title: Anti-tumor activity of the proteasome inhibitor BSc2118 against human multiple myeloma.
abstract: Introduction of bortezomib, the first generation of proteasome inhibitor, has significantly improved the median overall survival of patients with multiple myeloma (MM). However, the dose-limiting adverse events and acquired drug resistance limit its long-term usage. Here, we report in vitro and in vivo anti-MM activity of the irreversible proteasome inhibitor BSc2118. BSc2118 inhibited the chymotrypsin-like (CT-L) proteasome activity, accompanied by accumulation of ubiquitinated proteins. BSc2118 suppressed tumor cell growth through induction of G2/M phase arrest and induced apoptosis via activation of the apoptotic signaling cascade, in association with up-regulation of p53 and p21. Importantly, BSc2118 was active in vitro against MM cells' acquired bortezomib resistance. Of note, BSc2118 also displayed a novel anti-angiogenesis activity both in vitro and in vivo. Lastly, BSc2118 exhibited a broader safety dose range and higher anti-tumor efficacy in vivo in a human MM xenograft mouse model, compared to bortezomib. Together, these findings indicate the in vitro and in vivo anti-MM activities of BSc2118 through induction of cell cycle arrest and apoptosis, as well as inhibition of tumor angiogenesis. They also suggest that BSc2118 might, at least in vitro, partially overcome acquired bortezomib resistance, likely associated with inhibition of autophagy.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China.
authors.forename: Meirong
authors.initials: M
authors.lastname: Zang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China.
authors.forename: Zengjun
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China.
authors.forename: Lanting
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Hematology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Cancer Center, The First Hospital of Jilin University, Changchun, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kuckelkorn
authors.affiliation: Department of Neurology, University hospital Essen, Essen, Germany.
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Doeppner
authors.affiliation: Department of Neurology, University hospital Essen, Essen, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
authors.affiliation: Cancer Research Institute, Central South University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education; Hunan, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China. Electronic address: qiulg@ihcams.ac.cn.
authors.forename: Lugui
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Cancer Center, The First Hospital of Jilin University, Changchun, China. Electronic address: Fengyanjin@jlu.edu.cn.
authors.forename: Fengyan
authors.initials: F
authors.lastname: Jin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002073:Butanes / Q000627:therapeutic use*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009842:Oligopeptides / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000627:therapeutic use*; D011719:Pyrazines / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C513723:BSc2118; D001897:Boronic Acids; D002073:Butanes; D016328:NF-kappa B; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D011719:Pyrazines; D016159:Tumor Suppressor Protein p53; D000069286:Bortezomib; D020169:Caspases; D046988:Proteasome Endopeptidase Complex
keywords: Anti-angiogenesis; Autophagy; Bortezomib resistance; Multiple myeloma; Proteasome inhibitor