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Combined effects of Lenvatinib and iodine-131 on cell apoptosis in nasopharyngeal carcinoma through inducing endoplasmic reticulum stress

Nasopharyngeal carcinoma (NPC) is a type of malignant tumor characterized by high invasiveness, metastatic potential and worldwide incidence among patients with head and neck cancer. It has previously been demonstrated that Lenvatinib (LEB) is an efficient anti-cancer agent by multi-targeting of tyr...

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Autores principales: Wang, Guoyu, Zhuang, Juhua, Ni, Jing, Ye, Ying, He, Saifei, Xia, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143866/
https://www.ncbi.nlm.nih.gov/pubmed/30233679
http://dx.doi.org/10.3892/etm.2018.6652
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author Wang, Guoyu
Zhuang, Juhua
Ni, Jing
Ye, Ying
He, Saifei
Xia, Wei
author_facet Wang, Guoyu
Zhuang, Juhua
Ni, Jing
Ye, Ying
He, Saifei
Xia, Wei
author_sort Wang, Guoyu
collection PubMed
description Nasopharyngeal carcinoma (NPC) is a type of malignant tumor characterized by high invasiveness, metastatic potential and worldwide incidence among patients with head and neck cancer. It has previously been demonstrated that Lenvatinib (LEB) is an efficient anti-cancer agent by multi-targeting of tyrosine kinase inhibitors. Iodine-131 (I-131) therapy has been accepted for the treatment of thyroid cancer and other carcinomas. In the present study, the combined effects of LEB and I-131 were investigated on NPC and the potential signal pathway mediated by LEB and I-131 on NPC cells was explored. Inhibitory effects of LEB and I-131 for NPC cells growth were investigated via MTT assay. Migration and invasion of NPC cells was studied by aggression assays following incubation of LEB and I-131. Apoptosis of NPC cells and tissues were analyzed via flow cytometry and TUNEL assay, respectively. Apoptosis-related gene expression levels in NPC cells following treatment with LEB and I-131 were determined by western blotting. Endoplasmic reticulum (ER) stress in NPC cells were analyzed in NPC cells and tumor tissues. Immunohistochemistry was used to analyze the efficacy of LEB and I-131 in NPC-tumor bearing mice. The results demonstrated that combined treatment of LEB and I-131 significantly inhibited growth, apoptosis, migration and invasion of NPC cells compared with single agent therapy. Apoptosis-related gene expression levels of caspase-3 and caspase-9 were upregulated by LEB and I-131, whereas B call lymphoma-2, and P53 were downregulated in NPC cells and tumor tissues. In addition, signal mechanism analysis demonstrated that combined treatment of LEB and I-131 promoted expression levels of activating transcription factor 6, inositol-requiring protein 1 (IER1), protein kinase RNA-like endoplasmic reticulum kinase (RERK), and C/EBP homologous protein in NPC cells. Furthermore, combined treatment of LEB and I-131 markedly inhibited in vivo growth of NPC and further prolonged survival of experimental mice compared with single agent and control groups. Immunohistochemistry indicated that c-jun N-terminal kinase and Caspase-3 were increased in NPS tumor tissues in xenograft models treated with LEB and I-131. Apoptotic bodies were also increased in tumors treated by LEB and I-131. In conclusion, these findings indicate that combined treatment of LEB and I-131 may inhibit NPC growth and aggression through upregulation of ER stress, suggesting combined treatment of LEB and I-131 may be a potential therapeutic schedule for the treatment of NPC.
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spelling pubmed-61438662018-09-19 Combined effects of Lenvatinib and iodine-131 on cell apoptosis in nasopharyngeal carcinoma through inducing endoplasmic reticulum stress Wang, Guoyu Zhuang, Juhua Ni, Jing Ye, Ying He, Saifei Xia, Wei Exp Ther Med Articles Nasopharyngeal carcinoma (NPC) is a type of malignant tumor characterized by high invasiveness, metastatic potential and worldwide incidence among patients with head and neck cancer. It has previously been demonstrated that Lenvatinib (LEB) is an efficient anti-cancer agent by multi-targeting of tyrosine kinase inhibitors. Iodine-131 (I-131) therapy has been accepted for the treatment of thyroid cancer and other carcinomas. In the present study, the combined effects of LEB and I-131 were investigated on NPC and the potential signal pathway mediated by LEB and I-131 on NPC cells was explored. Inhibitory effects of LEB and I-131 for NPC cells growth were investigated via MTT assay. Migration and invasion of NPC cells was studied by aggression assays following incubation of LEB and I-131. Apoptosis of NPC cells and tissues were analyzed via flow cytometry and TUNEL assay, respectively. Apoptosis-related gene expression levels in NPC cells following treatment with LEB and I-131 were determined by western blotting. Endoplasmic reticulum (ER) stress in NPC cells were analyzed in NPC cells and tumor tissues. Immunohistochemistry was used to analyze the efficacy of LEB and I-131 in NPC-tumor bearing mice. The results demonstrated that combined treatment of LEB and I-131 significantly inhibited growth, apoptosis, migration and invasion of NPC cells compared with single agent therapy. Apoptosis-related gene expression levels of caspase-3 and caspase-9 were upregulated by LEB and I-131, whereas B call lymphoma-2, and P53 were downregulated in NPC cells and tumor tissues. In addition, signal mechanism analysis demonstrated that combined treatment of LEB and I-131 promoted expression levels of activating transcription factor 6, inositol-requiring protein 1 (IER1), protein kinase RNA-like endoplasmic reticulum kinase (RERK), and C/EBP homologous protein in NPC cells. Furthermore, combined treatment of LEB and I-131 markedly inhibited in vivo growth of NPC and further prolonged survival of experimental mice compared with single agent and control groups. Immunohistochemistry indicated that c-jun N-terminal kinase and Caspase-3 were increased in NPS tumor tissues in xenograft models treated with LEB and I-131. Apoptotic bodies were also increased in tumors treated by LEB and I-131. In conclusion, these findings indicate that combined treatment of LEB and I-131 may inhibit NPC growth and aggression through upregulation of ER stress, suggesting combined treatment of LEB and I-131 may be a potential therapeutic schedule for the treatment of NPC. D.A. Spandidos 2018-10 2018-08-23 /pmc/articles/PMC6143866/ /pubmed/30233679 http://dx.doi.org/10.3892/etm.2018.6652 Text en Copyright: © Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Wang, Guoyu
Zhuang, Juhua
Ni, Jing
Ye, Ying
He, Saifei
Xia, Wei
Combined effects of Lenvatinib and iodine-131 on cell apoptosis in nasopharyngeal carcinoma through inducing endoplasmic reticulum stress
title Combined effects of Lenvatinib and iodine-131 on cell apoptosis in nasopharyngeal carcinoma through inducing endoplasmic reticulum stress
title_full Combined effects of Lenvatinib and iodine-131 on cell apoptosis in nasopharyngeal carcinoma through inducing endoplasmic reticulum stress
title_fullStr Combined effects of Lenvatinib and iodine-131 on cell apoptosis in nasopharyngeal carcinoma through inducing endoplasmic reticulum stress
title_full_unstemmed Combined effects of Lenvatinib and iodine-131 on cell apoptosis in nasopharyngeal carcinoma through inducing endoplasmic reticulum stress
title_short Combined effects of Lenvatinib and iodine-131 on cell apoptosis in nasopharyngeal carcinoma through inducing endoplasmic reticulum stress
title_sort combined effects of lenvatinib and iodine-131 on cell apoptosis in nasopharyngeal carcinoma through inducing endoplasmic reticulum stress
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143866/
https://www.ncbi.nlm.nih.gov/pubmed/30233679
http://dx.doi.org/10.3892/etm.2018.6652
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