A novel phosphoramide compound, DCZ0847, displays in vitro and in vivo anti-myeloma activity, alone or in combination with bortezomib. (28th May 2020)

• Record Type: Journal Article
• Authors: Chen, Gege; Hu, Ke; Sun, Haiguo; Zhou, Jinfeng; Song, Dongliang; Xu, Zhijian; Gao, Lu; Lu, Ye; Cheng, Yao; Feng, Qilin; Zhang, Hui; Wang, Yingcong; Hu, Liangning; Lu, Kang; Wu, Xiaosong; Li, Bo; Zhu, Weiliang; Shi, Jumei
• Is Part Of: Cancer letters. Volume 478(2020)
• Page Start: 45
• Page End: 55
• Publication Date: 2020-05-28
• Subjects: Multiple myeloma -- Bone marrow microenvironment -- DNA damage -- JAK2/STAT3 pathway; BSA bovine serum albumin -- BM bone marrow -- BMM bone marrow microenvironment -- BMSC bone marrow stromal cell -- PBMCs peripheral blood mononuclear cells -- CCK Cell Counting Kit -- DAPI 4′, 6-diamidino-2-phenylindole -- EdU 5-ethynyl-2′-deoxyuridine -- FBS fetal bovine serum -- IHC immunohistochemistry -- H&E hematoxylin and eosin -- IC50 half-maximal inhibitory concentration -- IL interleukin -- JAK2 Janus kinase 2 -- MM multiple myeloma -- MMP mitochondrial membrane potential -- p phosphorylated -- PARP poly (ADP-ribose) polymerase -- PBS phosphate-buffered saline -- PI propidium iodide -- SD standard deviation -- STAT3 signal transducer and activator of transcription 3 -- TUNEL terminal deoxynucleotidyl transferase dUTP nick-end labeling; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.03.006
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Multiple myeloma (MM) is an incurable hematological malignancy, for which novel effective therapies are urgently needed. We synthesized a novel phosphoramide compound, DCZ0847, showing a potent anti-myeloma activity both in vitro and in vivo . DCZ0847 showed high cytotoxicity towards primary MM cells but had no effect on normal cells and was well tolerated in vivo . The anti-myeloma activity of DCZ0847 was associated with inhibition of cell proliferation; promotion of cell apoptosis via mitochondrial transmembrane potential collapse and caspase-mediated extrinsic or intrinsic apoptotic pathways; and the induction of G2/M phase arrest via downregulation of CDC25C, CDK1, and cyclin B1. In particular, DCZ0847 induced DNA damage and triggered a DNA-damage response by enhancing the levels of γ-H2A.X, phosphorylated (p)-ATM, p-ATR, p-Chk1, and p-Chk2. Additionally, DCZ0847 was able to overcome the bone marrow stromal cells-induced proliferation of MM cells and blocked JAK2/STAT3 signaling. Importantly, DCZ0847 acted synergistically with bortezomib, with the combination exerting greater cytotoxic effects in vitro and in vivo . Together, our results indicate that DCZ0847, alone or in combination with bortezomib, may represent a potential new therapy for patients with MM. Highlights: DCZ0847 had high cytotoxicity in primary MM cells but did not affect normal cells. DCZ0847 had a synergistic effect with bortezomib and was well tolerated in vivo . DCZ0847 inhibited MM proliferation, promoted apoptosis and triggered G2 M phase arrest. DCZ0847 induced DNA damage and triggered a DNA damage response. DCZ0847 reversed the cytoprotective effects of BMM and blocked JAK2/STAT3 signaling.