Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines

2017 · Mixed · Low evidence

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MixedLow evidencePaper 2296

Study snapshot

Publicationmanual · 2017

Study typein_vitro

Reported directionMixed

Evidence ratingLow

Abstract

Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines Karanam NK, Srinivasan K, Ding L, Sishc B, Saha D, Story MD. Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines. Cell Death Dis. 2017 Mar 30;8(3):e2711. doi: 10.1038/cddis.2017.136. Abstract The use of tumor-treating fields (TTFields) has revolutionized the treatment of recurrent and newly diagnosed glioblastoma (GBM). TTFields are low-intensity, intermediate frequency, alternating electric fields that are applied to tumor regions and cells using non-invasive arrays. The predominant mechanism by which TTFields are thought to kill tumor cells is the disruption of mitosis. Using five non-small cell lung cancer (NSCLC) cell lines we found that there is a variable response in cell proliferation and cell killing between these NSCLC cell lines that was independent of p53 status. TTFields treatment increased the G2/M population, with a concomitant reduction in S-phase cells followed by the appearance of a sub-G1 population indicative of apoptosis. Temporal changes in gene expression during TTFields exposure was evaluated to identify molecular signaling changes underlying the differential TTFields response. The most differentially expressed genes were associated with the cell cycle and cell proliferation pathways. However, the expression of genes found within the BRCA1 DNA- damage response were significantly downregulated (P<0.05) during TTFields treatment. DNA double-strand break (DSB) repair foci increased when cells were exposed to TTFields as did the appearance of chromatid-type aberrations, suggesting an interphase mechanism responsible for cell death involving DNA repair. Exposing cells to TTFields immediately following ionizing radiation resulted in increased chromatid aberrations and a reduced capacity to repair DNA DSBs, which were likely responsible for at least a portion of the enhanced cell killing seen with the combination. These findings suggest that TTFields induce a state of 'BRCAness' leading to a conditional susceptibility resulting in enhanced sensitivity to ionizing radiation and provides a strong rationale for the use of TTFields as a combined modality therapy with radiation or other DNA-damaging agents. ncbi.nlm.nih.gov

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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

PopulationNon-small cell lung cancer (NSCLC) cell lines (five cell lines)

Sample size5

ExposureNot supplied

Evidence strengthLowConfidence: 78% · Peer reviewed: yes

Main findings

In five NSCLC cell lines, TTFields produced variable effects on proliferation and cell killing, increased the G2/M population with reduced S-phase cells, and was followed by a sub-G1 population consistent with apoptosis. BRCA1 DNA-damage response genes were significantly downregulated during TTFields exposure, and DSB repair foci and chromatid-type aberrations increased; applying TTFields immediately after ionizing radiation increased chromatid aberrations and reduced DSB repair capacity, consistent with enhanced cell killing with the combination.

Outcomes measured

Cell proliferation
Cell killing/apoptosis (sub-G1 population)
Cell cycle distribution (G2/M, S-phase)
Gene expression changes (cell cycle/proliferation pathways; BRCA1 DNA-damage response genes)
DNA double-strand break (DSB) repair foci
Chromatid-type aberrations
Capacity to repair DNA DSBs after ionizing radiation
Sensitivity to ionizing radiation when combined with TTFields

Limitations

In vitro study in NSCLC cell lines; generalizability to humans/clinical outcomes not addressed in abstract
TTFields exposure parameters (frequency, intensity, duration) not specified in abstract
Variable response across cell lines noted

View raw extracted JSON

{
  "study_type": "in_vitro",
  "exposure": {
    "band": null,
    "source": "tumor-treating fields (TTFields)",
    "frequency_mhz": null,
    "sar_wkg": null,
    "duration": null
  },
  "population": "Non-small cell lung cancer (NSCLC) cell lines (five cell lines)",
  "sample_size": 5,
  "outcomes": [
    "Cell proliferation",
    "Cell killing/apoptosis (sub-G1 population)",
    "Cell cycle distribution (G2/M, S-phase)",
    "Gene expression changes (cell cycle/proliferation pathways; BRCA1 DNA-damage response genes)",
    "DNA double-strand break (DSB) repair foci",
    "Chromatid-type aberrations",
    "Capacity to repair DNA DSBs after ionizing radiation",
    "Sensitivity to ionizing radiation when combined with TTFields"
  ],
  "main_findings": "In five NSCLC cell lines, TTFields produced variable effects on proliferation and cell killing, increased the G2/M population with reduced S-phase cells, and was followed by a sub-G1 population consistent with apoptosis. BRCA1 DNA-damage response genes were significantly downregulated during TTFields exposure, and DSB repair foci and chromatid-type aberrations increased; applying TTFields immediately after ionizing radiation increased chromatid aberrations and reduced DSB repair capacity, consistent with enhanced cell killing with the combination.",
  "effect_direction": "mixed",
  "limitations": [
    "In vitro study in NSCLC cell lines; generalizability to humans/clinical outcomes not addressed in abstract",
    "TTFields exposure parameters (frequency, intensity, duration) not specified in abstract",
    "Variable response across cell lines noted"
  ],
  "evidence_strength": "low",
  "confidence": 0.78,
  "peer_reviewed_likely": "yes",
  "keywords": [
    "tumor-treating fields",
    "TTFields",
    "alternating electric fields",
    "non-small cell lung cancer",
    "NSCLC",
    "BRCA1",
    "DNA damage response",
    "double-strand break repair",
    "chromatid aberrations",
    "ionizing radiation",
    "radiosensitization",
    "apoptosis",
    "cell cycle"
  ],
  "suggested_hubs": []
}

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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: 10.1038/cddis.2017.136
PubMed: Not supplied

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