Isocucurbitacin B inhibits glioma growth through PI3K/AKT pathways and increases glioma sensitivity to TMZ by inhibiting hsa-mir-1286a  

作　　者：Mingyu Han Junsha An Sui Li Huali Fan Li Wang Qing Du Junrong Du Yuxin Yang Yuqin Song Fu Peng 

机构地区：[1]Department of Pharmacology,Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry,Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology,West China School of Pharmacy,Sichuan University,Chengdu 610041,Sichuan,China [2]Department of Epidemiology and Health Statistics,West China School of Public Health and West China Fourth Hospital,Sichuan University,Chengdu 610041,Sichuan,China [3]Integrated Traditional Chinese and Western Medicine Department,Sichuan Clinical Research Center for Cancer,Sichuan Cancer Hospital&Institute,Sichuan Cancer Center,Affiliated Cancer Hospital of University of Electronic Science and Technology of China,Chengdu 610041,Sichuan,China [4]Waigaoqiao Free Trade Zone,WuXi Biologics,Shanghai 214122,China [5]Livzon Pharmaceutical Group Inc,Zhuhai 519090,Guangdong,China [6]Chongqing Western Biomedical Technology Co.Ltd.,Chongqing 400039,China

出　　处：《Cancer Drug Resistance》2024年第1期772-796,共25页癌症耐药(英文)

基　　金：supported by National Natural Science Foundation of China(No.82003879);Project of Science and Technology Department of Sichuan Province(No.2023NSFSC1928;2023NSFSC1992);Young Elite Scientists Sponsorship Program by China Association for Science and Technology(No.CACM-2020-QNRC1-01);the Fundamental Research Funds for the central Universities.

摘　　要：Aim:Glioma accounts for 81%of all cancers of the nervous system cancers and presents one of the most drug-resistant malignancies,resulting in a relatively high mortality rate.Despite extensive efforts,the complete treatment options for glioma remain elusive.The effect of isocucurbitacin B(isocuB),a natural compound extracted from melon pedicels,on glioma has not been investigated.This study aims to investigate the inhibitory effect of isocuB on glioma and elucidate its underlying mechanisms,with the objective of developing it as a potential therapeutic agent for glioma.Methods:We used network pharmacology and bioinformatics analysis to predict potential targets and associated pathways of isocuB in glioma.Subsequently,the inhibitory effect of isocuB on glioma and its related mechanisms were assessed through Counting Kit-8(CCK-8),wound healing,transwell,Western blot(WB),reverse transcription-quantitative polymerase chain reaction(RT-qPCR),and other in vitro experiments,alongside tumor formation experiments in nude mice.Results:Based on this investigation,it suggested that isocuB might inhibit the growth of gliomas through the PI3K-AKT and MAPK pathways.Additionally,we proposed that isocuB may enhance glioma drug sensitivity to temozolomide(TMZ)via modulation of hsa-mir-1286a.The CCK-8 assay revealed that isocuB exhibited inhibitory effects on U251 and U87 proliferation and outperformed TMZ.Wound healing and transwell experiments showed that isocuB inhibited the invasion and migration of U251 cells by suppressing the activity of MMP-2/9,N-cadherin,and Vimentin.The TdT-mediated dUTP-biotin nick end labeling(TUNEL)and flow cytometry(FCM)assays revealed that isocuB induced cell apoptosis through inhibition of BCL-2.Subsequently,we conducted RT-qPCR and WB experiments,which revealedthat PI3K/AKT and MAPK pathways might be involved in the mechanism of the inhibition isocuB on glioma.Additionally,isocuB promoted the sensitivity of glioma U251 to TMZ by inhibiting hsa-mir-1286a.Furthermore,weconstructed TMZ-resistant U251

关 键 词：Isocucurbitacin B GLIOMA network pharmacology hsa-mir-1286a drug sensitivity 

分 类 号：R73[医药卫生—肿瘤]