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japoniconea induces apoptosis of bortezomib-sensitive and -resistant myeloma cells in vitro and in vivo by targeting IKKβ

引用

Cancer Biology & Medicine 2022年第5期19卷 651-668页

作者： Zilu Zhang Chenjing Ye Jia Liu Wenbin Xu Chao Wu Qing Yu Xiaoguang Xu Xinyi Zeng Huizi Jin Yingli Wu Hua Yan Shanghai Institute of Hematology Affiliated Ruijin Hospital of Shanghai Jiao Tong University School of MedicineShanghai 200025China VIP Health Center Affiliated Ruijin Hospital of Shanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs School of PharmacyShanghai Jiao Tong UniversityShanghai 200240China Hongqiao International Institute of Medicine Shanghai Tongren Hospital/Faculty of Basic MedicineChemical Biology Division of Shanghai Universities E-InstitutesKey Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineShanghai 200025China

Objective:Multiple myeloma(MM)remains incurable with high rates of *** therapeutic drugs are therefore urgently needed to improve the ***(JA),a natural product isolated from Inula japonica Thunb,has shown good anti-MM potential.A comprehensive study should therefore be conducted to identify both the in vitro and in vivo mechanisms of the anti-MM effects of ***:CCK8 assays and flow cytometry were used to detect the proliferation,apoptosis,and cell cycle of MM cell lines when treated with *** vivo experiments were conducted using subcutaneous xenograft mouse *** also identified possible targets and the mechanism of JA using RNA-seq and c-Map databases,and identified the specific targets of JA in bortezomib-sensitive and-resistant MM cell lines using CETSA,DARTS,and rescue ***,JA and bortezomib were used separately or together to characterize their possible synergistic ***:In vitro,JA inhibited proliferation,and induced apoptosis and G2/M phase arrest in MM cell lines,and selectively killed primary CD138+MM *** vivo,JA also demonstrated a strong anti-tumor effect with no observable *** addition,JA showed synergetic effects in combination with bortezomib,and enhanced the anti-tumor effect of bortezomib in bortezomibresistant *** and DARTS confirmed direct binding of JA to NF-κB inhibitor kinase beta(IKKβ),and overexpression of IKKβor knockdown of IκBαpartially rescued the apoptosis induced by ***:JA exhibited strong anti-tumor effects in *** sensitized myeloma cells to bortezomib and overcame NF-κB-induced drug resistance by inhibiting IKKβ,providing a new treatment strategy for MM patients.

关键词： Multiple myeloma NF-κB japoniconea bortezomib drug resistance

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