Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China.
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
J Exp Clin Cancer Res. 2020 Jun 9;39(1):105. doi: 10.1186/s13046-020-01597-9.
DCZ3301, a novel aryl-guanidino compound previously reported by our group, exerts cytotoxic effects against multiple myeloma (MM), diffused large B cell lymphoma (DLBCL), and T-cell leukemia/lymphoma. However, the underlying mechanism of its action remains unknown.
We generated bortezomib (BTZ)-resistant cell lines, treated them with various concentrations of DCZ3301 over varying periods, and studied its effect on colony formation, cell proliferation, apoptosis, cell cycle, DNA synthesis, and DNA damage response. We validated our results using in vitro and in vivo experimental models.
DCZ3301 overcame bortezomib (BTZ) resistance through regulation of the G/M checkpoint in multiple myeloma (MM) in vitro and in vivo. Furthermore, treatment of BTZ-resistant cells with DCZ3301 restored their drug sensitivity. DCZ3301 induced M phase cell cycle arrest in MM mainly via inhibiting DNA repair and enhancing DNA damage. Moreover, DCZ3301 promoted the phosphorylation of ATM, ATR, and their downstream proteins, and these responses were blocked by the ATM specific inhibitor KU55933.
Our study provides a proof-of-concept that warrants the clinical evaluation of DCZ3301 as a novel anti-tumor compound against BTZ resistance in MM.
本研究组先前报道的新型芳基胍化合物 DCZ3301 对多发性骨髓瘤（MM）、弥漫性大 B 细胞淋巴瘤（DLBCL）和 T 细胞白血病/淋巴瘤均具有细胞毒性作用。然而，其作用机制尚不清楚。
我们构建了硼替佐米（BTZ）耐药细胞系，用不同浓度的 DCZ3301 处理不同时间，研究其对集落形成、细胞增殖、凋亡、细胞周期、DNA 合成和 DNA 损伤反应的影响。我们使用体外和体内实验模型验证了我们的结果。
DCZ3301 通过调节体外和体内多发性骨髓瘤（MM）中的 G/M 检查点克服了硼替佐米（BTZ）耐药。此外，用 DCZ3301 处理 BTZ 耐药细胞恢复了其药物敏感性。DCZ3301 通过抑制 DNA 修复和增强 DNA 损伤诱导 MM 中 M 期细胞周期停滞。此外，DCZ3301 促进 ATM、ATR 及其下游蛋白的磷酸化，而这些反应被 ATM 特异性抑制剂 KU55933 阻断。
我们的研究提供了一个概念验证，证明了 DCZ3301 作为一种新型抗肿瘤化合物，可用于临床评估治疗 MM 中的 BTZ 耐药。
