Vestibular schwannoma(VS),one of characteristic tumors of neurofibromatosis type 2(NF2),is an intracranial tumor that arises from Schwann cells of the vestibular nerve.VS results in hearing loss,tinnitus,dizziness,and even death,but there are currently no FDA-approved drugs for treatment.In this study,we established a high-throughput screening to discover effective compounds that could inhibit the viability of VS cells.Among 1019 natural products from the Korea Chemical Bank screened,we found that celastrol,a pentacyclic triterpene derived from a Tripterygium Wilfordi plant,exerted potent inhibitory effect on the viability of VS cells with an IC50 value of 0.5 μM.Celastrol(0.5,1 μM)dose-dependently inhibited the proliferation of primary VS cells derived from VS patients.Celastrol also inhibited the growth,and induced apoptosis of two other VS cell lines(HEI-193 and SC4).Aberrant activation of Wnt/β-catenin signaling has been found in VS isolated from clinically defined NF2 patients.In HEI-193 and SC4 cells,we demonstrated that celastrol(0.1,0.5 μM)dose-dependently inhibited TOPFlash reporter activity and protein expression of β-catenin,but not mRNA level of β-catenin.Furthermore,celastrol accelerated the degradation of β-catenin by promoting the formation of the β-catenin destruction complex.In nude mice bearing VS cell line SC4 allografts,administration of celastrol(1.25 mg·kg-1·d-1,i.p.once every 3 days for 2 weeks)significantly suppressed the tumor growth without showing toxicity.Collectively,this study demonstrates that celastrol can inhibit Wnt/β-catenin signaling by promoting the degradation of β-catenin,consequently inhibiting the growth of VS.

Na Hui Kim;Minji Kwon;Jiwoo Jung;Hyo Byeong Chae;Jiwoo Lee;Yeo-Jun Yoon;In Seok Moon;Ho K.Lee;Wan Namkung;Konstantina M.Stankovic;Se A.Lee;Jong Dae Lee;Sin-Aye Park

Department of ICT Environmental Health System,Graduate School,Soonchunhyang University,Asan-si 31538,Republic of Korea;Department of Biomedical Laboratory Science,College of Medical Sciences,Soonchunhyang University,Asan-si 31538,Republic of Korea;Department of Otorhinolaryngology,Yonsei University,College of Medicine,Seoul 03722,Republic of Korea;Colllege of Pharmacy and Yonsei Institute of Pharmaceutical Sciences,Yonsei University,Yeonsu-gu,Incheon 21983,Republic of Korea;Department of Otolaryngology-Head and Neck Surgery,Stanford University School of Medicine,Stanford,CA 94305,USA;Department of Otorhinolaryngology-Head and Neck Surgery,Soonchunhyang University Bucheon Hospital,Bucheon 14584,Republic of Korea

中国药理学报（英文版）

[1]Na Hui Kim;Minji Kwon;Jiwoo Jung;Hyo Byeong Chae;Jiwoo Lee;Yeo-Jun Yoon;In Seok Moon;Ho K.Lee;Wan Namkung;Konstantina M.Stankovic;Se A.Lee;Jong Dae Lee;Sin-Aye Park-.Celastrol suppresses the growth of vestibular schwannoma in mice by promoting the degradation of β-catenin)[J].中国药理学报（英文版）,2022(11):2993-3001

pentacyclic,Wilfordi,TOPFlash

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