Preclinical activity of DCZ3301, a novel aryl-guanidino compound in the therapy of multiple myeloma.
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.
['Gao|Minjie|M|', 'Li|Bo|B|', 'Sun|Xi|X|', 'Zhou|Yunfei|Y|', 'Wang|Yingcong|Y|', 'Tompkins|Van S|VS|', 'Xu|Zhijian|Z|', 'Indima|Nekitsing|N|', 'Wang|Houcai|H|', 'Xiao|Wenqin|W|', 'Gao|Lu|L|', 'Chen|Gege|G|', 'Wu|Huiqun|H|', 'Wu|Xiaosong|X|', 'Kong|Yuanyuan|Y|', 'Xie|Bingqian|B|', 'Zhang|Yiwen|Y|', 'Chang|Gaomei|G|', 'Hu|Liangning|L|', 'Yang|Guang|G|', 'Dai|Bojie|B|', 'Tao|Yi|Y|', 'Zhu|Weiliang|W|', 'Shi|Jumei|J|']
D000818:Animals D000970:Antineoplastic Agents D017209:Apoptosis D015153:Blotting, Western D002460:Cell Line D002478:Cells, Cultured D004797:Enzyme-Linked Immunosorbent Assay D006801:Humans D015850:Interleukin-6 D053078:Membrane Potential, Mitochondrial D059630:Mesenchymal Stem Cells D051379:Mice D009101:Multiple Myeloma D050796:STAT3 Transcription Factor D042461:Vascular Endothelial Growth Factor A
DCZ3301 Multiple Myeloma synergistic cytotoxicity antitumor activities