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. Miller; Yijian 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

doi:10.1016/j.ebiom.2019.05.034

Tumour-specific amplitude-modulated radiofrequency electromagnetic fields induce differentiation of hepatocellular carcinoma via targeting Ca_v3.2 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

Research output: Contribution to journal › Article › peer-review

36 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 Ca_v3·2 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 language	English (US)
Pages (from-to)	209-224
Number of pages	16
Journal	EBioMedicine
Volume	44
DOIs	https://doi.org/10.1016/j.ebiom.2019.05.034
State	Published - 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

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.ebiom.2019.05.034

Cite this

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 Ca_v3.2 T-type voltage-gated calcium channels and Ca²⁺ influx. EBioMedicine, 44, 209-224. https://doi.org/10.1016/j.ebiom.2019.05.034

Tumour-specific amplitude-modulated radiofrequency electromagnetic fields induce differentiation of hepatocellular carcinoma via targeting Ca_v3.2 T-type voltage-gated calcium channels and Ca²⁺ influx. / Jimenez, Hugo; Wang, Minghui; Zimmerman, Jacquelyn W. et al.
In: EBioMedicine, Vol. 44, 06.2019, p. 209-224.

Research output: Contribution to journal › Article › peer-review

Jimenez, H, Wang, M, Zimmerman, JW, Pennison, MJ, Sharma, S, Surratt, T, Xu, ZX, Brezovich, I, Absher, D, Myers, RM, DeYoung, B, Caudell, DL, Chen, D, Lo, HW, Lin, HK, Godwin, DW, Olivier, M, Ghanekar, A, Chen, K, Miller, LD, Gong, Y, Capstick, M, D'Agostino, RB, Munden, R, Merle, P, Barbault, A, Blackstock, AW, Bonkovsky, HL, Yang, GY, Jin, G, Liu, L, Zhang, W, Watabe, K, Blackman, CF & Pasche, BC 2019, 'Tumour-specific amplitude-modulated radiofrequency electromagnetic fields induce differentiation of hepatocellular carcinoma via targeting Ca_v3.2 T-type voltage-gated calcium channels and Ca²⁺ influx', EBioMedicine, vol. 44, pp. 209-224. https://doi.org/10.1016/j.ebiom.2019.05.034

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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 = "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",

publisher = "Elsevier BV",

}

TY - JOUR

T1 - 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

AU - Jimenez, Hugo

AU - Wang, Minghui

AU - Zimmerman, Jacquelyn W.

AU - Pennison, Michael J.

AU - Sharma, Sambad

AU - Surratt, Trevor

AU - Xu, Zhi Xiang

AU - Brezovich, Ivan

AU - Absher, Devin

AU - Myers, Richard M.

AU - DeYoung, Barry

AU - Caudell, David L.

AU - Chen, Dongquan

AU - Lo, Hui Wen

AU - Lin, Hui Kuan

AU - Godwin, Dwayne W.

AU - Olivier, Michael

AU - Ghanekar, Anand

AU - Chen, Kui

AU - Miller, Lance D.

AU - Gong, Yijian

AU - Capstick, Myles

AU - D'Agostino, Ralph B.

AU - Munden, Reginald

AU - Merle, Philippe

AU - Barbault, Alexandre

AU - Blackstock, Arthur W.

AU - Bonkovsky, Herbert L.

AU - Yang, Guang Yu

AU - Jin, Guangxu

AU - Liu, Liang

AU - Zhang, Wei

AU - Watabe, Kounosuke

AU - Blackman, Carl F.

AU - Pasche, Boris C.

PY - 2019/6

Y1 - 2019/6

N2 - 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.

AB - 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.

KW - AM RF EMF

KW - Advanced hepatocellular carcinoma

KW - Amplitude-modulated

KW - CACNA1H

KW - Ca 3·2

KW - Calcium influx

KW - Electromagnetic fields

KW - Radiofrequency

KW - T-type voltage gated calcium channels

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VL - 44

SP - 209

EP - 224

JO - EBioMedicine

JF - EBioMedicine

ER -

Tumour-specific amplitude-modulated radiofrequency electromagnetic fields induce differentiation of hepatocellular carcinoma via targeting Ca_v3.2 T-type voltage-gated calcium channels and Ca²⁺ influx

Abstract

Keywords

ASJC Scopus subject areas

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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

Keywords

ASJC Scopus subject areas

Access to Document

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Cite this

Tumour-specific amplitude-modulated radiofrequency electromagnetic fields induce differentiation of hepatocellular carcinoma via targeting Ca_v3.2 T-type voltage-gated calcium channels and Ca²⁺ influx