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Ca2+ and CACNA1H mediate targeted suppression of breast cancer brain metastasis by AM RF EMF.
Sharma, Sambad; Wu, Shih-Ying; Jimenez, Hugo; Xing, Fei; Zhu, Dongqin; Liu, Yin; Wu, Kerui; Tyagi, Abhishek; Zhao, Dan; Lo, Hui-Wen; Metheny-Barlow, Linda; Sun, Peiqing; Bourland, John D; Chan, Michael D; Thomas, Alexandra; Barbault, Alexandre; D'Agostino, Ralph B; Whitlow, Christopher T; Kirchner, Volker; Blackman, Carl; Pasche, Boris; Watabe, Kounosuke.
Afiliação
  • Sharma S; Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Wu SY; Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Jimenez H; Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Xing F; Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Zhu D; Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Liu Y; Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Wu K; Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Tyagi A; Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Zhao D; Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Lo HW; Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Metheny-Barlow L; Department of Radiation Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Sun P; Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Bourland JD; Department of Radiation Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Chan MD; Department of Radiation Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Thomas A; Department of Hematology and Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Barbault A; TheraBionic GmbH, Ettlingen, Germany.
  • D'Agostino RB; Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Whitlow CT; Department of Radiology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Kirchner V; Genolier Cancer Center, Genolier, Switzerland.
  • Blackman C; Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Pasche B; Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America.
  • Watabe K; Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America. Electronic address: kwatabe@wakehealth.edu.
EBioMedicine ; 44: 194-208, 2019 Jun.
Article em En | MEDLINE | ID: mdl-31129098
ABSTRACT

BACKGROUND:

Brain metastases are a major cause of death in patients with metastatic breast cancer. While surgical resection and radiation therapy are effective treatment modalities, the majority of patients will succumb from disease progression. We have developed a novel therapy for brain metastases that delivers athermal radiofrequency electromagnetic fields that are amplitude-modulated at breast cancer specific frequencies (BCF).

METHODS:

27.12 MHz amplitude-modulated BCF were administered to a patient with a breast cancer brain metastasis by placing a spoon-shaped antenna on the anterior part of the tongue for three one-hour treatments every day. In preclinical models, a BCF dose, equivalent to that delivered to the patient's brain, was administered to animals implanted with either brain metastasis patient derived xenografts (PDXs) or brain-tropic cell lines. We also examined the efficacy of combining radiation therapy with BCF treatment. Additionally, the mechanistic underpinnings associated with cancer inhibition was identified using an agnostic approach.

FINDINGS:

Animal studies demonstrated a significant decrease in growth and metastases of brain-tropic cell lines. Moreover, BCF treatment of PDXs established from patients with brain metastases showed strong suppression of their growth ability. Importantly, BCF treatment led to significant and durable regression of brain metastasis of a patient with triple negative breast cancer. The tumour inhibitory effect was mediated by Ca2+ influx in cancer cells through CACNA1H T-type voltage-gated calcium channels, which, acting as the cellular antenna for BCF, activated CAMKII/p38 MAPK signalling and inhibited cancer stem cells through suppression of ß-catenin/HMGA2 signalling. Furthermore, BCF treatment downregulated exosomal miR-1246 level, which in turn decreased angiogenesis in brain environment. Therefore, targeted growth inhibition of breast cancer metastases was achieved through CACNA1H.

INTERPRETATION:

We demonstrate that BCF, as a single agent or in combination with radiation, is a novel treatment approach to the treatment of brain metastases. This paradigm shifting modality warrants further clinical trials for this unmet medical need.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Neoplasias da Mama / Cálcio / Canais de Cálcio Tipo T / Magnetoterapia Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Neoplasias da Mama / Cálcio / Canais de Cálcio Tipo T / Magnetoterapia Idioma: En Ano de publicação: 2019 Tipo de documento: Article