Tumour-specific amplitude-modulated radiofrequency electromagnetic fields induce differentiation of hepatocellular carcinoma via targeting Cav3.2 T-type voltage-gated calcium channels and Ca2+ influxResearch in context
Hugo Jimenez,
Minghui Wang,
Jacquelyn W. Zimmerman,
Michael J. Pennison,
Sambad Sharma,
Trevor Surratt,
Zhi-Xiang Xu,
Ivan Brezovich,
Devin Absher,
Richard M. Myers,
Barry DeYoung,
David L. Caudell,
Dongquan Chen,
Hui-Wen Lo,
Hui-Kuan Lin,
Dwayne W. Godwin,
Michael Olivier,
Anand Ghanekar,
Kui Chen,
Lance D. Miller,
Yijian Gong,
Myles Capstick,
Ralph B. D'Agostino, Jr,
Reginald Munden,
Philippe Merle,
Alexandre Barbault,
Arthur W. Blackstock,
Herbert L. Bonkovsky,
Guang-Yu Yang,
Guangxu Jin,
Liang Liu,
Wei Zhang,
Kounosuke Watabe,
Carl F. Blackman,
Boris C. Pasche
Affiliations
Hugo Jimenez
Department of Cancer Biology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Minghui Wang
Department of Cancer Biology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Jacquelyn W. Zimmerman
Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, United States of America; Division of Haematology/Oncology, The University of Alabama at Birmingham, Birmingham, AL, United States of America
Michael J. Pennison
Department of Cancer Biology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Sambad Sharma
Department of Cancer Biology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Trevor Surratt
Department of Cancer Biology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Zhi-Xiang Xu
Division of Haematology/Oncology, The University of Alabama at Birmingham, Birmingham, AL, United States of America
Ivan Brezovich
Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL, United States of America
Devin Absher
HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States of America
Richard M. Myers
HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States of America
Barry DeYoung
Department of Pathology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
David L. Caudell
Department of Pathology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Dongquan Chen
Division of Preventive Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States of America
Hui-Wen Lo
Department of Cancer Biology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Hui-Kuan Lin
Department of Cancer Biology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Dwayne W. Godwin
Department of Neurobiology and Anatomy, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Michael Olivier
Section of Molecular Medicine, Department of Medicine, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Anand Ghanekar
Department of Surgery, University Health Network, Toronto, Ontario, Canada
Kui Chen
Toronto General Hospital Research Institute, Toronto, Ontario, Canada
Lance D. Miller
Department of Cancer Biology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Yijian Gong
IT'IS Foundation, Swiss Federal Institute of Technology, Zurich, Switzerland
Myles Capstick
IT'IS Foundation, Swiss Federal Institute of Technology, Zurich, Switzerland
Ralph B. D'Agostino, Jr
Department of Biostatistical Sciences, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Reginald Munden
Department of Radiology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Philippe Merle
Croix-Rousse University Hospital, Hepato-Gastroenterology and Digestive Oncology, Lyon, France
Alexandre Barbault
TheraBionic GmbH, Ettlingen, Germany
Arthur W. Blackstock
Department of Radiation Oncology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Herbert L. Bonkovsky
Section on Gastroenterology, Department of Medicine, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Guang-Yu Yang
Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, United States of America
Guangxu Jin
Department of Cancer Biology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Liang Liu
Department of Cancer Biology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Wei Zhang
Department of Cancer Biology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Kounosuke Watabe
Department of Cancer Biology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America
Carl F. Blackman
Department of Cancer Biology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America; Corresponding authors.
Boris C. Pasche
Department of Cancer Biology, Wake Forest Baptist Medical Centre, Winston-Salem, NC, United States of America; Corresponding authors.
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: Advanced hepatocellular carcinoma, T-type voltage gated calcium channels, Calcium influx, Cav 3·2, CACNA1H, Amplitude-modulated, Radiofrequency, Electromagnetic fields, AM RF EMF
