BEMER Electromagnetic Field Therapy Reduces Cancer Cell Radioresistance by Enhanced ROS Formation and Induced DNA Damage
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.
This is part of the original study. For the full version visit the following link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154536/
BEMER therapy decreases radioresistance and increases DSB numbers dependent on BEMER signal intensity
To elucidate whether the radiosensitizing effect of BEMER therapy is related with increased signal intensity and increased number of radiation-induced DNA double strand breaks (DSBs), we applied the BEMER signal with varying intensities between 2.7 and 35 μT 1 h after 6-Gy X-ray irradiation (Fig 8A). In A549, UTSCC15 and MiaPaCa2 but not DLD1 cells, BEMER therapy accomplished radiosensitization in a signal intensity-dependent manner compared with BEMER sham-treated, irradiated controls (Fig 8B). Accordingly, DSB numbers of A549 and UTSCC15 cells were significantly elevated by BEMER EMF exposure intensity-dependently compared to controls (Fig 8C and 8D). These results suggest a connection between BEMER therapy-mediated radiosensitization and DSB induction.
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.
BEMER therapy increases ROS levels leading to radiosensitization via increased induction of DSBs
Connecting ROS as essential regulator of metabolomic processes and DNA damaging factor, we tested for different ROS scavengers (here sodium pyruvat, MnTBAP, Carboxy-PTIO) given prior to BEMER therapy (Fig 9A). While sodium pyruvate only abolished the effect of BEMER therapy in UTSCC15 but not in A549 cells (Fig 9B), the ROS scavengers MnTBAP and Carboxy-PTIO abrogated the BEMER-mediated radiosensitization in both cell lines leading to similar clonogenic survival as observed for BEMER sham-treated, irradiated controls (Fig 9B). Next, we tested the effect of MnTBAP and Carboxy-PTIO pretreatment on DSB induction upon BEMER treatment and irradiation and found that both scavengers reduced DSB numbers to a level similar to controls (Fig 9C). These findings indicate that the radiosensitization mediates by the BEMER therapy elicits from increased ROS levels and subsequent generation of DSBs.
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.
This is part of the original study. For the full version visit the following link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154536/
