Abstract
The benefits of high-fever range hyperthermia have been utilized in medicine from the Ancient Greek culture to the present day. Amplitude-modulated electro-hyperthermia, induced by a 13.56 MHz radiofrequency current (mEHT, or Oncothermia), has been an emerging means of delivering loco-regional clinical hyperthermia as a complementary of radiation-, chemo-, and molecular targeted oncotherapy. This unique treatment exploits the metabolic shift in cancer, resulting in elevated oxidative glycolysis (Warburg effect), ion concentration, and electric conductivity. These promote the enrichment of electric fields and induce heat (controlled at 42 °C), as well as ion fluxes and disequilibrium through tumor cell membrane channels. By now, accumulating preclinical studies using in vitro and in vivo models of different cancer types have revealed details of the mechanism and molecular background of the oncoreductive effects of mEHT monotherapy. These include the induction of DNA double-strand breaks, irreversible heath and cell stress, and programmed cells death; the upregulation of molecular chaperones and damage (DAMP) signaling, which may contribute to a secondary immunogenic tumor cell death. In combination therapies, mEHT proved to be a good chemosensitizer through increasing drug uptake and tumor reductive effects, as well as a good radiosensitizer by downregulating hypoxia-related target genes. Recently, immune stimulation or intratumoral antigen-presenting dendritic cell injection have been able to extend the impact of local mEHT into a systemic “abscopal” effect. The complex network of pathways emerging from the published mEHT experiments has not been overviewed and arranged yet into a framework to reveal links between the pieces of the “puzzle”. In this paper, we review the mEHT-related damage mechanisms published in tumor models, which may allow some geno-/phenotype treatment efficiency correlations to be exploited both in further research and for more rational clinical treatment planning when mEHT is involved in combination therapies.
Highlights
High fever-range hyperthermia has been successfully used in clinical oncology for complementing radiation, chemo, or even molecular-targeted therapies [1,2,3,4]
We essentially considered research papers that were published in peer-reviewed journals accessed through PubMed by searching for the terms “oncothermia”, “electrohyperthermia”, or “electro-hyperthermia”, linked or not with the phrase “modulated”
Gene expression array revealed the upregulation of the pro-apoptotic tumor necrosis factor receptor superfamily (FAS)- and c-JUN N-terminal kinase (JNK)-mediated pathways with a potential to drive this process [18]
Summary
High fever-range hyperthermia has been successfully used in clinical oncology for complementing radiation-, chemo-, or even molecular-targeted therapies [1,2,3,4]. Tumor selectivity of mEHT treatment is based on the metabolic reprogramming in cancer, resulting in its elevated glycose uptake, oxidative glycolysis (Warburg effect), ion concentration, and electric permittivity (conductivity) compared to adjacent normal tissues [13]. This principle has been exploited in 2-deoxy-2-[18F] fluoro-D-glucose (FDG) uptake-driven positron emission tomography (FDG-PET/CT) imaging [14]. Our purpose is to highlight major damage pathways activated by mEHT in different tumors to be exploited for more efficient combination treatments of this locally targetable, non-invasive modality with traditional and novel targeted oncotherapy regimens
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