Effects of radiation on the epidermal growth factor receptor pathway in the heart

Vijayalakshmi Sridharan, Sunil K. Sharma, Eduardo G. Moros, Peter M. Corry, Preeti Tripathi, Benjamin J. Lieblong, Chandan Guha, Martin Hauer-Jensen, Marjan Boerma

Research output: Contribution to journalArticle

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Abstract

Purpose: Radiation-induced heart disease (RIHD) is a serious side-effect of thoracic radiotherapy. The epidermal growth factor receptor (EGFR) pathway is essential for the function and survival of cardiomyocytes. Hence, agents that target the EGFR pathway are cardiotoxic. Tocotrienols protect from radiation injury, but may also enhance the therapeutic effects of EGFR pathway inhibitors in cancer treatment. This study investigated the effects of local irradiation on the EGFR pathway in the heart and tests whether tocotrienols may modify radiation-induced changes in this pathway. Methods: Male Sprague-Dawley rats received image-guided localized heart irradiation with 21 Gy. Twenty four hours before irradiation, rats received a single dose of tocotrienol-enriched formulation or vehicle by oral gavage. At time points from 2 h to 9 months after irradiation, left ventricular expression of EGFR pathway mediators was studied. Results: Irradiation caused a decrease in the expression of epidermal growth factor (EGF) and neuregulin-1 (Nrg-1) mRNA from 6 h up to 10 weeks, followed by an upregulation of these ligands and the receptor erythroblastic leukemia viral oncogene homolog (ErbB)4 at 6 months. In addition, the upregulation of Nrg-1 was statistically significant up to 9 months after irradiation. A long-term upregulation of ErbB2 protein did not coincide with changes in transcription or post-translational interaction with the chaperone heat shock protein 90 (HSP90). Pretreatment with tocotrienols prevented radiation-induced changes at 2 weeks. Conclusions: Local heart irradiation causes long-term changes in the EGFR pathway. Studies have to address how radiation may interact with cardiotoxic effects of EGFR inhibitors.

Original languageEnglish (US)
Pages (from-to)539-547
Number of pages9
JournalInternational Journal of Radiation Biology
Volume89
Issue number7
DOIs
StatePublished - Jul 2013

Fingerprint

Radiation Effects
Epidermal Growth Factor Receptor
Tocotrienols
Radiation
Neuregulin-1
Up-Regulation
HSP90 Heat-Shock Proteins
Radiation Injuries
Therapeutic Uses
Oncogenes
Epidermal Growth Factor
Cardiac Myocytes
Sprague Dawley Rats
Heart Diseases
Leukemia
Radiotherapy
Thorax
Ligands
Messenger RNA
Neoplasms

Keywords

  • Epidermal growth factor receptor pathway
  • Neuregulin-1
  • Radiation-induced heart disease
  • Tocotrienols

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Radiological and Ultrasound Technology

Cite this

Sridharan, V., Sharma, S. K., Moros, E. G., Corry, P. M., Tripathi, P., Lieblong, B. J., ... Boerma, M. (2013). Effects of radiation on the epidermal growth factor receptor pathway in the heart. International Journal of Radiation Biology, 89(7), 539-547. https://doi.org/10.3109/09553002.2013.782110

Effects of radiation on the epidermal growth factor receptor pathway in the heart. / Sridharan, Vijayalakshmi; Sharma, Sunil K.; Moros, Eduardo G.; Corry, Peter M.; Tripathi, Preeti; Lieblong, Benjamin J.; Guha, Chandan; Hauer-Jensen, Martin; Boerma, Marjan.

In: International Journal of Radiation Biology, Vol. 89, No. 7, 07.2013, p. 539-547.

Research output: Contribution to journalArticle

Sridharan, V, Sharma, SK, Moros, EG, Corry, PM, Tripathi, P, Lieblong, BJ, Guha, C, Hauer-Jensen, M & Boerma, M 2013, 'Effects of radiation on the epidermal growth factor receptor pathway in the heart', International Journal of Radiation Biology, vol. 89, no. 7, pp. 539-547. https://doi.org/10.3109/09553002.2013.782110
Sridharan, Vijayalakshmi ; Sharma, Sunil K. ; Moros, Eduardo G. ; Corry, Peter M. ; Tripathi, Preeti ; Lieblong, Benjamin J. ; Guha, Chandan ; Hauer-Jensen, Martin ; Boerma, Marjan. / Effects of radiation on the epidermal growth factor receptor pathway in the heart. In: International Journal of Radiation Biology. 2013 ; Vol. 89, No. 7. pp. 539-547.
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abstract = "Purpose: Radiation-induced heart disease (RIHD) is a serious side-effect of thoracic radiotherapy. The epidermal growth factor receptor (EGFR) pathway is essential for the function and survival of cardiomyocytes. Hence, agents that target the EGFR pathway are cardiotoxic. Tocotrienols protect from radiation injury, but may also enhance the therapeutic effects of EGFR pathway inhibitors in cancer treatment. This study investigated the effects of local irradiation on the EGFR pathway in the heart and tests whether tocotrienols may modify radiation-induced changes in this pathway. Methods: Male Sprague-Dawley rats received image-guided localized heart irradiation with 21 Gy. Twenty four hours before irradiation, rats received a single dose of tocotrienol-enriched formulation or vehicle by oral gavage. At time points from 2 h to 9 months after irradiation, left ventricular expression of EGFR pathway mediators was studied. Results: Irradiation caused a decrease in the expression of epidermal growth factor (EGF) and neuregulin-1 (Nrg-1) mRNA from 6 h up to 10 weeks, followed by an upregulation of these ligands and the receptor erythroblastic leukemia viral oncogene homolog (ErbB)4 at 6 months. In addition, the upregulation of Nrg-1 was statistically significant up to 9 months after irradiation. A long-term upregulation of ErbB2 protein did not coincide with changes in transcription or post-translational interaction with the chaperone heat shock protein 90 (HSP90). Pretreatment with tocotrienols prevented radiation-induced changes at 2 weeks. Conclusions: Local heart irradiation causes long-term changes in the EGFR pathway. Studies have to address how radiation may interact with cardiotoxic effects of EGFR inhibitors.",
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