Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells

2019 · Mixed · Low evidence

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MixedLow evidencePaper 1906

Study snapshot

Publicationmanual · 2019

Study typein_vitro

Reported directionMixed

Evidence ratingLow

Abstract

Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells Neuhaus E, Zirjacks L, Ganser K, Klumpp L, Schüler U, Zips D, Eckert F, Huber SM. Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells. Cancers (Basel). 2019 Jan 18;11(1). pii: E110. doi: 10.3390/cancers11010110. Abstract Tumor treating fields (TTFields) represent a novel FDA-approved treatment modality for patients with newly diagnosed or recurrent glioblastoma multiforme. This therapy applies intermediate frequency alternating electric fields with low intensity to the tumor volume by the use of non-invasive transducer electrode arrays. Mechanistically, TTFields have been proposed to impair formation of the mitotic spindle apparatus and cytokinesis. In order to identify further potential molecular targets, here the effects of TTFields on Ca2+- signaling, ion channel activity in the plasma membrane, cell cycle, cell death, and clonogenic survival were tested in two human glioblastoma cell lines in vitro by fura-2 Ca2+ imaging, patch-clamp cell-attached recordings, flow cytometry and pre-plated colony formation assay. In addition, the expression of voltage-gated Ca2+ (Cav) channels was determined by real-time RT-PCR and their significance for the cellular TTFields response defined by knock-down and pharmacological blockade. As a result, TTFields stimulated in a cell line-dependent manner a Cav1.2-mediated Ca2+entry, G₁ or S phase cell cycle arrest, breakdown of the inner mitochondrial membrane potential and DNA degradation, and/or decline of clonogenic survival suggesting a tumoricidal action of TTFields. Moreover, inhibition of Cav1.2 by benidipine aggravated in one glioblastoma line the TTFields effects suggesting that Cav1.2-triggered signaling contributes to cellular TTFields stress response. In conclusion, the present study identified Cav1.2 channels as TTFields target in the plasma membrane and provides the rationale to combine TTFields therapy with Ca2+ antagonists that are already in clinical use. mdpi.com

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AI evidence extraction

Structured fields below were generated from the paper’s abstract and metadata to make the evidence easier to inspect. Automated extraction may be incomplete or incorrect; verify important details against the original paper.

Study typein_vitro

Effect directionmixed

PopulationTwo human glioblastoma cell lines (in vitro)

Sample sizeNot supplied

ExposureNot supplied

Evidence strengthLowConfidence: 74% · Peer reviewed: yes

Main findings

TTFields stimulated, in a cell line-dependent manner, Cav1.2-mediated Ca2+ entry and were associated with G1 or S phase cell cycle arrest, mitochondrial membrane potential breakdown, DNA degradation, and/or reduced clonogenic survival. Inhibition of Cav1.2 by benidipine aggravated TTFields effects in one glioblastoma line, suggesting Cav1.2-related signaling contributes to a cellular stress response to TTFields.

Outcomes measured

Ca2+ signaling
Ion channel activity (Cav1.2-mediated Ca2+ entry)
Cell cycle arrest (G1 or S phase)
Inner mitochondrial membrane potential breakdown
DNA degradation
Cell death
Clonogenic survival
Voltage-gated Ca2+ (Cav) channel expression
Effect modification by Cav1.2 inhibition (benidipine), knock-down, pharmacological blockade

Limitations

In vitro study in two glioblastoma cell lines; generalizability to humans/clinical outcomes not addressed in the abstract
Exposure parameters (frequency, intensity, duration) not specified in the abstract
Cell line-dependent responses reported

View raw extracted JSON

{
  "study_type": "in_vitro",
  "exposure": {
    "band": null,
    "source": "tumor treating fields (TTFields) therapy",
    "frequency_mhz": null,
    "sar_wkg": null,
    "duration": null
  },
  "population": "Two human glioblastoma cell lines (in vitro)",
  "sample_size": null,
  "outcomes": [
    "Ca2+ signaling",
    "Ion channel activity (Cav1.2-mediated Ca2+ entry)",
    "Cell cycle arrest (G1 or S phase)",
    "Inner mitochondrial membrane potential breakdown",
    "DNA degradation",
    "Cell death",
    "Clonogenic survival",
    "Voltage-gated Ca2+ (Cav) channel expression",
    "Effect modification by Cav1.2 inhibition (benidipine), knock-down, pharmacological blockade"
  ],
  "main_findings": "TTFields stimulated, in a cell line-dependent manner, Cav1.2-mediated Ca2+ entry and were associated with G1 or S phase cell cycle arrest, mitochondrial membrane potential breakdown, DNA degradation, and/or reduced clonogenic survival. Inhibition of Cav1.2 by benidipine aggravated TTFields effects in one glioblastoma line, suggesting Cav1.2-related signaling contributes to a cellular stress response to TTFields.",
  "effect_direction": "mixed",
  "limitations": [
    "In vitro study in two glioblastoma cell lines; generalizability to humans/clinical outcomes not addressed in the abstract",
    "Exposure parameters (frequency, intensity, duration) not specified in the abstract",
    "Cell line-dependent responses reported"
  ],
  "evidence_strength": "low",
  "confidence": 0.74,
  "peer_reviewed_likely": "yes",
  "keywords": [
    "TTFields",
    "tumor treating fields",
    "alternating electric fields",
    "glioblastoma",
    "Cav1.2",
    "voltage-gated calcium channels",
    "Ca2+ imaging",
    "patch-clamp",
    "cell cycle arrest",
    "clonogenic survival",
    "benidipine"
  ],
  "suggested_hubs": [
    {
      "slug": "cancer-ttfields",
      "weight": 0.95,
      "reason": "Study investigates tumor treating fields (TTFields) mechanisms and cellular effects in glioblastoma cells."
    }
  ]
}

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AI-extracted fields are generated from the abstract and metadata and may be incomplete or incorrect. This material is for informational purposes and is not medical advice.

Identifiers and source

DOI: 10.3390/cancers11010110
PubMed: Not supplied

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