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, 11 (12), e0167931
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BEMER Electromagnetic Field Therapy Reduces Cancer Cell Radioresistance by Enhanced ROS Formation and Induced DNA Damage

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BEMER Electromagnetic Field Therapy Reduces Cancer Cell Radioresistance by Enhanced ROS Formation and Induced DNA Damage

Katja Storch et al. PLoS One.

Abstract

Each year more than 450,000 Germans are expected to be diagnosed with cancer subsequently receiving standard multimodal therapies including surgery, chemotherapy and radiotherapy. On top, molecular-targeted agents are increasingly administered. Owing to intrinsic and acquired resistance to these therapeutic approaches, both the better molecular understanding of tumor biology and the consideration of alternative and complementary therapeutic support are warranted and open up broader and novel possibilities for therapy personalization. Particularly the latter is underpinned by the increasing utilization of non-invasive complementary and alternative medicine by the population. One investigated approach is the application of low-dose electromagnetic fields (EMF) to modulate cellular processes. A particular system is the BEMER therapy as a Physical Vascular Therapy for which a normalization of the microcirculation has been demonstrated by a low-frequency, pulsed EMF pattern. Open remains whether this EMF pattern impacts on cancer cell survival upon treatment with radiotherapy, chemotherapy and the molecular-targeted agent Cetuximab inhibiting the epidermal growth factor receptor. Using more physiological, three-dimensional, matrix-based cell culture models and cancer cell lines originating from lung, head and neck, colorectal and pancreas, we show significant changes in distinct intermediates of the glycolysis and tricarboxylic acid cycle pathways and enhanced cancer cell radiosensitization associated with increased DNA double strand break numbers and higher levels of reactive oxygen species upon BEMER treatment relative to controls. Intriguingly, exposure of cells to the BEMER EMF pattern failed to result in sensitization to chemotherapy and Cetuximab. Further studies are necessary to better understand the mechanisms underlying the cellular alterations induced by the BEMER EMF pattern and to clarify the application areas for human disease.

Conflict of interest statement

The BEMER Int. AG had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Importantly, this does also not affect our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. BEMER device and application.
(A) The electromagnetic field (EMF) with a pulse-duration of 30 ms and a pulse-frequency of 30 Hz was generated by a commercially available control unit B.Box Classic (BEMER AG Int.) with 10 different levels of magnetic field intensity (from 0 μT to 35 μT). (B) The mattress applicator with a flat coil system specifically designed for cell culture. (C) Mattress applicator measurements and scheme of how cell culture plates were placed for BEMER therapy (red rectangles).
Fig 2
Fig 2. The specific BEMER EMF pattern impacts on cancer cell metabolism.
(A) Pie chart showing the number of detected metabolites categorized by pathways (Σ 225). (B) Heatmap comparing levels of metabolites in BEMER signal treated (~13 μT, 8 min) and BEMER sham-treated (sham) A549 cells. Red and blue indicate up- and downregulation, respectively. Cells were cultured in 3D lrECM for 24 h prior to BEMER treatment. (C) Amount of indicated metabolites in A549 cells without (sham) and with BEMER EMF exposure. (D) Scheme of glycolysis and TCA cycle. Metabolites in blue were downregulated, in red upregulated and in black unaffected upon BEMER therapy compared with sham-treated controls. Metabolites depicted in green were not measured in the metabolome analysis. All results represent mean ± SD. Student's t-test. n = 5. * P < 0.05; ** P < 0.01.
Fig 3
Fig 3. BEMER therapy mediates radiosensitization of cancer cells.
(A) Phase contrast images and (B) basal surviving fraction of 3D grown colonies of BEMER treated (~13 μT, 8 min, 1 h, 24 h) and BEMER sham-treated (sham) cancer cell lines. (C) Flow chart of colony formation assay. (D) Clonogenic cell survival after BEMER therapy (~13 μT, 8 min, 1 h, 24 h) combined with radiotherapy (2 and 6 Gy). All results represent mean ± SD. Student's t-test. n = 3. * P < 0.05; ** P < 0.01.
Fig 4
Fig 4. BEMER therapy radiosensitizes microtumors.
(A) Flow chart of colony formation assay. (B) Basal surviving fraction of BEMER (~13 μT, 8 min, 1 h, 24 h) treated and BEMER sham-treated (sham) microtumors. (C) Clonogenic survival after BEMER therapy (~13 μT, 8 min, 1 h, 24 h) combined with radiotherapy (2 and 6 Gy). All results represent mean ± SD. Student's t-test compares BEMER therapy versus sham samples. n = 3. * P < 0.05; ** P < 0.01.
Fig 5
Fig 5. BEMER therapy-mediated radiosensitization depends on treatment intervals and frequency.
(A) Flow chart of colony formation assay. (B) Clonogenic survival after BEMER therapy (~13 μT, 8 min) combined with 6-Gy irradiation of indicated cell lines. BEMER sham-treated (sham) and irradiated cells served as control. Time intervals of 0, 1, 6, and 24 h between BEMER therapy and radiotherapy were applied. (C) Flow chart of colony formation assay. (D) Clonogenic survival of one time or two time BEMER therapy (~13 μT, 8 min) combined with 6-Gy irradiation of indicated cell lines (BEMER sham-treated (sham), irradiated cells as control). All results represent mean ± SD. Student's t-test. n = 3. * P < 0.05; ** P < 0.01. n.s., not significant.
Fig 6
Fig 6. Sensitivity to chemotherapy and Cetuximab is not influenced by BEMER therapy.
(A) Flow chart of colony formation assay. Cells were plated in 3D lrECM, treated with respective agents followed by BEMER therapy 23 h later. (B) Basal surviving fraction after Cisplatin (0.1 μM; DMEM as control) treatment and BEMER therapy (~13 μT, 8 min). (C) Basal surviving fraction after Gemcitabine (10 nM; DMEM as control) treatment and BEMER therapy (~13 μT, 8 min). BEMER sham-treated (sham) cells served as control. (D) Basal surviving fraction after Cetuximab (5 μg/ml; IgG as control) treatment and BEMER therapy (~13 μT, 8 min). IgG-treated cells served as control. All results represent mean ± SD. Student's t-test. n = 3. * P < 0.05; ** P < 0.01. n.s., not significant.
Fig 7
Fig 7. BEMER therapy-mediated radiosensitization remains unaltered upon chemotherapy and Cetuximab.
(A) Flow chart of colony formation assay. (B) Clonogenic survival after 6-Gy irradiation combined with BEMER therapy (~13 μT, 8 min) and Cisplatin (0.1 μM; DMEM as control). (C) Clonogenic survival after 6-Gy irradiation combined with BEMER therapy (~13 μT, 8 min) and Gemcitabine (10 nM; DMEM as control). Sham-treated (sham) but irradiated cells served as control. (D) Clonogenic survival after 6-Gy irradiation combined with BEMER therapy (~13 μT, 8 min) and Cetuximab (5 μg/ml; IgG as control). IgG-treated, irradiated cells served as control. All results represent mean ± SD. Student's t-test. n = 3. * P < 0.05; ** P < 0.01. n.s., not significant.
Fig 8
Fig 8. BEMER signal intensity determines radiosensitization and DSB numbers.
(A) Flow chart of colony formation assay and foci assay. (B) Clonogenic survival after 6-Gy irradiation combined with BEMER therapy (2.7–35 μT; 8 min) of A549 and UTSCC15 cells. (C) Immunofluorescence images show nuclei with γH2AX/53BP1-positive foci after 6-Gy irradiation with (~13 or ~35 μT; 8 min) and without BEMER therapy in A549 cells. (D) Number of γH2AX/53BP1-positive DSBs 24 h after irradiation in A549 and UTSCC15 cells. BEMER sham-treated (sham), irradiated cells served as control. All results represent mean ± SD. Student's t-test. n = 3. * P < 0.05; ** P < 0.01.
Fig 9
Fig 9. BEMER therapy induces elevated ROS levels resulting in increased DSB numbers.
(A) Flow chart of colony formation assay and foci assay. (B) Surviving fraction of indicated cell lines treated with sodium pyruvate (10 μM), MnTBAP (50 μM) or Carboxy-PTIO (50 μM) in combination with BEMER therapy and radiotherapy. (C) Number of γH2AX/53BP1-positive DSBs 24 h after irradiation in A549 and UTSCC15 cells. Cells were treated with indicated scavenger agents and BEMER therapy (~35 μT, 8 min). BEMER sham-treated (sham), irradiated cells served as control. All results represent mean ± SD. Student's t-test. n = 3. ** P < 0.01. n.s., not significant.

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Grant support

The research and authors were in part supported by the BEMER Int. AG (Liechtenstein) and grants from the Deutsche Krebshilfe (108976 to N.C.), the European Union (RADIATE; GA No. 642623 to N.C.) and the EFRE Europäische Fonds für regionale Entwicklung, Europa fördert Sachsen (100066308). This work was also supported in part by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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