Advertisement

Journal of Radiation Oncology

, Volume 6, Issue 3, pp 307–315 | Cite as

Radiation injury to cardiac arteries and myocardium is reduced by soy isoflavones

  • Michael M. Dominello
  • Matthew D. Fountain
  • Shoshana E. Rothstein
  • Alexa C. Cannon
  • Lisa M. Abernathy
  • David Hoogstra
  • Wei Chen
  • Michael C. Joiner
  • Gilda G. HillmanEmail author
Original Research

Abstract

Objective

The negative effects of incidental radiation on the heart and its vessels, particularly in the treatment of locally advanced non-small cell lung cancer, esophageal cancer, left-sided breast cancer, and lymphoma, are known. Late cardiac events induced by radiotherapy including coronary artery disease, ischemia, congestive heart failure, and myocardial infarction can manifest months to years after radiotherapy. We have previously demonstrated that soy isoflavones mitigate inflammatory responses induced in lungs by thoracic irradiation resulting in decreased vascular damage, inflammation, and fibrosis. In the current study, we investigate the use of soy isoflavones to protect cardiac vessels and myocardium from radiation injury.

Methods

Mice received a single dose of 10-Gy thoracic irradiation and daily oral treatment with soy isoflavones. At different time points, hearts were processed for histopathology studies to evaluate the effect of soy isoflavones on radiation-induced damage to cardiac vessels and myocardium.

Results

Radiation damage to arteries and myocardium was detected by 16 weeks after radiation. Soy isoflavones given in conjunction with thoracic irradiation were found to reduce damage to the artery walls and radiation-induced fibrosis in the myocardium.

Conclusion

Our histopathological findings suggest a radioprotective role of soy isoflavones to prevent cardiac injury. This approach could translate to the use of soy isoflavones as a safe complement to thoracic radiotherapy with the goal of improving the overall survival in patients whose cancer has been successfully controlled by the radiotherapy but who otherwise succumb to heart toxicity.

Keywords

Radiation Soy isoflavones Heart arteries Myocardium Radioprotection 

Notes

Acknowledgements

This work was supported by RTOG CCOP funded through U10CA037422 by the National Cancer Institute, the National Cancer Institute grant R21CA155518, Wayne State University Boost grant, and Wayne State University Research Bridge fund. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or National Institutes of Health. We thank Christopher Yunker for his excellent technical assistance, Kali Hankerd for data organization, and Dr. Lonardo from the Pathology Department at Wayne State University for his guidance in histology. The Microscopy, Imaging and Cytometry Resources Core is supported, in part, by the NIH Center grant P30 CA022453 to the Karmanos Cancer Institute at Wayne State University and the Perinatology Research Branch of the National Institutes of Child Health and Development at Wayne State University.

Compliance with ethical standards

Funding

This study was funded by RTOG CCOP funded through U10CA037422 by the National Cancer Institute, the National Cancer Institute grant R21CA155518, Wayne State University Boost grant, and Wayne State University Research Bridge fund, the USA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or National Institutes of Health.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and the use of animals were followed. The animal protocol was approved by Wayne State University Animal Investigation Committee. Mice were housed and handled in facilities accredited by the American Association for the Accreditation of Laboratory Animal Care. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Informed consent

Statement of informed consent was not applicable since the manuscript does not contain any patient data.

References

  1. 1.
    Gagliardi G, Constine LS, Moiseenko V, Correa C, Pierce LJ, Allen AM, Marks LB (2010) Radiation dose-volume effects in the heart. Int J Radiat Oncol Biol Phys 76(3 Suppl):S77–S85. doi: 10.1016/j.ijrobp.2009.04.093 CrossRefPubMedGoogle Scholar
  2. 2.
    Taunk NK, Haffty BG, Kostis JB, Goyal S (2015) Radiation-induced heart disease: pathologic abnormalities and putative mechanisms. Front Oncol 5:39. doi: 10.3389/fonc.2015.00039 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Stewart FA, Seemann I, Hoving S, Russell NS (2013) Understanding radiation-induced cardiovascular damage and strategies for intervention. Clin Oncol 25(10):617–624. doi: 10.1016/j.clon.2013.06.012 CrossRefGoogle Scholar
  4. 4.
    Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H (2015) Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. The Lancet Oncology 16(2):187–199. doi: 10.1016/S1470-2045(14)71207-0 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Bronnum D, Correa C, Cutter D, Gagliardi G, Gigante B, Jensen MB, Nisbet A, Peto R, Rahimi K, Taylor C, Hall P (2013) Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 368(11):987–998. doi: 10.1056/NEJMoa1209825 CrossRefPubMedGoogle Scholar
  6. 6.
    Sardaro A, Petruzzelli MF, D’Errico MP, Grimaldi L, Pili G, Portaluri M (2012) Radiation-induced cardiac damage in early left breast cancer patients: risk factors, biological mechanisms, radiobiology, and dosimetric constraints. Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. 103(2):133–142. doi: 10.1016/j.radonc.2012.02.008 CrossRefGoogle Scholar
  7. 7.
    Cella L, Liuzzi R, Conson M, D’Avino V, Salvatore M, Pacelli R (2013) Multivariate normal tissue complication probability modeling of heart valve dysfunction in Hodgkin lymphoma survivors. Int J Radiat Oncol Biol Phys 87(2):304–310. doi: 10.1016/j.ijrobp.2013.05.049 CrossRefPubMedGoogle Scholar
  8. 8.
    Darby SC, Cutter DJ, Boerma M, Constine LS, Fajardo LF, Kodama K, Mabuchi K, Marks LB, Mettler FA, Pierce LJ, Trott KR, Yeh ET, Shore RE (2010) Radiation-related heart disease: current knowledge and future prospects. Int J Radiat Oncol Biol Phys 76(3):656–665. doi: 10.1016/j.ijrobp.2009.09.064 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Tapio S (2016) Pathology and biology of radiation-induced cardiac disease. J Radiat Res. doi: 10.1093/jrr/rrw064 PubMedPubMedCentralGoogle Scholar
  10. 10.
    Seemann I, Gabriels K, Visser NL, Hoving S, te Poele JA, Pol JF, Gijbels MJ, Janssen BJ, van Leeuwen FW, Daemen MJ, Heeneman S, Stewart FA (2012) Irradiation induced modest changes in murine cardiac function despite progressive structural damage to the myocardium and microvasculature. Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. 103(2):143–150. doi: 10.1016/j.radonc.2011.10.011 CrossRefGoogle Scholar
  11. 11.
    Ghobadi G, van der Veen S, Bartelds B, de Boer RA, Dickinson MG, de Jong JR, Faber H, Niemantsverdriet M, Brandenburg S, Berger RM, Langendijk JA, Coppes RP, van Luijk P (2012) Physiological interaction of heart and lung in thoracic irradiation. Int J Radiat Oncol Biol Phys 84(5):e639–e646. doi: 10.1016/j.ijrobp.2012.07.2362 CrossRefPubMedGoogle Scholar
  12. 12.
    Hillman GG, Singh-Gupta V, Hoogstra DJ, Abernathy L, Rakowski J, Yunker CK, Rothstein SE, Sarkar FH, Gadgeel S, Konski AA, Lonardo F, Joiner MC (2013a) Differential effect of soy isoflavones in enhancing high intensity radiotherapy and protecting lung tissue in a pre-clinical model of lung carcinoma. Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. 109(1):117–125. doi: 10.1016/j.radonc.2013.08.015 CrossRefGoogle Scholar
  13. 13.
    Hillman GG, Singh-Gupta V, Lonardo F, Hoogstra DJ, Abernathy LM, Yunker CK, Rothstein SE, Rakowski J, Sarkar FH, Gadgeel S, Konski AA, Joiner MC (2013b) Radioprotection of lung tissue by soy isoflavones. Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer. 8(11):1356–1364. doi: 10.1097/JTO.0b013e3182a4713e CrossRefGoogle Scholar
  14. 14.
    Fountain MD, Abernathy LM, Lonardo F, Rothstein SE, Dominello MM, Yunker CK, Chen W, Gadgeel S, Joiner MC, Hillman GG (2015) Radiation-induced esophagitis is mitigated by soy isoflavones. Front Oncol 5:238. doi: 10.3389/fonc.2015.00238 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hebert JR, Rosen A (1996) Nutritional, socioeconomic, and reproductive factors in relation to female breast cancer mortality: findings from a cross-national study. Cancer Detect Prev 20(3):234–244PubMedGoogle Scholar
  16. 16.
    Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JA (1998) Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139(10):4252–4263. doi: 10.1210/endo.139.10.6216 CrossRefPubMedGoogle Scholar
  17. 17.
    Banerjee S, Li Y, Wang Z, Sarkar FH (2008) Multi-targeted therapy of cancer by genistein. Cancer Lett 269(2):226–242. doi: 10.1016/j.canlet.2008.03.052 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Hillman GG, Singh-Gupta V (2011) Soy isoflavones sensitize cancer cells to radiotherapy. Free Radic Biol Med 51(2):289–298. doi: 10.1016/j.freeradbiomed.2011.04.039 CrossRefPubMedGoogle Scholar
  19. 19.
    Hillman GG, Singh-Gupta V, Runyan L, Yunker CK, Rakowski JT, Sarkar FH, Miller S, Gadgeel SM, Sethi S, Joiner MC, Konski AA (2011) Soy isoflavones radiosensitize lung cancer while mitigating normal tissue injury. Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. 101(2):329–336. doi: 10.1016/j.radonc.2011.10.020 CrossRefGoogle Scholar
  20. 20.
    Abernathy LM, Fountain MD, Rothstein SE, David JM, Yunker CK, Rakowski J, Lonardo F, Joiner MC, Hillman GG (2015) Soy Isoflavones promote radioprotection of normal lung tissue by inhibition of radiation-induced activation of macrophages and neutrophils. Journal of Thoracic Oncology : Official publication of the International Association for the Study of Lung Cancer 10(12):1703–1712. doi: 10.1097/JTO.0000000000000677 CrossRefGoogle Scholar
  21. 21.
    Ahmad IU, Forman JD, Sarkar FH, Hillman GG, Heath E, Vaishampayan U, Cher ML, Andic F, Rossi PJ, Kucuk O (2010) Soy isoflavones in conjunction with radiation therapy in patients with prostate cancer. Nutr Cancer 62(7):996–1000. doi: 10.1080/01635581.2010.509839 CrossRefPubMedGoogle Scholar
  22. 22.
    Hillman GG, Lonardo F, Hoogstra DJ, Rakowski J, Yunker CK, Joiner MC, Dyson G, Gadgeel S, Singh-Gupta V (2014) Axitinib improves radiotherapy in murine xenograft lung tumors. Transl Oncol. doi: 10.1016/j.tranon.2014.04.002 PubMedPubMedCentralGoogle Scholar
  23. 23.
    Kruse JJ, Zurcher C, Strootman EG, Bart CI, Schlagwein N, Leer JW, Wondergem J (2001) Structural changes in the auricles of the rat heart after local ionizing irradiation. Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology 58(3):303–311CrossRefGoogle Scholar
  24. 24.
    Boerma M, Zurcher C, Esveldt I, Schutte-Bart CI, Wondergem J (2004) Histopathology of ventricles, coronary arteries and mast cell accumulation in transverse and longitudinal sections of the rat heart after irradiation. Oncol Rep 12(2):213–219PubMedGoogle Scholar
  25. 25.
    Boerma M, Roberto KA, Hauer-Jensen M (2008) Prevention and treatment of functional and structural radiation injury in the rat heart by pentoxifylline and alpha-tocopherol. Int J Radiat Oncol Biol Phys 72(1):170–177. doi: 10.1016/j.ijrobp.2008.04.042 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Messina M, Kucuk O, Lampe JW (2006) An overview of the health effects of isoflavones with an emphasis on prostate cancer risk and prostate-specific antigen levels. J AOAC Int 89(4):1121–1134PubMedGoogle Scholar
  27. 27.
    Munro IC, Harwood M, Hlywka JJ, Stephen AM, Doull J, Flamm WG, Adlercreutz H (2003) Soy isoflavones: a safety review. Nutr Rev 61(1):1–33CrossRefPubMedGoogle Scholar
  28. 28.
    Messina M, Wu AH (2009) Perspectives on the soy-breast cancer relation. Am J Clin Nutr 89(5):1673S–1679S. doi: 10.3945/ajcn.2009.26736V CrossRefPubMedGoogle Scholar
  29. 29.
    Wu AH, Lee E, Vigen C (2013) Soy isoflavones and breast cancer. Am Soc Clin Oncol Educ Book Am Soc Clin Oncol Meet 102–6. doi:  10.1200/EdBook_AM.2013.33.102.
  30. 30.
    Palma DA, Senan S, Oberije C, Belderbos J, de Dios NR, Bradley JD, Barriger RB, Moreno-Jimenez M, Kim TH, Ramella S, Everitt S, Rengan R, Marks LB, De Ruyck K, Warner A, Rodrigues G (2013a) Predicting esophagitis after chemoradiation therapy for non-small cell lung cancer: an individual patient data meta-analysis. Int J Radiat Oncol Biol Phys 87(4):690–696. doi: 10.1016/j.ijrobp.2013.07.029 CrossRefPubMedGoogle Scholar
  31. 31.
    Palma DA, Senan S, Tsujino K, Barriger RB, Rengan R, Moreno M, Bradley JD, Kim TH, Ramella S, Marks LB, De Petris L, Stitt L, Rodrigues G (2013b) Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis. Int J Radiat Oncol Biol Phys 85(2):444–450. doi: 10.1016/j.ijrobp.2012.04.043 CrossRefPubMedGoogle Scholar
  32. 32.
    Xu RY, Zhu XF, Yang Y, Ye P (2013) High-sensitive cardiac troponin T. Journal of Geriatric Cardiology : JGC 10(1):102–109. doi: 10.3969/j.issn.1671-5411.2013.01.015 PubMedPubMedCentralGoogle Scholar
  33. 33.
    Kang J, Demaria S, Formenti S (2016) Current clinical trials testing the combination of immunotherapy with radiotherapy. Journal for Immunotherapy of cancer. 4:51. doi: 10.1186/s40425-016-0156-7 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Hillman GG, Reich LA, Rothstein SE, Abernathy LM, Fountain MD, Hankerd K, Yunker CK, Rakowski JT, Quemeneur E, Slos P (2017) Radiotherapy and MVA-MUC1-IL-2 vaccine act synergistically for inducing specific immunity to MUC-1 tumor antigen. Journal for Immunotherapy of Cancer 5:4. doi: 10.1186/s40425-016-0204-3 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Michael M. Dominello
    • 1
  • Matthew D. Fountain
    • 1
    • 2
  • Shoshana E. Rothstein
    • 1
  • Alexa C. Cannon
    • 1
  • Lisa M. Abernathy
    • 1
    • 2
    • 3
  • David Hoogstra
    • 1
  • Wei Chen
    • 1
  • Michael C. Joiner
    • 1
  • Gilda G. Hillman
    • 1
    • 2
    Email author
  1. 1.Department of Oncology, Division of Radiation Oncology, Karmanos Cancer InstituteWayne State University School of MedicineDetroitUSA
  2. 2.Department of Immunology & Microbiology, Karmanos Cancer InstituteWayne State University School of MedicineDetroitUSA
  3. 3.Department of Microbiology and ImmunologyIndiana University School of Medicine at Notre DameSouth BendUSA

Personalised recommendations