Abstract
Whereas the anti-neoplastic activity of extremely low frequency magnetic fields (ELF-EMF) is well-documented in literature, little is known about its underlying anti-cancer mechanisms and induced types of cell death. Here, for the first time, we reported induction of necroptosis, a specific type of programed necrotic cell death, in MC4-L2 breast cancer cell lines following a 2 h/day exposure to a 100 Hz, 1 mT ELF-EMF for five days. For in vivo assessment, inbred BALB/c mice bearing established MC-4L2 tumors were exposed to 100 mT, 1 Hz ELF-EMF 2 h daily for a period of 28-day, following which tumors were dissected and fixed for evaluation of tumor biomarkers expression and types of cell death induced using TUNEL assay, Immunohistochemistry and H&E staining. Peripheral blood samples were also collected for assessing pro-inflammatory cytokine profile following exposure. An exaggerated proinflammatory response evident form enhancement of IFN-γ (4.8 ± 0.24 folds) and TNF-α (3.1 ± 0.19 folds) and number of tumors infiltrating lymphocytes (TILs), specially CD8+ Th cells (~20 folds), proposed occurrence of necroptosis in vivo. Meanwhile, exposure could effectively suppress tumor growth and expression of Ki-67, CD31, VEGFR2 and MMP-9. In vitro studies on ELF-EMF exposed MC-4L2 cells demonstrated a meaningful increase in phosphorylation of RIPK1/RIPK3/MLKL proteins and cleavage of caspase-9/caspase-3, confirming occurrence of both necroptosis and apoptosis. Complementary in vitro studies by treating ELF-EMF exposed MC-4L2 cells with verapamil (a calcium channel inhibitor), N-acetyl cysteine (a ROS scavenger) or calcium chloride confirmed the role of elevated intracellular calcium and ROS levels in ELF-EMF induced necroptosis.
Highlights
Focus on application of non-ionizing, extremely low frequency magnetic fields (ELF-electromagnetic fields (EMFs)) as an alternative approach for treating cancer is rapidly rising nowadays
Overall, results of present study demonstrated that along with apoptosis, necroptosis is a prominent form of cell death induced by exposure to ELF-EMF which is dependent on elevated intracellular levels of reactive oxygen species (ROS) and calcium
Exposure to ELF-EMF induced a pro-inflammatory response in vivo resembling those of necroptosis
Summary
Focus on application of non-ionizing, extremely low frequency magnetic fields (ELF-EMF) as an alternative approach for treating cancer is rapidly rising nowadays. Modulatory effects of electromagnetic fields (EMFs) on living cells and tissues has long been documented in vitro and in vivo, our understanding from mechanisms of these interactions still remains in its infancy and far from being completely understood [1, 2] In this context, recent studies on extremely low frequency electromagnetic fields (ELF-EMFs), produced by several household devices and industrial networks, have shown that these non-ionizing waves can affect multiple biological processes in living matter including expression of genes and proteins, as well as modulating physiological pathways governing cellular proliferation, differentiation or integrity either in direct or indirect ways [3,4,5,6,7]. Diversities in applied magnetic fields strengths, in addition to the lack of a generally accepted mechanism of action, has made it difficult to compare the results of exposure to ELF-EMF in different studies and come up with a unit treatment protocol
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