DNA fragmentation and caspase-independent programmed cell death by modulated electrohyperthermia

N. Meggyeshazi, G. Andocs, L. Balogh, P. Balla, G. Kiszner, I. Teleki, A. Jeney, T. Krenács

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Background and purpose. The electric field and the concomitant heat (electrohyperthermia) can synergistically induce cell death in tumor tissue, due to elevated glycolysis, ion concentration, and permittivity in malignant compared with nonmalignant tissues. Here we studied the mechanism and time course of tumor destruction caused by electrohyperthermia. Material and methods. Bilateral implants of HT29 colorectal cancer in the femoral regions of Balb/c (nu/nu) mice were treated with a single 30-min shot of modulated, 13.56-MHz, radiofrequency-generated electrohyperthermia (mEHT). Tumors at 0, 1, 4, 8, 14, 24, 48, and 72 h posttreatment were studied for morphology, DNA fragmentation, and cell death response-related protein expression using tissue microarrays, immunohistochemistry, Western immunoblots, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. Results. Modulated EHT treatment induced significant tumor destruction in HT29 xenografts with a peak of a sevenfold increase compared with the untreated controls. The significant treatment-related elevation of DNA fragmentation-detected with TUNEL assay-and apoptotic bodies between 24 and 72 h posttreatment was proof of a programmed cell death response. This was associated with significant mitochondrial accumulation of bax and mitochondrial-to-cytoplasmic release of cytochrome c proteins between 8 and 14 h. Cleaved caspase-3 levels were low and mainly localized to inflammatory cells. The substantial cytoplasmic-to-nuclear translocation of apoptosis-inducing factor (AIF) and its 57-kDa activated fragment detected between 14 and 24 h after treatment indicated AIF as an effector for DNA fragmentation. Conclusion. Modulated EHT treatment can induce programmed cell death-related tumor destruction in HT29 colorectal adenocarcinoma xenografts, which dominantly follows a caspase-independent subroutine.

Original languageEnglish
Pages (from-to)815-822
Number of pages8
JournalStrahlentherapie und Onkologie
Volume190
Issue number9
DOIs
Publication statusPublished - 2014

Fingerprint

DNA Fragmentation
Caspases
Cell Death
Apoptosis Inducing Factor
Neoplasms
Heterografts
DNA Nucleotidylexotransferase
Glycolysis
Therapeutics
Transferases
Thigh
Cytochromes c
Caspase 3
Colorectal Neoplasms
Proteins
Adenocarcinoma
Hot Temperature
Western Blotting
Immunohistochemistry
Ions

Keywords

  • Caspase-independent cell death
  • Colorectal cancer xenograft
  • DNA fragmentation
  • Modulated electrohyperthermia
  • Programmed tumor cell death

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Oncology

Cite this

DNA fragmentation and caspase-independent programmed cell death by modulated electrohyperthermia. / Meggyeshazi, N.; Andocs, G.; Balogh, L.; Balla, P.; Kiszner, G.; Teleki, I.; Jeney, A.; Krenács, T.

In: Strahlentherapie und Onkologie, Vol. 190, No. 9, 2014, p. 815-822.

Research output: Contribution to journalArticle

Meggyeshazi, N. ; Andocs, G. ; Balogh, L. ; Balla, P. ; Kiszner, G. ; Teleki, I. ; Jeney, A. ; Krenács, T. / DNA fragmentation and caspase-independent programmed cell death by modulated electrohyperthermia. In: Strahlentherapie und Onkologie. 2014 ; Vol. 190, No. 9. pp. 815-822.
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T1 - DNA fragmentation and caspase-independent programmed cell death by modulated electrohyperthermia

AU - Meggyeshazi, N.

AU - Andocs, G.

AU - Balogh, L.

AU - Balla, P.

AU - Kiszner, G.

AU - Teleki, I.

AU - Jeney, A.

AU - Krenács, T.

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AB - Background and purpose. The electric field and the concomitant heat (electrohyperthermia) can synergistically induce cell death in tumor tissue, due to elevated glycolysis, ion concentration, and permittivity in malignant compared with nonmalignant tissues. Here we studied the mechanism and time course of tumor destruction caused by electrohyperthermia. Material and methods. Bilateral implants of HT29 colorectal cancer in the femoral regions of Balb/c (nu/nu) mice were treated with a single 30-min shot of modulated, 13.56-MHz, radiofrequency-generated electrohyperthermia (mEHT). Tumors at 0, 1, 4, 8, 14, 24, 48, and 72 h posttreatment were studied for morphology, DNA fragmentation, and cell death response-related protein expression using tissue microarrays, immunohistochemistry, Western immunoblots, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. Results. Modulated EHT treatment induced significant tumor destruction in HT29 xenografts with a peak of a sevenfold increase compared with the untreated controls. The significant treatment-related elevation of DNA fragmentation-detected with TUNEL assay-and apoptotic bodies between 24 and 72 h posttreatment was proof of a programmed cell death response. This was associated with significant mitochondrial accumulation of bax and mitochondrial-to-cytoplasmic release of cytochrome c proteins between 8 and 14 h. Cleaved caspase-3 levels were low and mainly localized to inflammatory cells. The substantial cytoplasmic-to-nuclear translocation of apoptosis-inducing factor (AIF) and its 57-kDa activated fragment detected between 14 and 24 h after treatment indicated AIF as an effector for DNA fragmentation. Conclusion. Modulated EHT treatment can induce programmed cell death-related tumor destruction in HT29 colorectal adenocarcinoma xenografts, which dominantly follows a caspase-independent subroutine.

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KW - Modulated electrohyperthermia

KW - Programmed tumor cell death

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