Application of hyperthermia in addition to ionizing irradiation fosters necrotic cell death and HMGB1 release of colorectal tumor cells

Petra Schildkopf, Benjamin Frey, Frederick Mantel, Oliver J. Ott, Eva Maria Weiss, Renate Sieber, Christina Janko, Rolf Sauer, Rainer Fietkau, Udo S. Gaipl

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49 Scopus citations


Colorectal cancer is the second leading cause of death in developed countries. Tumor therapies should on the one hand aim to stop the proliferation of tumor cells and to kill them, and on the other hand stimulate a specific immune response against residual cancer cells. Dying cells are modulators of the immune system contributing to anti-inflammatory or pro-inflammatory responses, depending on the respective cell death form. The positive therapeutic effects of temperature-controlled hyperthermia (HT), when combined with ionizing irradiation (X-ray), were the origin to examine whether combinations of X-ray with HT can induce immune activating tumor cell death forms, also characterized by the release of the danger signal HMGB1. Human colorectal tumor cells with differing radiosensitivities were treated with combinations of HT (41.5 °C for 1 h) and X-ray (5 or 10 Gy). Necrotic cell death was prominent after X-ray and could be further increased by HT. Apoptosis remained quite low in HCT 15 and SW480 cells. X-ray and combinations with HT arrested the tumor cells in the radiosensitive G2 cell cycle phase. The amount of released HMGB1 protein was significantly enhanced after combinatorial treatments in comparison to single ones. We conclude that combining X-ray with HT may induce anti-tumor immunity as a result of the predominant induction of inflammatory necrotic tumor cells and the release of HMGB1.

Original languageEnglish (US)
Pages (from-to)1014-1020
Number of pages7
JournalBiochemical and Biophysical Research Communications
Issue number1
StatePublished - Jan 1 2010

Bibliographical note

Funding Information:
This work was supported by the ELAN Fond [ST-] of the Friedrich-Alexander University of Erlangen-Nuremberg and by the German Research Foundation [DFG HE 4490/3-1 and SFB 643]. We thank Dr. Sennewald and Dipl.-Ing. Martin Wadepohl for the fruitful discussions about the technique and application of temperature-controlled hyperthermia.


  • Anti-tumor immunity
  • Colorectal cancer
  • HMGB1
  • Hyperthermia
  • Ionizing irradiation
  • Necrosis


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