Radioactive 125I seeds inhibit cell growth and epithelial-mesenchymal transition in human glioblastoma multiforme via a ROS-mediated signaling pathway

BackgroundGlioblastoma multiforme (GBM) is the most common primary central nervous system neoplasm in adults. Radioactive 125I seed implantation has been widely applied in the treatment of cancers. Moreover, previous clinical trials have confirmed that 125I seeds treatment was an effective therapy in GBM. We sought to investigate the effect of 125I seed on GBM cell growth and Epithelial-mesenchymal transition (EMT).MethodsCells were exposed to irradiation at different doses. Colony-formation assay, EdU assay, cell cycle analysis, and TUNEL assay were preformed to investigate the radiation sensitivity. The effects of 125I seeds irradiation on EMT were measured by transwell, Boyden and wound-healing assays. The levels of reactive oxygen species (ROS) were measured by DCF-DA assay. Moreover, the radiation sensitivity and EMT were investigated with or without pretreatment with glutathione. Additionally, nude mice with tumors were measured after treated with radiation.ResultsRadioactive 125I seeds are more effective than X-ray irradiation in inhibiting GBM cell growth. Moreover, EMT was effectively inhibited by 125I seed irradiation. A mechanism study indicated that GBM cell growth and EMT inhibition were induced by 125I seeds with the involvement of a ROS-mediated signaling pathway.ConclusionsRadioactive 125I seeds exhibit novel anticancer activity via a ROS-mediated signaling pathway. These findings have clinical implications for the treatment of patients with GBM by 125I seeds.

[1]  R. Mirimanoff,et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma. , 2005, The New England journal of medicine.

[2]  Huachen Gan,et al.  Trihydrophobin 1 Interacts with PAK1 and Regulates ERK/MAPK Activation and Cell Migration* , 2009, Journal of Biological Chemistry.

[3]  A. Ashworth,et al.  Tankyrase-targeted therapeutics: expanding opportunities in the PARP family , 2012, Nature Reviews Drug Discovery.

[4]  Y. Liu,et al.  Radioactive 125I Seed Inhibits the Cell Growth, Migration, and Invasion of Nasopharyngeal Carcinoma by Triggering DNA Damage and Inactivating VEGF-A/ERK Signaling , 2013, PloS one.

[5]  Andrew Burgess,et al.  Loss of human Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the cyclin B-Cdc2/PP2A balance , 2010, Proceedings of the National Academy of Sciences.

[6]  Liying Wang,et al.  Regulation of Lung Cancer Cell Migration and Invasion by Reactive Oxygen Species and Caveolin-1* , 2010, The Journal of Biological Chemistry.

[7]  K. Seong,et al.  PAK1 tyrosine phosphorylation is required to induce epithelial-mesenchymal transition and radioresistance in lung cancer cells. , 2014, Cancer research.

[8]  Jingwei Shao,et al.  Intracellular distribution and mechanisms of actions of photosensitizer Zinc(II)-phthalocyanine solubilized in Cremophor EL against human hepatocellular carcinoma HepG2 cells. , 2013, Cancer letters.

[9]  R. Warnick,et al.  Safety and efficacy of permanent iodine-125 seed implants and carmustine wafers in patients with recurrent glioblastoma multiforme. , 2008, Journal of neurosurgery.

[10]  M. Trippel,et al.  Interstitial brachytherapy with iodine-125 seeds for low grade brain stem gliomas in adults: Diagnostic and therapeutic intervention in a one-step procedure , 2013, Clinical Neurology and Neurosurgery.

[11]  A. Olivi,et al.  Treatment of recurrent glioblastoma multiforme with GliaSite brachytherapy. , 2005, International journal of radiation oncology, biology, physics.

[12]  R. Mirimanoff,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[13]  R. Stupp,et al.  High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[14]  V. Schreiber,et al.  The diverse roles and clinical relevance of PARPs in DNA damage repair: current state of the art. , 2012, Biochemical pharmacology.

[15]  M. Rugge,et al.  Correction: Oxidative DNA damage correlates with cell immortalization and mir-92 expression in hepatocellular carcinoma , 2012, BMC Cancer.

[16]  G. Nikkhah,et al.  Epithelial-to-mesenchymal(-like) transition as a relevant molecular event in malignant gliomas. , 2013, Cancer letters.

[17]  A. Zeiher,et al.  CD40 Ligand Inhibits Endothelial Cell Migration by Increasing Production of Endothelial Reactive Oxygen Species , 2002, Circulation.

[18]  Paulo A. S. Nuin,et al.  EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer , 2012, BMC Cancer.

[19]  Rugge Massimo,et al.  Oxidative DNA damage correlates with cell immortalization and mir-92 expression in hepatocellular carcinoma , 2012, BMC Cancer.

[20]  T. Schwartz,et al.  The role of dose escalation with intracavitary brachytherapy in the treatment of localized CNS malignancies: outcomes and toxicities of a prospective study. , 2010, Brachytherapy.

[21]  R. Mikkelsen,et al.  Biological chemistry of reactive oxygen and nitrogen and radiation-induced signal transduction mechanisms , 2003, Oncogene.

[22]  Frank Berthold,et al.  Stereotactic brachytherapy with iodine-125 seeds for the treatment of inoperable low-grade gliomas in children: long-term outcome. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  Huishu Yuan,et al.  Percutaneous computed tomography/ultrasonography-guided permanent iodine-125 implantation as salvage therapy for recurrent squamous cell cancers of head and neck , 2010, Cancer biology & therapy.

[24]  Tianfeng Chen,et al.  Selenocystine induces reactive oxygen species-mediated apoptosis in human cancer cells. , 2009, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[25]  G. Nikkhah,et al.  Activation of canonical WNT/β-catenin signaling enhances in vitro motility of glioblastoma cells by activation of ZEB1 and other activators of epithelial-to-mesenchymal transition. , 2012, Cancer letters.

[26]  Yanyong Yang,et al.  Gamma-ray Irradiation Impairs Dendritic Cell Migration to CCL19 by Down-regulation of CCR7 and Induction of Cell Apoptosis , 2011, International journal of biological sciences.

[27]  T. Teshima,et al.  Particle irradiation suppresses metastatic potential of cancer cells. , 2005, Cancer research.

[28]  Yong Zhao,et al.  The biological effect of 125I seed continuous low dose rate irradiation in CL187 cells , 2009, Journal of experimental & clinical cancer research : CR.

[29]  J. Lemon,et al.  Elevated DNA damage in a mouse model of oxidative stress: impacts of ionizing radiation and a protective dietary supplement. , 2008, Mutagenesis.

[30]  Yong Zhao,et al.  Relative Biological Effectiveness and Cell-Killing Efficacy of Continuous Low-Dose-Rate 125I Seeds on Prostate Carcinoma Cells In Vitro , 2010, Integrative cancer therapies.

[31]  H. Shirato,et al.  Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma. , 2014, Neuro-oncology.

[32]  Peng Wang,et al.  Sox2 suppresses the invasiveness of breast cancer cells via a mechanism that is dependent on Twist1 and the status of Sox2 transcription activity , 2013, BMC Cancer.

[33]  P. Jiang,et al.  Permanent Implantation of Iodine-125 Seeds as a Salvage Therapy for Recurrent Head and Neck Carcinoma After Radiotherapy , 2012, Cancer investigation.

[34]  A Rimner,et al.  Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma. , 2001, Cancer research.

[35]  Tao Jiang,et al.  Understanding high grade glioma: molecular mechanism, therapy and comprehensive management. , 2013, Cancer letters.

[36]  Edouard I Azzam,et al.  Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury. , 2012, Cancer letters.

[37]  V. Singh,et al.  Oxidative stress and antioxidant status in primary bone and soft tissue sarcoma , 2011, BMC Cancer.

[38]  Robert A. Weinberg,et al.  The basics of epithelial-mesenchymal transition. , 2009, The Journal of clinical investigation.

[39]  O. Inanami,et al.  Ionizing radiation induces mitochondrial reactive oxygen species production accompanied by upregulation of mitochondrial electron transport chain function and mitochondrial content under control of the cell cycle checkpoint. , 2012, Free radical biology & medicine.

[40]  I. Barillot,et al.  Treatment of T1-T2 rectal tumors by contact therapy and interstitial brachytherapy. , 2004, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[41]  Peng Huang,et al.  Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? , 2009, Nature Reviews Drug Discovery.

[42]  Hui-shu Yuan,et al.  Interstitial permanent implantation of 125I seeds as salvage therapy for re-recurrent rectal carcinoma , 2009, International Journal of Colorectal Disease.

[43]  Raghu Kalluri,et al.  The basics of epithelial-mesenchymal transition. , 2009, The Journal of clinical investigation.

[44]  Santosh Kesari,et al.  Malignant gliomas in adults. , 2008, The New England journal of medicine.

[45]  Michael Gibson,et al.  Non-small cell lung cancer cells survived ionizing radiation treatment display cancer stem cell and epithelial-mesenchymal transition phenotypes , 2013, Molecular Cancer.

[46]  Yong Zhao,et al.  The direct biologic effects of radioactive 125I seeds on pancreatic cancer cells PANC-1, at continuous low-dose rates. , 2009, Cancer biotherapy & radiopharmaceuticals.

[47]  H. van Loveren,et al.  Permanent iodine-125 interstitial implants for the treatment of recurrent glioblastoma multiforme. , 2000, Neurosurgery.