Theranostics 2017; 7(15):3690-3699. doi:10.7150/thno.18345 This issue Cite

Research Paper

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

Minjie Gao1*, Bo Li2*, Xi Sun1*, 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 Zhang 1, Gaomei Chang1, Liangning Hu1, Guang Yang1, Bojie Dai5, Yi Tao1✉, Weiliang Zhu2✉, Jumei Shi1✉

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.

Citation:
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. https://www.thno.org/v07p3690.htm
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Abstract

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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


Citation styles

APA
Gao, M., Li, B., Sun, X., Zhou, Y., Wang, Y., Tompkins, V.S., 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. (2017). Preclinical activity of DCZ3301, a novel aryl-guanidino compound in the therapy of multiple myeloma. Theranostics, 7(15), 3690-3699. https://doi.org/10.7150/thno.18345.

ACS
Gao, M.; Li, B.; Sun, X.; Zhou, Y.; Wang, Y.; Tompkins, V.S.; 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.

NLM
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. https://www.thno.org/v07p3690.htm

CSE
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. 2017. Preclinical activity of DCZ3301, a novel aryl-guanidino compound in the therapy of multiple myeloma. Theranostics. 7(15):3690-3699.

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