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

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. MillerYijian Gong, Myles Capstick, Ralph B. D'Agostino, 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

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)209-224
Number of pages16
JournalEBioMedicine
Volume44
DOIs
StatePublished - Jun 2019

Keywords

  • AM RF EMF
  • Advanced hepatocellular carcinoma
  • Amplitude-modulated
  • CACNA1H
  • Ca 3·2
  • Calcium influx
  • Electromagnetic fields
  • Radiofrequency
  • T-type voltage gated calcium channels

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Jimenez, H., Wang, M., Zimmerman, J. W., Pennison, M. J., Sharma, S., Surratt, T., Xu, Z. X., Brezovich, I., Absher, D., Myers, R. M., DeYoung, B., Caudell, D. L., Chen, D., Lo, H. W., Lin, H. K., Godwin, D. W., Olivier, M., Ghanekar, A., Chen, K., ... Pasche, B. C. (2019). 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. EBioMedicine, 44, 209-224. https://doi.org/10.1016/j.ebiom.2019.05.034