Preclinical activity of DCZ3301, a novel aryl-guanidino compound in the therapy of multiple myeloma

Minjie Gao^1*, Bo Li^2*, Xi Sun^1*, Yunfei Zhou², Yingcong Wang¹, Van S. Tompkins³, Zhijian Xu², Nekitsing Indima⁴, Houcai Wang¹, Wenqin Xiao¹, Lu Gao¹, Gege Chen¹, Huiqun Wu¹, Xiaosong Wu¹, Yuanyuan Kong¹, Bingqian Xie¹, Yiwen Zhang¹, Gaomei Chang¹, Liangning Hu¹, Guang Yang¹, Bojie Dai⁵, Yi Tao^1✉, Weiliang Zhu^2✉, Jumei Shi^1✉

1. Department of Hematology, Shanghai Tenth People's Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China;
2. CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
3. Biochemistry, Biophysics, and Molecular Biology Department, Iowa State University, Ames, IA, USA;
4. Department of Radiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China;
5. College of life science and technology, Tongji University, Shanghai 200092, China.
* These authors contributed equally to this work.

Abstract

We synthesized a novel aryl-guanidino compound, DCZ3301, and found that it has potent cytotoxicity against multiple human cancer cell lines. The anticancer activity was most potent against multiple myeloma (MM). DCZ3301 induced cytotoxicity in MM cell lines, as well as patient myeloma cells, in part by decreasing mitochondrial membrane potential to induce apoptosis. In contrast, DCZ3301 had no cytotoxic effect on normal cells. DCZ3301 also inhibited cell cycling and caused a G2/M accumulation that corresponded with downregulation of Cdc25C, CDK1, and Cyclin B1. DCZ3301 retained its activity against MM cells in the presence of exogenous cytokines (IL-6 or VEGF) or bone marrow stromal cells (BMSCs) and reduced activity of multiple signaling pathways (STAT3, NFκB, AKT, ERK1/2) in MM but not normal cells. The STAT3 pathway played an important role in modulating DCZ3301-mediated cytotoxicity. Knockdown of STAT3 using siRNA in MM cells enhanced DCZ3301-induced cytotoxicity, whereas overexpression of STAT3 in MM cells partially protected them from apoptosis. In addition, DCZ3301 inhibited VEGF and IL-6 secretion in a dose-dependent fashion in a co-culture of MM cells and BMSCs. Combining DCZ3301 with bortezomib induced synergistic cytotoxicity in MM cell lines and primary MM cells. Finally, in vivo efficacy of DCZ3301 was confirmed in an MM xenograft mouse model. Together, these results provide a rationale for translation of this small-molecule inhibitor, either alone or in combination, to the clinic against MM.

Keywords: Multiple Myeloma, DCZ3301, antitumor activities, synergistic cytotoxicity

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How to cite this article:
Gao M, Li B, Sun X, Zhou Y, Wang Y, Tompkins VS, Xu Z, Indima N, Wang H, Xiao W, Gao L, Chen G, Wu H, Wu X, Kong Y, Xie B, Zhang Y, Chang G, Hu L, Yang G, Dai B, Tao Y, Zhu W, Shi J. Preclinical activity of DCZ3301, a novel aryl-guanidino compound in the therapy of multiple myeloma. Theranostics 2017; 7(15):3690-3699. doi:10.7150/thno.18345. Available from http://www.thno.org/v07p3690.htm