PMID- 28891980 OWN - NLM STAT- MEDLINE DCOM- 20180503 LR - 20240327 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 18 IP - 9 DP - 2017 Sep 11 TI - Sinomenine Hydrochloride Inhibits Human Glioblastoma Cell Growth through Reactive Oxygen Species Generation and Autophagy-Lysosome Pathway Activation: An In Vitro and In Vivo Study. LID - 10.3390/ijms18091945 [doi] LID - 1945 AB - 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. FAU - Jiang, Yumao AU - Jiang Y AD - Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment of Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100000, China. 13683301305@163.com. FAU - Jiao, Yue AU - Jiao Y AD - Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment of Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100000, China. Jiaoyue_medicine@163.com. FAU - Wang, Zhiguo AU - Wang Z AD - Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment of Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100000, China. zhgw68_8@tom.com. FAU - Li, Tao AU - Li T AD - Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment of Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100000, China. hndxlitao@163.com. FAU - Liu, Yang AU - Liu Y AD - Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment of Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100000, China. echoinapril@163.com. FAU - Li, Yujuan AU - Li Y AD - Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment of Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100000, China. lyjdcl@163.com. FAU - Zhao, Xiaoliang AU - Zhao X AD - Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment of Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100000, China. Zhaoxiaoliang1218@aliyun.com. FAU - Wang, Danqiao AU - Wang D AD - Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment of Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100000, China. dq_wang96@sohu.com. LA - eng PT - Journal Article DEP - 20170911 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Antineoplastic Agents) RN - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors) RN - 0 (MAP1LC3B protein, human) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Morphinans) RN - 0 (Reactive Oxygen Species) RN - 0 (TFEB protein, human) RN - 63LT81K70N (sinomenine) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) SB - IM MH - Animals MH - Antineoplastic Agents/pharmacology/*therapeutic use MH - Apoptosis/drug effects MH - *Autophagy MH - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism MH - Brain Neoplasms/*drug therapy/metabolism MH - Cell Line, Tumor MH - Glioblastoma/*drug therapy/metabolism MH - Humans MH - JNK Mitogen-Activated Protein Kinases/metabolism MH - Lysosomes/*drug effects/metabolism MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Microtubule-Associated Proteins/metabolism MH - Morphinans/pharmacology/*therapeutic use MH - Reactive Oxygen Species/metabolism MH - TOR Serine-Threonine Kinases/metabolism PMC - PMC5618594 OTO - NOTNLM OT - autophagy OT - glioblastoma OT - lysosome OT - reactive oxygen species OT - sinomenine hydrochloride COIS- The authors declare no conflicts of interest. EDAT- 2017/09/12 06:00 MHDA- 2018/05/04 06:00 PMCR- 2017/09/01 CRDT- 2017/09/12 06:00 PHST- 2017/07/27 00:00 [received] PHST- 2017/09/03 00:00 [revised] PHST- 2017/09/06 00:00 [accepted] PHST- 2017/09/12 06:00 [entrez] PHST- 2017/09/12 06:00 [pubmed] PHST- 2018/05/04 06:00 [medline] PHST- 2017/09/01 00:00 [pmc-release] AID - ijms18091945 [pii] AID - ijms-18-01945 [pii] AID - 10.3390/ijms18091945 [doi] PST - epublish SO - Int J Mol Sci. 2017 Sep 11;18(9):1945. doi: 10.3390/ijms18091945.