Necroptosis triggered by ROS accumulation and Ca2+ overload, partly explains the inflammatory responses and anti-cancer effects associated with 1Hz, 100 mT ELF-MF in vivo

Abstract

Background: Focus on application of non-ionizing, extremely low frequency magnetic elds (ELF-EMF) as an alternative approach for treating cancer is rapidly rising nowadays. Nevertheless, little is known about the underlying anti-tumoral mechanism of action of them.Methods: In the present study, for the rst time, we reported that along with apoptosis, 2 h/day exposure to 100 Hz, 1 mT ELF-EMF for a 5-day period, can induce necroptosis, a speci c type of programed necrotic cell death, by promoting RIPK1/RIPK3/MLKL pathway which may also be responsible for observed pro-in ammatory responses in vivo, evident from an increase in plasma levels of proin ammatory cytokines including TNF-α, IL-1β, IL-2, IL-6, IL-17A and IFN-γ. Alongside, 30-day exposure to this system could also signi cantly suppress tumor growth and expression of markers of tumor cell proliferation, angiogenesis, and metastasis, namely Ki-67, CD31, VEGFR2 and MMP-9.Results: The number of tumor in ltrating lymphocytes (TILs), especially CD8+ T h cells were signi cantly increased following exposure to ELF-EMF. Interestingly, pretreating cancer cells with N-acetyl cysteine, a free-radical scavenger, or verapamil, an L-type calcium channel blocker in vitro, could diminish observed necroptotic and apoptotic responses while pretreating with calcium chloride, could aggravate responses.Conclusions: Overall, results of present study demonstrated that along with apoptosis, necroptosis is also

Magnetic Fields and Cancer: Epidemiology, Cellular Biology, and Theranostics

“…On the other hand, a common effect of exposure to SMF is the promotion of apoptosis and mitosis, but not of necrosis or modifications of the cell shape [182,183]. The unbalance of the apoptotic process could be linked to Ca 2+ fluxes that are, in turn, dependent on the effect on the plasma membrane that is exerted by SMF [184][185][186][187]. Other possible effects of SMFs that may lead to perturbation of the apoptotic rate, such as an alteration of the gene pattern expression or the increase of oxygen free-radicals, could be, in turn, a co-carcinogenic factor leading normal cells, most likely with other sub-lethal changes, to contribute to the development of diseases [183].…”

Differential biological responses of adherent and non-adherent (cancer and non-cancerous) cells to variable extremely low frequency magnetic fields

“…Besides, mechanical forces between cells and extracellular matrix (ECM) can change cell morphology, function, spreading, and volume 38 , 39 . There are several investigations in which the effect of ELF-EMF on voltage gated calcium channels has been reported that would lead to increase intracellular calcium levels 40 , 41 . Although, there is no evidence of the ELF-EMF effects on mechanosensitive calcium channels like Piezo1, it could be a possible mechanism to stimulate oxidative stress and morphological alterations, cell swelling through cytoskeleton re-organization, as well.…”

Ion channels as molecular targets of glioblastoma electrotherapy

“…Extremely low-frequency electromagnetic fields (ELF-EMF, 8 Hz for 48 h) reportedly stimulate Ca 2+ influx in B16-F10 melanoma cells that is blunted by L-and T-type Ca v channel blockers (Wang et al, 2021). Functionally, ELF-EMF (1 mT, 100 Hz 1.3 ms, 2 h/day for 5 days) have been demonstrated to induce cell death in MC4-L2 breast cancer cells in a verapamil-sensitive manner (Barati et al, 2021). Likewise, a growth-impairing action of ELF-EMF (5-10 µT, frequency-modulated in a 25-6 Hz and 6-25 Hz frequency pattern, 1 h/day for 3-5 days) has been demonstrated in HeLa (cervix carcinoma), MDA-MB-231, and MCF-7 (both breast carcinoma), as well as B16-BL6 (mouse melanoma) cells but not in three non-malignant cell lines (Buckner et al, 2015).…”

“…In vitro (e.g., Rozek et al, 1987;García-Sancho et al, 1994;Morgado-Valle et al, 1998;Aldinucci et al, 2000;Djamgoz et al, 2001;Verdugo-Díiaz et al, 2002;Rosen, 2003;Grassi et al, 2004;Giladi et al, 2014aGiladi et al, , 2017Bertagna et al, 2022;Toda et al, 2022) and preclinical in vivo studies (e.g., Kirson et al, 2007Kirson et al, , 2009aGiladi et al, 2014a,b;Buckner et al, 2015;Castellví et al, 2015;Li et al, 2016;Voloshin et al, 2016, Jo et al, 2018Kim et al, 2018;Voloshin et al, 2020a;Barati et al, 2021;Wu et al, 2021;Davidi et al, 2022;Huegel et al, 2022), as well as randomized controlled clinical trials (e.g., Mooney, 1990;Linovitz et al, 2002;Foley et al, 2008;Stupp et al, 2017), have accumulated some evidence for a responsiveness of physiological processes to weak external EMF. As a consequence, the US Food and Drug Administration (FDA) has approved electrotherapies in the low frequency to radiofrequency band and the non-hyperthermia-inducing, nonelectroporating, non-ionizing energy spectrum.…”