Modulated Electro-Hyperthermia Resolves Radioresistance of Panc1 Pancreas Adenocarcinoma and Promotes DNA Damage and Apoptosis In Vitro

Int J Mol Sci. 2020 Jul 19;21(14):5100. doi: 10.3390/ijms21145100.


The poor outcome of pancreas ductal adenocarcinomas (PDAC) is frequently linked to therapy resistance. Modulated electro-hyperthermia (mEHT) generated by 13.56 MHz capacitive radiofrequency can induce direct tumor damage and promote chemo- and radiotherapy. Here, we tested the effect of mEHT either alone or in combination with radiotherapy using an in vivo model of Panc1, a KRAS and TP53 mutant, radioresistant PDAC cell line. A single mEHT shot of 60 min induced ~50% loss of viable cells and morphological signs of apoptosis including chromatin condensation, nuclear shrinkage and apoptotic bodies. Most mEHT treatment related effects exceeded those of radiotherapy, and these were further amplified after combining the two modalities. Treatment related apoptosis was confirmed by a significantly elevated number of annexin V single-positive and cleaved/activated caspase-3 positive tumor cells, as well as sub-G1-phase tumor cell fractions. mEHT and mEHT+radioterapy caused the moderate accumulation of γH2AX positive nuclear foci, indicating DNA double-strand breaks and upregulation of the cyclin dependent kinase inhibitor p21waf1 besides the downregulation of Akt signaling. A clonogenic assay revealed that both mono- and combined treatments affected the tumor progenitor/stem cell populations too. In conclusion, mEHT treatment can contribute to tumor growth inhibition and apoptosis induction and resolve radioresistance of Panc1 PDAC cells.

Keywords: Panc1 pancreas adenocarcinoma; caspase-dependent apoptosis; modulated electro-hyperthermia (mEHT); p21waf1 upregulation; resolution of radioresistance.

MeSH terms

  • Apoptosis
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Carcinoma, Pancreatic Ductal / therapy*
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Proliferation
  • Combined Modality Therapy
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA Damage
  • Humans
  • Hyperthermia, Induced / methods*
  • Neoplastic Stem Cells / pathology
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / therapy*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Radiation Tolerance
  • Radiofrequency Therapy


  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Proto-Oncogene Proteins c-akt