Xuejie Gao1, Bo Li2, Anqi Ye3, Houcai Wang1, Yongsheng Xie1, Dandan Yu1, Zhijian Xu2, Bingqing Shi1, Hui Zhang1, Qilin Feng1, Ke Hu1, Yong Zhang2, Cheng Huang1, Guang Yang1, Jumei Shi4, Weiliang Zhu5. 1. Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China. 2. CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. 3. Shanghai Children's Medical Center, Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China. 4. Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China. shijumei@tongji.edu.cn. 5. CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. wlzhu@simm.ac.cn.
Abstract
BACKGROUND: Multiple myeloma (MM) is a highly aggressive and incurable clonal plasma cell disease with a high rate of recurrence. Thus, the development of new therapies is urgently needed. DCZ0805, a novel compound synthesized from osalmide and pterostilbene, has few observed side effects. In the current study, we intend to investigate the therapeutic effects of DCZ0805 in MM cells and elucidate the molecular mechanism underlying its anti-myeloma activity. METHODS: We used the Cell Counting Kit-8 assay, immunofluorescence staining, cell cycle assessment, apoptosis assay, western blot analysis, dual-luciferase reporter assay and a tumor xenograft mouse model to investigate the effect of DCZ0805 treatment both in vivo and in vitro. RESULTS: The results showed that DCZ0805 treatment arrested the cell at the G0/G1 phase and suppressed MM cells survival by inducing apoptosis via extrinsic and intrinsic pathways. DCZ0805 suppressed the NF-κB signaling pathway activation, which may have contributed to the inhibition of cell proliferation. DCZ0805 treatment remarkably reduced the tumor burden in the immunocompromised xenograft mouse model, with no obvious toxicity observed. CONCLUSION: The findings of this study indicate that DCZ0805 can serve as a novel therapeutic agent for the treatment of MM.
BACKGROUND:Multiple myeloma (MM) is a highly aggressive and incurable clonal plasma cell disease with a high rate of recurrence. Thus, the development of new therapies is urgently needed. DCZ0805, a novel compound synthesized from osalmide and pterostilbene, has few observed side effects. In the current study, we intend to investigate the therapeutic effects of DCZ0805 in MM cells and elucidate the molecular mechanism underlying its anti-myeloma activity. METHODS: We used the Cell Counting Kit-8 assay, immunofluorescence staining, cell cycle assessment, apoptosis assay, western blot analysis, dual-luciferase reporter assay and a tumor xenograft mouse model to investigate the effect of DCZ0805 treatment both in vivo and in vitro. RESULTS: The results showed that DCZ0805 treatment arrested the cell at the G0/G1 phase and suppressed MM cells survival by inducing apoptosis via extrinsic and intrinsic pathways. DCZ0805 suppressed the NF-κB signaling pathway activation, which may have contributed to the inhibition of cell proliferation. DCZ0805 treatment remarkably reduced the tumor burden in the immunocompromised xenograft mouse model, with no obvious toxicity observed. CONCLUSION: The findings of this study indicate that DCZ0805 can serve as a novel therapeutic agent for the treatment of MM.
Authors: Brian A Walker; Konstantinos Mavrommatis; Christopher P Wardell; T Cody Ashby; Michael Bauer; Faith E Davies; Adam Rosenthal; Hongwei Wang; Pingping Qu; Antje Hoering; Mehmet Samur; Fadi Towfic; Maria Ortiz; Erin Flynt; Zhinuan Yu; Zhihong Yang; Dan Rozelle; John Obenauer; Matthew Trotter; Daniel Auclair; Jonathan Keats; Niccolo Bolli; Mariateresa Fulciniti; Raphael Szalat; Philippe Moreau; Brian Durie; A Keith Stewart; Hartmut Goldschmidt; Marc S Raab; Hermann Einsele; Pieter Sonneveld; Jesus San Miguel; Sagar Lonial; Graham H Jackson; Kenneth C Anderson; Herve Avet-Loiseau; Nikhil Munshi; Anjan Thakurta; Gareth J Morgan Journal: Blood Date: 2018-06-08 Impact factor: 22.113
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