Abstract
In accordance with the classification of the International Agency for Research on Cancer, extremely low frequency magnetic fields (ELF-MF) are suspected to promote malignant progression by providing survival advantage to cancer cells through the activation of critical cytoprotective pathways. Among these, the major antioxidative and detoxification defence systems might be targeted by ELF-MF by conferring cells significant resistance against clinically-relevant cytotoxic agents. We investigated whether the hyperproliferation that is induced in SH-SY5Y human neuroblastoma cells by a 50 Hz, 1 mT ELF magnetic field was supported by improved defence towards reactive oxygen species (ROS) and xenobiotics, as well as by reduced vulnerability against both H2O2 and anti-tumor ROS-generating drug doxorubicin. ELF-MF induced a proliferative and survival advantage by activating key redox-responsive antioxidative and detoxification cytoprotective pathways that are associated with a more aggressive behavior of neuroblastoma cells. This was coupled with the upregulation of the major sirtuins, as well as with increased signaling activity of the erythroid 2-related nuclear transcription factor 2 (NRF2). Interestingly, we also showed that the exposure to 50 Hz MF as low as 100 µT may still be able to alter behavior and responses of cancer cells to clinically-relevant drugs.
Highlights
The use of electric devices and equipments in clinical practice, industrial environments, and common domestic situations generate extremely low frequency magnetic fields (ELF-MF) with frequencies of 0–60 Hz, and magnetic flux densities up to 10 mT1
As previously reported by some of us[10, 12], no time-dependent effect was detected. These results suggested that the 50 Hz, 1 mT ELF-MF induced a powerful time-independent increase in biomass growth of neuroblastoma cell cultures
SH-SY5Y cells that were exposed to the 1 mT MF continued to exhibit a statistically significant increase in the growth rate even after the power supply was switched off for 5 days (+43.8%, as compared to unexposed cells; P < 0.001), indicating that the hyperproliferative response of SH-SY5Y cells was not reverted by the removal of the MF
Summary
The use of electric devices and equipments in clinical practice, industrial environments, and common domestic situations generate extremely low frequency magnetic fields (ELF-MF) with frequencies of 0–60 Hz, and magnetic flux densities up to 10 mT1. The reports available so far are mostly limited to short-term studies, and this may represent a major weakness as ELF electromagnetic fields are nearly omnipresent, making chronic exposure to multiple ELF fields an everyday experience for most people[47] On this basis, the aim of this study was to provide a proof-of-concept that the cytoproliferative response of human neuroblastoma cells under continuous exposure to a 50 Hz, 1 mT magnetic field could be associated with simultaneous cytoprotective adaptations involving the enhancement of key ROS-targeting and detoxification enzymatic systems, through the possible regulation of the upstream SIRT/NRF2-dependent control. As it is suspected that ELF-MF lower than 1 mT (i.e., the new reference level established in 2010 by the International Commission on Non-Ionizing Radiation Protection guidelines for occupational exposures to power frequency ELF magnetic fields49) may result in significant alterations of cellular behavior[50], we wanted to verify whether the major effects that were elicited by 1 mT MF were detected when neuroblastoma cells were exposed to a 50 Hz, 100 μT MF
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