A novel phosphoramide compound, DCZ0847, displays in vitro and in vivo anti-myeloma activity, alone or in combination with bortezomib.

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.

• Authors: Gege Chen, Ke Hu, Haiguo Sun, Jinfeng Zhou, Dongliang Song, Zhijian Xu, Lu Gao, Ye Lu, Yao Cheng, Qilin Feng, Hui Zhang, Yingcong Wang, Liangning Hu, Kang Lu, Xiaosong Wu, Bo Li, Weiliang Zhu, Jumei Shi
• Journal: Cancer letters (Cancer Lett) Vol. 478 Pg. 45-55 (05 28 2020) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 32160976 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.

Chemical References

• Phosphoramides
• Bortezomib

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacology)
• Bortezomib (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Humans
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Multiple Myeloma (drug therapy, metabolism)
• Phosphoramides (administration & dosage, pharmacology)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays