastomas (GBMs) are grade IV central nervous system tumors characterized by a poor prognosis and a short median overall survival. Effective induction of GBM cell death is difficult because the GBM cell population is genetically unstable, resistant to chemotherapy and highly angiogenic. In recent studies, ubiquitin-specific protease 7 (USP7) is shown to scavenge ubiquitin from oncogenic protein substrates, so effective inhibition of USP7 may be a potential key treatment for GBM. Methods Immunohistochemistry and western blotting were used to detect the expression of USP7 in GBM tissues. In vitro apoptosis assay of USP7 inhibition was performed by western blotting, immunofluorescence, and flow cytometry. Anti-apoptotic substrates of USP7 were defined by Co-IP and TMT proteomics. Western blotting and IP were used to verify the relationship between USP7 and its substrate. In an in vivo experiment using an intracranial xenograft model in nude mice was constructed to assess the therapeutic effect of target USP7. Results Immunohistochemistry and western blotting confirmed that USP7 was significantly upregulated in glioblastoma samples. In in vitro experiments, inhibition of USP7 in GBM induced significant apoptosis. Co-IP and TMT proteomics identified a key anti-apoptotic substrate of USP7, ADP-ribosylation factor 4 (ARF4). Western blotting and IP confirmed that USP7 interacted directly with ARF4 and catalyzed the removal of the K48-linked polyubiquitinated chain that binded to ARF4. In addition, in vivo experiments revealed that USP7 inhibition significantly suppressed tumor growth and promoted the expression of apoptotic genes. Conclusions Targeted inhibition of USP7 enhances the ubiquitination of ARF4 and ultimately mediates the apoptosis of GBM cells. In a clinical sense, P5091 as a novel specific inhibitor of USP7 may be an effective approach for the treatment of GBM.

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Endoplasmic reticulum stress‑induced cell death as a potential mechanism for targeted therapy in glioblastoma (Review)

Cited by 9 publications

References 195 publications

Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models

Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models

The landscape of circRNAs in gliomas temozolomide resistance: Insights into molecular pathways

USP7 inhibition induces apoptosis in glioblastoma by enhancing ubiquitination of ARF4

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