Modulated Electro-Hyperthermia-Induced Tumor Damage Mechanisms Revealed in Cancer Models

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.

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Angiotensin II-Induced Cardiac Effects Are Modulated by Endocannabinoid-Mediated CB1 Receptor Activation

“…For antigen retrieval, heating for 20 min in Tris-ethylenediaminetetraacetic acid (EDTA) buffer pH 9.0 (0.1 M Tris-base and 0.01 M EDTA) using an Avair electric pressure cooker (ELLA 6 LUX(D6K2A), Bitalon Ltd., Pécs, Hungary) followed by a 20 min cooling with an open lid was applied. Non-specific proteins were blocked in 3 % bovine serum albumin (BSA, #82-100-6, Millipore, Kankakee, IL, USA) diluted in 0.1 M Tris-buffered saline (TBS, pH 7.4) containing 0.01% sodium-azide for 30 min [ 38 ]. The sections were incubated with the primary antibodies (Anti-Troponin T (Cardiac Muscle) clone 9C2.1 (mouse), 1:50 dilution, Sigma-Aldrich; and CB1 Receptor Polyclonal Antibody (rabbit), 1:250 dilution, Cayman Chemicals, Ann Arbor, MI, USA) diluted in 1% BSA/TBS+TWEEN (TBST, pH 7.4) for 2 h. Afterward, Alexa 546 goat anti-mouse (Thermo Fisher Scientific, Waltham, MA, USA) and Alexa 488 goat anti-rabbit (Thermo Fisher Scientific, Waltham, MA, USA) secondary fluorescent antibodies (dilution 1:100) were used for 1h incubation.…”

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