Tumour-specific amplitude-modulated radiofrequency electromagnetic fields induce differentiation of hepatocellular carcinoma via targeting Cav3.2 T-type voltage-gated calcium channels and Ca2+ influx

Abstract

Background Administration of amplitude modulated 27·12 MHz radiofrequency electromagnetic fields (AM RF EMF) by means of a spoon-shaped applicator placed on the patient's tongue is a newly approved treatment for advanced hepatocellular carcinoma (HCC). The mechanism of action of tumour-specific AM RF EMF is largely unknown. Methods Whole body and organ-specific human dosimetry analyses were performed. Mice carrying human HCC xenografts were exposed to AM RF EMF using a small animal AM RF EMF exposure system replicating human dosimetry and exposure time. We performed histological analysis of tumours following exposure to AM RF EMF. Using an agnostic genomic approach, we characterized the mechanism of action of AM RF EMF. Findings Intrabuccal administration results in systemic delivery of athermal AM RF EMF from head to toe at levels lower than those generated by cell phones held close to the body. Tumour shrinkage results from differentiation of HCC cells into quiescent cells with spindle morphology. AM RF EMF targeted antiproliferative effects and cancer stem cell inhibiting effects are mediated by Ca 2+ influx through Ca v 3·2 T-type voltage-gated calcium channels (CACNA1H) resulting in increased intracellular calcium concentration within HCC cells only. Interpretation Intrabuccally-administered AM RF EMF is a systemic therapy that selectively block the growth of HCC cells. AM RF EMF pronounced inhibitory effects on cancer stem cells may explain the exceptionally long responses observed in several patients with advanced HCC. Fund Research reported in this publication was supported by the National Cancer Institute's Cancer Centre Support Grant award number P30CA012197 issued to the Wake Forest Baptist Comprehensive Cancer Centre (BP) and by funds from the Charles L. Spurr Professorship Fund (BP). DWG is supported by R01 AA016852 and P50 AA026117.

Ca2+ and CACNA1H mediate targeted suppression of breast cancer brain metastasis by AM RF EMF

“…We previously reported that cellular calcium flux was affected by low energy electromagnetic fields, which were amplitude-modulated at specific frequencies [[24], [25], [26]]. In our study of hepatocellular carcinoma, we discovered that T-type voltage gated calcium channels (VGCC) mediate hepatocellular carcinoma specific AM RF EMF cell growth inhibition of hepatocellular carcinoma cell lines and xenografts [13]. Therefore, we treated breast cancer cells with ethosuximide, a pan T-type VGCC inhibitor, and found that the growth suppressive effect of BCF was significantly abrogated (Fig.…”

“…The exposure system RF output was set for delivery of a SAR level of 255 mW/kg within the brain. This SAR was selected so that it is 1) within the range of previously demonstrated in vitro activity (30–400 mW/kg) [16] and 2) within the range of wbSAR1g and psSAR1g in patients receiving treatment with the TheraBionic device (1–352 mW/kg) [13]. All study protocols were approved by the Wake Forest Institutional Animal Care and Use Committee (IACUC).…”

“…In July 2018, the TheraBionic P1 medical device emitting hepatocellular carcinoma-specific AM RF EMF received European regulatory approval as a class IIa, low risk systemic treatment for patients with advanced hepatocellular carcinoma who have failed or are intolerant to first- and second-line therapies [12]. Additional dosimetry studies have recently demonstrated that AM RF EMF are delivered from head to toe in patients receiving treatment administered by means of an antenna placed in their mouth with similar SAR in the brain and the liver [13]. Therefore, AM RF EMF could be ideal for treating brain metastatic disease which has limited treatment options available.…”

CACNA1H downregulation induces skeletal muscle atrophy involving endoplasmic reticulum stress activation and autophagy flux blockade

“…T-type Ca 2+ channels (T-channels) can be activated by small depolarizations of the plasma membrane and have been implicated in a variety of physiological processes, including fertilization, neuronal firing, cancer therapy, hormone secretion and muscle fiber development [8][9][10][11][12] . Bijlenga 13 .…”

Targeting Ca2+ Signaling in the Initiation, Promotion and Progression of Hepatocellular Carcinoma

“…T-type voltage-operated Ca 2+ channels may also be involved in regulating the proliferation and differentiation of liver cancer stem cells. Radiofrequency electromagnetic fields have been shown to induce tumor shrinkage in several cancers, including HCC (treatment options, Figure 4 ) [ 14 ]. In a study of the mechanisms involved, employing mouse HCC xenograft tumors and Huh-7 liver cells, Jimenez and colleagues found that the application of an amplitude modulated radiofrequency electromagnetic field (optimized for treatment of HCC tumors), increases Ca 2+ entry to HCC cells via T-type voltage-operated Ca 2+ channels, resulting in an increase in [Ca 2+ ] cyt and cell death.…”