PMID- 36059985 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220907 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 13 DP - 2022 TI - Qu-Du-San-Jie decoction induces growth inhibition and vascular normalization in NF2-associated vestibular schwannoma. PG - 941854 LID - 10.3389/fphar.2022.941854 [doi] LID - 941854 AB - Background: Neurofibromatosis type 2 (NF2) is a rare genetic syndrome that predisposes individuals to develop bilateral vestibular schwannomas (VSs) causing a high risk of life-threatening neurological complications. Traditional treatment options for NF2-associated VS usually cause neurological damage, and to date, there are no FDA-approved pharmacotherapies for NF2. The aim of this study was to evaluate the antitumor efficacy of Qu-Du-San-Jie (QDSJ) decoction, a traditional Chinese medicine formula, on NF2-associated VS and to investigate the potential underlying mechanisms. Methods: Ultra high-performance liquid chromatography-mass spectroscopy (UHPLC-MS) analysis was performed to identify the components of QDSJ and their targets. To determine the relationships between the putative targets of QDSJ and the differential genes of NF2-associated VS, the drug-disease crossover genes were screened using the UHPLC-MS data combined with our previous gene expression profiling data. The differentially expressed genes were imported into the STRING database to generate a PPI network. Differentially expressed gene targets and pathways were identified using GO and KEGG pathway enrichment analyses. The in vitro and in vivo drug efficacy of QDSJ decoction was tested using a patient-derived schwannoma cell line and a patient-derived xenograft mouse model, respectively. H&E staining, immunochemistry, and immunofluorescence staining were used to evaluate the cell proliferation and tumor vessels. Results: A total of 133 compounds were identified in QDSJ decoction using UHPLC-MS analysis. Network pharmacology showed that the regulation of necroptosis, apoptosis, cell cycle, angiogenesis, adherens junction, and neuroactive ligand-receptor interaction could be associated with the efficacy of QDSJ in treating NF2-associated VS. Treatment with QDSJ induced necrotic cell death and apoptosis of schwannoma cells in vitro and suppressed the tumor growth in vivo. Histopathological analysis revealed areas of cell necrosis and enlarged tumor blood vessels in the QDSJ-treated tumors. The numbers of cells positive for Cyclin D1 and Ki-67 were significantly reduced in QDSJ-treated tumors compared to control tumors. Immunofluorescence staining of CD31 and alphaSMA showed a decreased number and density of tumor vessels and normalized vessel structure in QDSJ-treated tumors. Conclusion: Our study demonstrates that QDSJ decoction shows significant antitumor activity against NF2-associated schwannoma and is a possible candidate for future clinical trials. CI - Copyright (c) 2022 Lin, Li, Zhang, Chu, Li, Bie, Tang, Gao, Li, Liao, Xin, Zhao, Liu and Ding. FAU - Lin, Jie AU - Lin J AD - School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China. FAU - Li, Shi-Wei AU - Li SW AD - Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. FAU - Zhang, Jing AU - Zhang J AD - Department of Neural Reconstruction, Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. FAU - Chu, Fu-Hao AU - Chu FH AD - School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China. AD - Research Center for Spleen and Stomach Diseases of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China. AD - Institute of Regulatory Science for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China. FAU - Li, Cheng-Ze AU - Li CZ AD - School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China. FAU - Bie, Zhi-Xu AU - Bie ZX AD - Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. FAU - Tang, Han-Lu AU - Tang HL AD - Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. FAU - Gao, Shan AU - Gao S AD - School of Chinese Materia Medicine, Beijing University of Chinese Medicine, Beijing, China. FAU - Li, Ping AU - Li P AD - Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China. FAU - Liao, Meng-Ting AU - Liao MT AD - Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China. FAU - Xin, Tian-Xi AU - Xin TX AD - School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China. FAU - Zhao, Fu AU - Zhao F AD - Department of Neural Reconstruction, Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. FAU - Liu, Pi-Nan AU - Liu PN AD - Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. AD - Department of Neural Reconstruction, Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. FAU - Ding, Xia AU - Ding X AD - School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China. AD - Research Center for Spleen and Stomach Diseases of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China. AD - Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China. LA - eng PT - Journal Article DEP - 20220819 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC9437245 OTO - NOTNLM OT - Qu-Du-San-Jie decoction OT - antiangiogenesis OT - neurofibromatosis type 2 OT - schwannoma OT - therapy COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/09/06 06:00 MHDA- 2022/09/06 06:01 PMCR- 2022/08/19 CRDT- 2022/09/05 03:47 PHST- 2022/05/11 00:00 [received] PHST- 2022/07/22 00:00 [accepted] PHST- 2022/09/05 03:47 [entrez] PHST- 2022/09/06 06:00 [pubmed] PHST- 2022/09/06 06:01 [medline] PHST- 2022/08/19 00:00 [pmc-release] AID - 941854 [pii] AID - 10.3389/fphar.2022.941854 [doi] PST - epublish SO - Front Pharmacol. 2022 Aug 19;13:941854. doi: 10.3389/fphar.2022.941854. eCollection 2022.