@article{79fd94a88e8d41e1b6a8c36075a89237,
title = "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 Ca2+ influx through Cav3·2 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.",
keywords = "AM RF EMF, Advanced hepatocellular carcinoma, Amplitude-modulated, CACNA1H, Ca 3·2, Calcium influx, Electromagnetic fields, Radiofrequency, T-type voltage gated calcium channels",
author = "Hugo Jimenez and Minghui Wang and Zimmerman, {Jacquelyn W.} and Pennison, {Michael J.} and Sambad Sharma and Trevor Surratt and Xu, {Zhi Xiang} and Ivan Brezovich and Devin Absher and Myers, {Richard M.} and Barry DeYoung and Caudell, {David L.} and Dongquan Chen and Lo, {Hui Wen} and Lin, {Hui Kuan} and Godwin, {Dwayne W.} and Michael Olivier and Anand Ghanekar and Kui Chen and Miller, {Lance D.} and Yijian Gong and Myles Capstick and D'Agostino, {Ralph B.} and Reginald Munden and Philippe Merle and Alexandre Barbault and Blackstock, {Arthur W.} and Bonkovsky, {Herbert L.} and Yang, {Guang Yu} and Guangxu Jin and Liang Liu and Wei Zhang and Kounosuke Watabe and Blackman, {Carl F.} and Pasche, {Boris C.}",
note = "Funding Information: 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. Funders had no role in study design, data collection, data analysis, interpretation, or writing of this report.The authors wish to acknowledge the support of the Wake Forest Baptist Comprehensive Cancer Centre Cancer Genomics, Proteomics, Flow Cytometry, Cellular Imaging, Biostatistics, and Bioinformatics Shared Resource, supported by the National Cancer Institute's Cancer Centre Support Grant award number P30CA012197 and Wake Forest Comparative Pathology Laboratory. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Funders had no role in study design, data collection, data analysis, interpretation, or writing of this report. Funding Information: 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 . Funders had no role in study design, data collection, data analysis, interpretation, or writing of this report. Funding Information: The authors wish to acknowledge the support of the Wake Forest Baptist Comprehensive Cancer Centre Cancer Genomics, Proteomics, Flow Cytometry, Cellular Imaging, Biostatistics, and Bioinformatics Shared Resource, supported by the National Cancer Institute 's Cancer Centre Support Grant award number P30CA012197 and Wake Forest Comparative Pathology Laboratory. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Funders had no role in study design, data collection, data analysis, interpretation, or writing of this report. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = jun,
doi = "10.1016/j.ebiom.2019.05.034",
language = "English (US)",
volume = "44",
pages = "209--224",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
}