Comment in Response to “Temozolomide in Glioblastoma Therapy: Role of Apoptosis, Senescence and Autophagy etc. by B. Kaina”

Westhoff, Mike‐Andrew; Baisch, Tim; Herbener, Verena J.; Karpel‐Massler, Georg; Debatin, Klaus‐Michael; Strobel, Hannah A.

doi:10.3390/biomedicines8040093

Cited by 6 publications

(4 citation statements)

References 16 publications

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“…Results obtained with concentrations much higher than what can be achieved in patients may only be helpful to elucidate toxicities and off-target effects [23]. While it has frequently been suggested that a single high drug dose might be a good surrogate for repeated re-administration, we find this notion lacking in evidence [24]. Despite advances in in silico modelling, defining the clinically relevant and achievable concentration of a novel agent a priori remains virtually impossible [25].…”

Section: Theophrastus Bombast Von Hohenheimmentioning

confidence: 88%

Considering the Experimental Use of Temozolomide in Glioblastoma Research

Herbener¹,

Burster

Goreth³

et al. 2020

Biomedicines

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Temozolomide (TMZ) currently remains the only chemotherapeutic component in the approved treatment scheme for Glioblastoma (GB), the most common primary brain tumour with a dismal patient’s survival prognosis of only ~15 months. While frequently described as an alkylating agent that causes DNA damage and thus—ultimately—cell death, a recent debate has been initiated to re-evaluate the therapeutic role of TMZ in GB. Here, we discuss the experimental use of TMZ and highlight how it differs from its clinical role. Four areas could be identified in which the experimental data is particularly limited in its translational potential: 1. transferring clinical dosing and scheduling to an experimental system and vice versa; 2. the different use of (non-inert) solvent in clinic and laboratory; 3. the limitations of established GB cell lines which only poorly mimic GB tumours; and 4. the limitations of animal models lacking an immune response. Discussing these limitations in a broader biomedical context, we offer suggestions as to how to improve transferability of data. Finally, we highlight an underexplored function of TMZ in modulating the immune system, as an example of where the aforementioned limitations impede the progression of our knowledge.

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Section: Theophrastus Bombast Von Hohenheimmentioning

confidence: 88%

Considering the Experimental Use of Temozolomide in Glioblastoma Research

Herbener¹,

Burster

Goreth³

et al. 2020

Biomedicines

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“…Autophagy and apoptosis were 2 important mechanisms and considered a new target for therapeutic interventions in brain tumors. 27 Therefore, searching key factors to regulate autophagy and apoptosis may be a vital step in the treatment of glioblastoma. However, the specific role of B4GalT1 for autophagy and apoptosis in glioblastoma remains unclear.…”

Section: Discussionmentioning

confidence: 99%

B4GalT1 Regulates Apoptosis and Autophagy of Glioblastoma In Vitro and In Vivo

Wang

Xie

2020

Technol Cancer Res Treat

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Our study was designed to investigate the role of B4GalT1 in glioblastoma, in vitro and in vivo, to detect whether B4GalT1 knockdown could regulate the development of glioblastoma, and further observe the relationship between B4GalT1 knockdown and the apoptosis and autophagy of glioblastoma. To begin, we looked at TCGA and GEPIA systems to predict the potential function of B4GalT1. Western blot and RT-PCR were used to analyze the expression, or mRNA level, of B4GalT1 at different tissue or cell lines. Next, the occurrence and development of glioblastoma, in vitro and in vivo, was observed by using B4GalT1 knocked down by lentivirus. Finally, the apoptosis and autophagy of glioblastoma was observed in vitro and in vivo. Results show that B4GalT1 was a highly variable gene, and GEPIA and TCGA systems show B4GalT1 expression in GBM tumor tissue was higher than in normal tissue. Pair-wise gene correlation analysis revealed a probable relationship between B4GalT1 and autophagy related proteins. The B4GalT1 expression and mRNA level were increased in tumor cells, or U87 cells. B4GalT1 knocked down by lentivirus could inhibit glioblastoma development, in vitro and in vivo, by reducing tumor weight and volume, increasing survival, and weakening tumor cells proliferation, migration, invasion. B4GalT1 knockdown could increase apoptosis and autophagy of glioblastoma in vitro and in vivo. Our study demonstrates that B4GalT1 may be able to regulate apoptosis and autophagy of glioblastoma. Bax, Bcl-2, cleaved caspase-3, Beclin-1, and LC3 s may be the downstream target factors of B4GalT1 in apoptosis and autophagy, which may provide a new strategy to reduce glioblastoma development by regulating apoptosis and autophagy.

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“…TMZ is frequently described as a DNA alkylating prodrug that induces double-strand breaks of the DNA which eventually lead to apoptosis (Karachi et al, 2018;Sharifzad et al, 2019). Recently, a debate has emerged casting doubt on the precise molecular function of this component (Strobel et al, 2019;Kaina, 2019;Stepanenko and Chekhonin, 2019;Westhoff et al, 2020;Herbener et al, 2020). According to the traditionally proposed model, TMZ alkylates bases that are present in the DNA, leading to a mismatch during replication and induces futile rounds of DNA repair, finally ending in DNA strand breaks and apoptosis (Kaina, 2019).…”

Section: Introductionmentioning

confidence: 99%

Critical View of Novel Treatment Strategies for Glioblastoma: Failure and Success of Resistance Mechanisms by Glioblastoma Cells

Burster

Traut

Yermekkyzy

et al. 2021

Front. Cell Dev. Biol.

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According to the invasive nature of glioblastoma, which is the most common form of malignant brain tumor, the standard care by surgery, chemo- and radiotherapy is particularly challenging. The presence of glioblastoma stem cells (GSCs) and the surrounding tumor microenvironment protects glioblastoma from recognition by the immune system. Conventional therapy concepts have failed to completely remove glioblastoma cells, which is one major drawback in clinical management of the disease. The use of small molecule inhibitors, immunomodulators, immunotherapy, including peptide and mRNA vaccines, and virotherapy came into focus for the treatment of glioblastoma. Although novel strategies underline the benefit for anti-tumor effectiveness, serious challenges need to be overcome to successfully manage tumorigenesis, indicating the significance of developing new strategies. Therefore, we provide insights into the application of different medications in combination to boost the host immune system to interfere with immune evasion of glioblastoma cells which are promising prerequisites for therapeutic approaches to treat glioblastoma patients.

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Comment in Response to “Temozolomide in Glioblastoma Therapy: Role of Apoptosis, Senescence and Autophagy etc. by B. Kaina”

Abstract: It is with great pleasure that we acknowledge the fact that our review on Temozolomide (TMZ) has initiated a discussion [...]

Cited by 6 publications

References 16 publications

Considering the Experimental Use of Temozolomide in Glioblastoma Research

Considering the Experimental Use of Temozolomide in Glioblastoma Research

B4GalT1 Regulates Apoptosis and Autophagy of Glioblastoma In Vitro and In Vivo

Critical View of Novel Treatment Strategies for Glioblastoma: Failure and Success of Resistance Mechanisms by Glioblastoma Cells

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