Cargando…

Sinomenine Hydrochloride Inhibits Human Glioblastoma Cell Growth through Reactive Oxygen Species Generation and Autophagy-Lysosome Pathway Activation: An In Vitro and In Vivo Study

Glioblastoma is the most common malignant primary brain tumor, and it is one of the causes of cancer fatality in both adult and pediatric populations. Patients with glioblastoma require chemotherapy after surgical resection and radiotherapy. Therefore, chemotherapy constitutes a viable approach for...

Descripción completa

Detalles Bibliográficos
Autores principales: Jiang, Yumao, Jiao, Yue, Wang, Zhiguo, Li, Tao, Liu, Yang, Li, Yujuan, Zhao, Xiaoliang, Wang, Danqiao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618594/
https://www.ncbi.nlm.nih.gov/pubmed/28891980
http://dx.doi.org/10.3390/ijms18091945
_version_ 1783267223304929280
author Jiang, Yumao
Jiao, Yue
Wang, Zhiguo
Li, Tao
Liu, Yang
Li, Yujuan
Zhao, Xiaoliang
Wang, Danqiao
author_facet Jiang, Yumao
Jiao, Yue
Wang, Zhiguo
Li, Tao
Liu, Yang
Li, Yujuan
Zhao, Xiaoliang
Wang, Danqiao
author_sort Jiang, Yumao
collection PubMed
description Glioblastoma is the most common malignant primary brain tumor, and it is one of the causes of cancer fatality in both adult and pediatric populations. Patients with glioblastoma require chemotherapy after surgical resection and radiotherapy. Therefore, chemotherapy constitutes a viable approach for the eradication of glioblastoma cells. In this study, the anti-tumor activity of sinomenine hydrochloride (SH) was evaluated in U87 and SF767 cells in vitro and in vivo. The results showed that SH potently inhibited U87 and SF767 cell viability and did not cause caspase-dependent cell death, as demonstrated by the absence of significant early apoptosis and caspase-3 cleavage. Instead, SH activated an autophagy-mediated cell death pathway, as indicated by the accumulated microtubule-associated protein light chain 3B (LC3B)-II, triggered autophagic flux and enhanced cell viability after pretreatment with autophagy inhibitors. SH-mediated autophagy in the two cell lines was implicated in reactive oxygen species (ROS) generation, protein kinase B (Akt)-mammalian target of rapamycin (mTOR) pathway suppression and c-Jun NH2-terminal kinase (JNK) pathway activation. The ROS antioxidant N-acetylcysteine (NAC), the Akt-specific activator insulin-like growth factor-1 (IGF-1) and the JNK-specific inhibitor SP600125 attenuated SH-induced autophagy. Moreover, ROS activated autophagy via the Akt-mTOR and JNK pathways. Additionally, SH treatment may promote lysosome biogenesis through activating transcription factor EB (TFEB). The in vivo study found that SH effectively suppressed glioblastoma growth without exhibiting significant toxicity. In conclusion, our findings reveal a novel mechanism of action of SH in cancer cells via the induction of autophagy through ROS generation and autophagy-lysosome pathway activation; these findings also supply a new potential therapeutic agent for the treatment of human glioblastoma.
format Online
Article
Text
id pubmed-5618594
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-56185942017-09-30 Sinomenine Hydrochloride Inhibits Human Glioblastoma Cell Growth through Reactive Oxygen Species Generation and Autophagy-Lysosome Pathway Activation: An In Vitro and In Vivo Study Jiang, Yumao Jiao, Yue Wang, Zhiguo Li, Tao Liu, Yang Li, Yujuan Zhao, Xiaoliang Wang, Danqiao Int J Mol Sci Article Glioblastoma is the most common malignant primary brain tumor, and it is one of the causes of cancer fatality in both adult and pediatric populations. Patients with glioblastoma require chemotherapy after surgical resection and radiotherapy. Therefore, chemotherapy constitutes a viable approach for the eradication of glioblastoma cells. In this study, the anti-tumor activity of sinomenine hydrochloride (SH) was evaluated in U87 and SF767 cells in vitro and in vivo. The results showed that SH potently inhibited U87 and SF767 cell viability and did not cause caspase-dependent cell death, as demonstrated by the absence of significant early apoptosis and caspase-3 cleavage. Instead, SH activated an autophagy-mediated cell death pathway, as indicated by the accumulated microtubule-associated protein light chain 3B (LC3B)-II, triggered autophagic flux and enhanced cell viability after pretreatment with autophagy inhibitors. SH-mediated autophagy in the two cell lines was implicated in reactive oxygen species (ROS) generation, protein kinase B (Akt)-mammalian target of rapamycin (mTOR) pathway suppression and c-Jun NH2-terminal kinase (JNK) pathway activation. The ROS antioxidant N-acetylcysteine (NAC), the Akt-specific activator insulin-like growth factor-1 (IGF-1) and the JNK-specific inhibitor SP600125 attenuated SH-induced autophagy. Moreover, ROS activated autophagy via the Akt-mTOR and JNK pathways. Additionally, SH treatment may promote lysosome biogenesis through activating transcription factor EB (TFEB). The in vivo study found that SH effectively suppressed glioblastoma growth without exhibiting significant toxicity. In conclusion, our findings reveal a novel mechanism of action of SH in cancer cells via the induction of autophagy through ROS generation and autophagy-lysosome pathway activation; these findings also supply a new potential therapeutic agent for the treatment of human glioblastoma. MDPI 2017-09-11 /pmc/articles/PMC5618594/ /pubmed/28891980 http://dx.doi.org/10.3390/ijms18091945 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jiang, Yumao
Jiao, Yue
Wang, Zhiguo
Li, Tao
Liu, Yang
Li, Yujuan
Zhao, Xiaoliang
Wang, Danqiao
Sinomenine Hydrochloride Inhibits Human Glioblastoma Cell Growth through Reactive Oxygen Species Generation and Autophagy-Lysosome Pathway Activation: An In Vitro and In Vivo Study
title Sinomenine Hydrochloride Inhibits Human Glioblastoma Cell Growth through Reactive Oxygen Species Generation and Autophagy-Lysosome Pathway Activation: An In Vitro and In Vivo Study
title_full Sinomenine Hydrochloride Inhibits Human Glioblastoma Cell Growth through Reactive Oxygen Species Generation and Autophagy-Lysosome Pathway Activation: An In Vitro and In Vivo Study
title_fullStr Sinomenine Hydrochloride Inhibits Human Glioblastoma Cell Growth through Reactive Oxygen Species Generation and Autophagy-Lysosome Pathway Activation: An In Vitro and In Vivo Study
title_full_unstemmed Sinomenine Hydrochloride Inhibits Human Glioblastoma Cell Growth through Reactive Oxygen Species Generation and Autophagy-Lysosome Pathway Activation: An In Vitro and In Vivo Study
title_short Sinomenine Hydrochloride Inhibits Human Glioblastoma Cell Growth through Reactive Oxygen Species Generation and Autophagy-Lysosome Pathway Activation: An In Vitro and In Vivo Study
title_sort sinomenine hydrochloride inhibits human glioblastoma cell growth through reactive oxygen species generation and autophagy-lysosome pathway activation: an in vitro and in vivo study
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618594/
https://www.ncbi.nlm.nih.gov/pubmed/28891980
http://dx.doi.org/10.3390/ijms18091945
work_keys_str_mv AT jiangyumao sinomeninehydrochlorideinhibitshumanglioblastomacellgrowththroughreactiveoxygenspeciesgenerationandautophagylysosomepathwayactivationaninvitroandinvivostudy
AT jiaoyue sinomeninehydrochlorideinhibitshumanglioblastomacellgrowththroughreactiveoxygenspeciesgenerationandautophagylysosomepathwayactivationaninvitroandinvivostudy
AT wangzhiguo sinomeninehydrochlorideinhibitshumanglioblastomacellgrowththroughreactiveoxygenspeciesgenerationandautophagylysosomepathwayactivationaninvitroandinvivostudy
AT litao sinomeninehydrochlorideinhibitshumanglioblastomacellgrowththroughreactiveoxygenspeciesgenerationandautophagylysosomepathwayactivationaninvitroandinvivostudy
AT liuyang sinomeninehydrochlorideinhibitshumanglioblastomacellgrowththroughreactiveoxygenspeciesgenerationandautophagylysosomepathwayactivationaninvitroandinvivostudy
AT liyujuan sinomeninehydrochlorideinhibitshumanglioblastomacellgrowththroughreactiveoxygenspeciesgenerationandautophagylysosomepathwayactivationaninvitroandinvivostudy
AT zhaoxiaoliang sinomeninehydrochlorideinhibitshumanglioblastomacellgrowththroughreactiveoxygenspeciesgenerationandautophagylysosomepathwayactivationaninvitroandinvivostudy
AT wangdanqiao sinomeninehydrochlorideinhibitshumanglioblastomacellgrowththroughreactiveoxygenspeciesgenerationandautophagylysosomepathwayactivationaninvitroandinvivostudy