Tumour-treating fields (TTFields): Investigations on the mechanism of action by electromagnetic exposure of cells in telophase/cytokinesis

Berkelmann, Lukas; Bader, Almke; Meshksar, Saba; Dierks, Anne; Majernik, Gökce Hatipoglu; Krauss, Joachim K.; Schwabe, Kerstin; Manteuffel, Dirk; Ngezahayo, Anaclet

doi:10.1038/s41598-019-43621-9

Cited by 55 publications

(39 citation statements)

References 35 publications

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“…It is understood that TTF show efficacy by disrupting mitotic capacity of the cell by inhibiting spindle apparatus formation [ 169 ]. However, there are clear morphological changes and this proposed mechanism does not fully explain or account for the genetic changes observed.…”

Section: Electrotherapymentioning

confidence: 99%

Ion Channels as Therapeutic Targets in High Grade Gliomas

Griffin

Khan

Basu

et al. 2020

Cancers

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Glioblastoma multiforme (GBM) is a lethal brain cancer with an average survival of 14–15 months even with exhaustive treatment. High grade gliomas (HGG) represent the leading cause of CNS cancer-related death in children and adults due to the aggressive nature of the tumour and limited treatment options. The scarcity of treatment available for GBM has opened the field to new modalities such as electrotherapy. Previous studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence indicates that not only are ion channels key in regulating electrical signaling and membrane potential of excitable cells, they perform a crucial role in the development and neoplastic progression of brain tumours. Unlike other tissue types, neural tissue is intrinsically electrically active and reliant on ion channels and their function. Ion channels are essential in cell cycle control, invasion and migration of cancer cells and therefore present as valuable therapeutic targets. This review aims to discuss the role that ion channels hold in gliomagenesis and whether we can target and exploit these channels to provide new therapeutic targets and whether ion channels hold the mechanistic key to the newfound success of electrotherapies.

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Section: Electrotherapymentioning

confidence: 99%

Ion Channels as Therapeutic Targets in High Grade Gliomas

Griffin

Khan

Basu

et al. 2020

Cancers

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“…Therefore, to understand the underlying mechanism of action www.nature.com/scientificreports/ of TTFields and establish an efficient strategy for combating cancer, we analysed gene expression according to the TP53 status on the variable cell response of GBM cell lines. The regulatory mechanism of the cell cycle and apoptosis by TTFields is well-known in cancer biology 28 . In addition, immune cell infiltration and immunogenic cell death by TTFields treatment have been previously reported 29,30 .…”

Section: Discussionmentioning

confidence: 99%

“…The regulatory mechanism of the cell cycle and apoptosis by TTFields is well-known in cancer biology 28 . In addition, immune cell infiltration and immunogenic cell death by TTFields treatment have been previously reported 29 , 30 .…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling of glioblastoma cell lines depending on TP53 status after tumor-treating fields (TTFields) treatment

Lee

Seo

Baek

et al. 2020

Sci Rep

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Glioblastoma is frequently associated with TP53 mutation, which is linked to a worse prognosis and response to conventional treatments (chemoradiotherapy). Therefore, targeting TP53 is a promising strategy to overcome this poor therapeutic response. Tumor-treating fields (TTFields) are a recently approved treatment for newly diagnosed glioblastoma, which involves direct application of lowintensity, intermediate-frequency alternating electric fields to the tumor, thereby offering a local tumor-killing effect. However, the influence of TP53 mutation status on the effectiveness of TTFields is controversial. Here, we identified the key gene signatures and pathways associated with TTFields in four glioblastoma cell lines varying in TP53 mutation status using gene profiling and functional annotation. Overall, genes associated with the cell cycle, cell death, and immune response were significantly altered by TTFields regardless of TP53 status. TTFields appeared to exert enhanced anticancer effects by altering the immune system in the inflammatory environment and regulating cell cycle-and cell death-related genes, but the precise genes influenced vary according to TP53 status. These results should facilitate detailed mechanistic studies on the molecular basis of TTFields to further develop this modality as combination therapy, which can improve the therapeutic effect and minimize side effects of chemoradiotherapy. Glioblastoma (GBM) a histological subtype of glioma in which most patients survive for an average of 12-15 months 1. In primary and secondary GBM, TP53 mutation is observed in up to 30% and 70% of cases, respectively, which results in a common molecular abnormality 2. TP53 is a major tumor suppressor that selectively eliminates mutated or damaged cells 3 , reduces the proliferation of cancer cells, and prevents the malignant transformation of normal cells 4. Moreover, TP53 regulates transcriptional target genes involved in many cellular responses including apoptosis 5 , senescence 6 , DNA repair 7 , and cell cycle 8 , among others. Several decades of research of glioma has shown that not only does TP53 serve a central role in the regulatory network of tumorigenesis, but also that the TP53 status is closely associated with the disease progression and survival of patients with GBM during radio-and chemotherapy 9,10. Several researchers have suggested that TP53-based targeted therapy is a promising approach for treating GBM, but its value as a prognostic marker in the clinical field is unclear. Microarray analysis is a useful method for evaluating therapies for GBM to detect differential expression between normal and cancer cells following treatment with specific drugs or physical procedures 11,12. TP53 has functional effects on the transcriptional profiles of genes in several cancer cell lines 13 , but the impact of tumortreating fields (TTFields) on GBM according to the TP53 status remains unknown. TTFields has been proposed as an effective cancer treatment in combination with other therapies 14. Alternating ele...

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“…At this narrow mitotic region, the power absorption (as consequence of TTFields delivery) was higher and dependent on field frequency. This effect was only appreciated when the mitotic furrow was aligned and parallel to the electric field and may explain why cell proliferation is not completely blocked by TTFields, but only partially decreased ( 19 ). Subsequent computational modeling calculated the electric field distribution in the brain during TTFields therapy and investigated the reliability of their predictions with respect to heterogeneous, anisotropic dielectric properties.…”

Section: Tumor Treating Fields: Physics Primer and Putative Mechanismmentioning

confidence: 99%

Tumor Treating Fields: At the Crossroads Between Physics and Biology for Cancer Treatment

et al. 2020

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Despite extraordinary advances that have been achieved in the last few decades, cancer continues to represent a leading cause of mortality worldwide. Lethal cancer types ultimately become refractory to standard of care approaches; thus, novel effective treatment options are desperately needed. Tumor Treating Fields (TTFields) are an innovative non-invasive regional anti-mitotic treatment modality with minimal systemic toxicity. TTFields are low intensity (1-3 V/cm), intermediate frequency (100-300 kHz) alternating electric fields delivered to cancer cells. In patients, TTFields are applied using FDA-approved transducer arrays, orthogonally positioned on the area surrounding the tumor region, with side effects mostly limited to the skin. The precise molecular mechanism of the anti-tumor effects of TTFields is not well-understood, but preclinical research on TTFields suggests it may act during two phases of mitosis: at metaphase, by disrupting the formation of the mitotic spindle, and at cytokinesis, by dielectrophoretic dislocation of intracellular organelles leading to cell death. This review describes the mechanism of action of TTFields and provides an overview of the most important in vitro studies that investigate the disruptive effects of TTFields in different cancer cells, focusing mainly on anti-mitotic roles. Lastly, we summarize completed and ongoing TTFields clinical trials on a variety of solid tumors.

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Tumour-treating fields (TTFields): Investigations on the mechanism of action by electromagnetic exposure of cells in telophase/cytokinesis

Cited by 55 publications

References 35 publications

Ion Channels as Therapeutic Targets in High Grade Gliomas

Ion Channels as Therapeutic Targets in High Grade Gliomas

Gene expression profiling of glioblastoma cell lines depending on TP53 status after tumor-treating fields (TTFields) treatment

Tumor Treating Fields: At the Crossroads Between Physics and Biology for Cancer Treatment

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