Amplitude-modulated radiofrequency electromagnetic fields target hepatocellular carcinoma stem cells through activation of Cav 3.2 T-type calcium channels.

Abstract

332 Background: Amplitude-modulated 27.12 MHz radiofrequency electromagnetic fields (AM RF EMF) delivered via a spoon-shaped antenna placed on the patient’s tongue result in shrinkage of the primary and metastatic tumors in patients with advanced hepatocellular carcinoma (HCC). (Costa FP, et al. Br J Cancer. 2011;105:640-648.) The mechanism by which AM RF EMF have direct antiproliferative effect and disruption of the mitotic spindle on cancer cells is largely unknown. (Zimmerman JW, et al. Br J Cancer. 2012;106:307-313.) Methods: We assessed the Specific Absorption Rate (SAR) level and distribution inside the human body. In vitro experiments with HCC cells were performed as previously described (Zimmerman). Immunodeficient mice were subcutaneously implanted with Huh-7 HCC cells or patient-derived xenografts (PDX). Mice were exposed to HCC-specific AM RF EMF using systems replicating human exposure levels and treatment duration. Tumor samples were examined for EMT and cell cycle markers. Results: Intrabuccal delivery results in whole-body absorption of AM RF EMF. Proliferation of hepatitis B positive and negative cell lines as well as HCC cancer stem cells (CSCs) are blocked by AM RF EMF through Cav 3.2 T-type voltage gated calcium channels (VGCC). Proliferation of HCC is inhibited in vivo and tumor shrinkage occurs by dedifferentiation of HCC cells into quiescent myofibroblasts while the growth of intestinal and blood marrow cells is unaltered. Conclusions: Whole-body SAR ranges from 0.2 to 1 mW/kg and is significantly below the international safety limits for human exposure. Intrabucally-administered AM RF EMF is a novel targeted therapy for systemic treatment of advanced HCC with minimal off target effects. Inhibition of HCC CSCs may explain the extremely long term survival (>5 years) of several patients with advanced HCC.