Author:
Hu Liangning,Li Bo,Chen Gege,Song Dongliang,Xu Zhijian,Gao Lu,Xi Mengyu,Zhou Jinfeng,Li Liping,Zhang Hui,Feng Qilin,Wang Yingcong,Lu Kang,Lu Yumeng,Bu Wenxuan,Wang Houcai,Wu Xiaosong,Zhu Weiliang,Shi Jumei
Abstract
Abstract
Background
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.
Methods
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.
Results
DCZ3301 overcame bortezomib (BTZ) resistance through regulation of the G2/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.
Conclusions
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.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Shanghai
National Key New Drug Creation and Manufacturing Program, Ministry of Science and Technology
Publisher
Springer Science and Business Media LLC
Cited by
6 articles.
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