Abstract
BackgroundCapacitive-resistive electric transfer (CRET) is a non-invasive therapeutic strategy that applies radiofrequency electric currents within the 400–600 kHz range to tissue repair and regeneration. Previous studies by our group have shown that 48 h of intermittent exposure to a 570 kHz CRET signal at a subthermal density of 50 μA/mm2 causes significant changes in the expression and activation of cell cycle control proteins, leading to cycle arrest in human cancer cell cultures. The present study investigates the relevance of the signal frequency in the response of the human neuroblastoma cell line NB69 to subthermal electric treatment with four different signal frequency currents within the 350–650 kHz range.MethodsTrypan blue assay, flow cytometry, immunofluorescence and immunoblot were used to study the effects of subthermal CRET currents on cell viability, cell cycle progression and the expression of several marker proteins involved in NB69 cell death and proliferation.ResultsThe results reveal that among the frequencies tested, only a 448 kHz signal elicited both proapoptotic and antiproliferative, statistically significant responses. The apoptotic effect would be due, at least in part, to significant changes induced by the 448 kHz signal in the expression of p53, Bax and caspase-3. The cytostatic response was preceded by alterations in the kinetics of the cell cycle and in the expression of proteins p-ERK1/2, cyclin D1 and p27, which is consistent with a potential involvement of the EGF receptor in electrically induced changes in the ERK1/2 pathway. This receives additional support from results indicating that the proapototic and antiproliferative responses to CRET can be transiently blocked when the electric stimulus is applied in the presence of PD98059, a chemical inhibitor of the ERK1/2 pathway.ConclusionThe understanding of the mechanisms underlying the ability of slowing down cancer cell growth through electrically-induced changes in the expression of proteins involved in the control of cell proliferation and apoptosis might afford new insights in the field of oncology.
Highlights
Capacitive-resistive electric transfer (CRET) is a non-invasive therapeutic strategy that applies radiofrequency electric currents within the 400–600 kHz range to tissue repair and regeneration
It has been reported that exposure to moderate levels of hyperthermia generated by 448kHz CRET currents can potentate the action of anti-tumor agents on human tongue squamous carcinoma cells HSC-4 [11], and that the potential effectiveness of CRET in cancer treatment may be enhanced by the ability of the RF current to heat metal nanoparticles embedded in the tumor tissue [12]
We have reported that, applied at a frequency of 448 kHz, these subthermic CRET signals induce significant changes in the proliferation of adipose-derived stem cells (ADSC) obtained from healthy volunteers, as well as in their adipogenic or chondrogenic differentiation [13,14,15]
Summary
Capacitive-resistive electric transfer (CRET) is a non-invasive therapeutic strategy that applies radiofrequency electric currents within the 400–600 kHz range to tissue repair and regeneration. We have reported that, applied at a frequency of 448 kHz, these subthermic CRET signals induce significant changes in the proliferation of adipose-derived stem cells (ADSC) obtained from healthy volunteers, as well as in their adipogenic or chondrogenic differentiation [13,14,15]. These results can be interpreted as indicative that, apart from the beneficial action of the electroinduced hyperthermia at the tissular level, the cellular response to the electric signal itself could significantly contribute to the therapeutic action of CRET treatments for tissue repair and regeneration
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