Effects of Copper Reduction on Angiogenesis-Related Factors in Recurrent Glioblastoma Cases

  • Jazayeri, Shima (Department of Nutrition, School of Public Health, Iran University of Medical Sciences) ;
  • Feli, Alireza (Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences) ;
  • Bitaraf, Mohammad Ali (Department of Neurosurgery, Imam Khomeini Hospital, Tehran University of Medical Sciences) ;
  • Dodaran, Masoud Solaymani (Minimally Invasive Surgery Research Center, Iran University of Medical Sciences) ;
  • Alikhani, Mazdak (Iran Gamma Knife Center) ;
  • Hosseinzadeh-Attar, Mohammad Javad (Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences)
  • 발행 : 2016.10.01


Purpose: To evaluate the therapeutic effects of copper reduction on angiogenesis-related factors in patients with glioblastoma multiforme treated by gamma knife radiosurgery. Materials and Methods: In the present block randomized, placebo-controlled trial, fifty eligible patients with a diagnosis of glioblastoma multiforme who were candidates for gamma knife radiosurgery were randomly assigned into two groups to receive daily either 1gr penicillamine and a low copper diet or placebo for three months. The intervention started on the same day as gamma knife radiosurgery. Serum interleukin-6 (IL-6), tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$), vascular endothelial growth factor (VEGF) and copper levels were measured at baseline and after the intervention. The serum copper level was used as the final index of compliance with the diet. In order to control probable side effects of intervention, laboratory tests were conducted at the beginning, middle and end of the study. Results: The patients had a mean age and Karnofsky Performance Scale of 43.7 years and 75 respectively. Mean serum copper levels were significantly reduced in intervention group. Mean survival time was 18.5 months in intervention group vs. 14.9 in placebo group. VEGF and IL-6 levels in the intervention group were also significantly reduced compared to the placebo group and $TNF-{\alpha}$ increased less. Conclusions: It seems that reducing the level of copper in the diet and dosing with penicillamine leads to decline of angiogenesis-related factors such as VEGF, IL-6 and $TNF-{\alpha}$. Approaches targeting angiogenesis may improve survival and can be used as a future therapeutic strategy.


Angiogenesis;copper;gamma knife;glioblastoma


연구 과제 주관 기관 : Tehran University of Medical Sciences


  1. Albulescu R, Codrici E, Popescu ID, et al (2013). Cytokine patterns in brain tumour progression. Mediators Inflamm, 2013, 979748.
  2. Anton K, Glod J (2014). An Orchestrated Response To Tumor Signals By Macrophages and Mesenchymal Stem Cells Potentiates Interleukin-6 Secretion In Glioblastoma. Cell death in therapy, 1.
  3. Antoniades V, Sioga A, Dietrich EM, et al (2013). Is copper chelation an effective anti-angiogenic strategy for cancer treatment? Med Hypotheses, 81, 1159-63.
  4. Brat DJ, Bellail AC, Van Meir EG (2005). The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol, 7, 122-33.
  5. Brem S, Grossman SA, Carson KA, et al (2005). Phase 2 trial of copper depletion and penicillamine as antiangiogenesis therapy of glioblastoma. Neuro Oncol, 7, 246-53.
  6. Carmeliet P (2005). Angiogenesis in life, disease and medicine. Nature, 438, 932-6.
  7. Chang Q, Bournazou E, Sansone P, et al (2013). The IL-6/JAK/stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia, 15, 848-IN45.
  8. Chen WH, Chen Y, Cui GH (2005). Effects of TNF-alpha and curcumin on the expression of VEGF in Raji and U937 cells and on angiogenesis in ECV304 cells. Chin Med J (Engl), 118, 2052-7.
  9. Davis FG, Freels S, Grutsch J, et al (1998). Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: an analysis based on Surveillance, Epidemiology, and End Results (SEER) data, 1973-1991. J Neurosurg, 88, 1-10.
  10. Farah P, Blanda R, Kromer C, et al (2016). Conditional survival after diagnosis with malignant brain and central nervous system tumor in the United States, 1995-2012. J Neurooncol, 128, 419-29.
  11. Fukumura D, Jain RK (2007). Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc Res, 74, 72-84.
  12. Gopinathan G, Milagre C, Pearce OM, et al (2015). Interleukin-6 Stimulates Defective Angiogenesis. Cancer Res, 75, 3098-107.
  13. Hanahan D, Folkman J (1996). Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. cell, 86, 353-64.
  14. Kaur B, Khwaja FW, Severson EA, et al (2005). Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol, 7, 134-53.
  15. Kim NH, Jung HJ, Shibasaki F, et al (2010). NBBA, a synthetic small molecule, inhibits TNF-alpha-induced angiogenesis by suppressing the NF-kappaB signaling pathway. Biochem Biophys Res Commun, 391, 1500-5.
  16. Koca T, Basaran H, Sezen D, et al (2014). Comparison of linear accelerator and helical tomotherapy plans for glioblastoma multiforme patients. Asian Pac J Cancer Prev, 15, 7811-6.
  17. Kumar A, Sunita P, Jha S, et al (2016). Daphnetin inhibits TNFalpha and VEGF-induced angiogenesis through inhibition of the IKKs/IkappaBalpha/NF-kappaB, Src/FAK/ERK1/2 and Akt Signaling Pathways. Clin Exp Pharmacol Physiol, 14, 1440-681.
  18. Kwon YW, Heo SC, Jeong GO, et al (2013). Tumor necrosis factor-alpha-activated mesenchymal stem cells promote endothelial progenitor cell homing and angiogenesis. Biochim Biophys Acta, 1832, 2136-44.
  19. Lai KC, Liu CJ, Lin TJ, et al (2016). Blocking TNF-alpha inhibits angiogenesis and growth of IFIT2-depleted metastatic oral squamous cell carcinoma cells. Cancer Lett, 370, 207-15.
  20. Liu Y, Yang G, Zhang J, et al (2015). Anti-TNF-alpha monoclonal antibody reverses psoriasis through dual inhibition of inflammation and angiogenesis. Int Immunopharmacol, 28, 731-43.
  21. Mihara M, Hashizume M, Yoshida H, et al (2012). IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci (Lond), 122, 143-59.
  22. Milstein JM, Cohen ME, Sinks LF (1985). The influence and reliability of neurologic assessment and Karnofsky performance score on prognosis. Cancer, 56, 1834-6.<1834::AID-CNCR2820561323>3.0.CO;2-A
  23. Mor V, Laliberte L, Morris JN, et al (1984). The Karnofsky performance status scale: an examination of its reliability and validity in a research setting. Cancer, 53, 2002-7.<2002::AID-CNCR2820530933>3.0.CO;2-W
  24. Nasulewicz A, Mazur A, Opolski A (2004). Role of copper in tumour angiogenesis-clinical implications. J Trace Elem Med Biol, 18, 1-8.
  25. Ni W, Luo L, Ping Z, et al (2014). Prognostic value of ALDH1A3 promoter methylation in gliob; astoma: a single center experience in Western China. Asian Pac J Cancer Prev, 16, 591-4.
  26. Pashaki AS, Hamed EA, Mohamadian K, et al (2014). Efficacy of high dose radiotherapy in post-operative treatment of glioblastoma multiform--a single institution report. Asian Pac J Cancer Prev, 15, 2793-6.
  27. Qin JJ, Wang JM, Du J, et al (2013). Radixin knockdown by RNA interference suppresses human glioblastoma cell growth in vitro and in vivo. Asian Pac J Cancer Prev, 15, 9805-12.
  28. Qin JJ, Liu ZX, Wang JM, et al (2015). Prognostic factors influencing clinical outcomes of malignant glioblastoma multiforme: clinical, immunophenotypic, and fluorescence in situ hybridization findings for 1p19q in 816 chinese cases. Asian Pac J Cancer Prev, 16, 971-7.
  29. Raluca BA, Cimpean AM, Cioca A, et al (2014). Endothelial Cell Proliferation and Vascular Endothelial Growth Factor Expression in Primary Colorectal Cancer and Corresponding Liver Metastases. Asian Pac J Cancer Prev, 16, 4549-53.
  30. Redmond KJ, Mehta M (2015). Stereotactic Radiosurgery for Glioblastoma. Cureus, 7, 413.
  31. Reiss Y, Machein MR, Plate KH (2005). The role of angiopoietins during angiogenesis in gliomas. Brain Pathol, 15, 311-7.
  32. Riaz SK, Iqbal Y, Malik M (2014). Diagnostic and therapeutic implications of the vascular endothelial growth factor family in cancer. Asian Pac J Cancer Prev, 16, 1677-82.
  33. Schmidt NO, Westphal M, Hagel C, et al (1999). Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int J Cancer, 84, 8-10.
  34. Shin MR, Kang SK, Kim YS, et al (2015). TNF-alpha and LPS activate angiogenesis via VEGF and SIRT1 signalling in human dental pulp cells. Int Endod J, 48, 705-16.
  35. Urso E, Maffia M (2015). Behind the Link between Copper and Angiogenesis: established mechanisms and an overview on the role of vascular copper transport systems. J Vasc Res, 52, 172-96.
  36. Wadhwa S, Mumper RJ (2013). D-penicillamine and other low molecular weight thiols: review of anticancer effects and related mechanisms. Cancer Lett, 337, 8-21.
  37. Wang L-F, Fokas E, Juricko J, et al (2008). Increased expression of EphA7 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients. BMC Cancer, 8, 1.
  38. Weathers SP, de Groot J (2015). VEGF manipulation in glioblastoma. J Clin Oncol, 29, 719.
  39. Xu H, Zhu J, Gu L, et al (2015). VEGFR2 Expression in Head and Neck Squamous Cell Carcinoma Cancer Cells Mediates Proliferation and Invasion. Asian Pac J Cancer Prev, 17, 2217-21.
  40. Yang HL, Chang HC, Lin SW, et al (2014). Antrodia salmonea inhibits TNF-alpha-induced angiogenesis and atherogenesis in human endothelial cells through the down-regulation of NF-kappaB and up-regulation of Nrf2 signaling pathways. J Ethnopharmacol, 151, 394-406.
  41. Yoshida D, Ikeda Y, Nakazawa S (1995). Suppression of tumor growth in experimental 9L gliosarcoma model by copper depletion. Neurol Med Chir, 35, 133-5.
  42. Yu J, Cao X-F, Zheng Y, et al (2013). Anti-VEGF Therapy with Bevacizumab--limited cardiovascular toxicity. Asian Pac J Cancer Prev, 15, 10769-72.
  43. Zhang Y, Yu LK, Lu GJ, et al (2013). Prognostic values of VEGF and endostatin with malignant pleural effusions in patients with lung cancer. Asian Pac J Cancer Prev, 15, 8435-40.