A novel M phase blocker, DCZ3301 enhances the sensitivity of bortezomib in resistant multiple myeloma through DNA damage and mitotic catastrophe

  • J Exp Clin Cancer Res. 2020 Jun 9;39(1):105. doi: 10.1186/s13046-020-01597-9.
Liangning Hu  1 ,  Bo Li  2 ,  Gege Chen  1 ,  Dongliang Song  1 ,  Zhijian Xu  2 ,  Lu Gao  1 ,  Mengyu Xi  2 ,  Jinfeng Zhou  1 ,  Liping Li  1 ,  Hui Zhang  1 ,  Qilin Feng  1 ,  Yingcong Wang  1 ,  Kang Lu  1 ,  Yumeng Lu  1 ,  Wenxuan Bu  1 ,  Houcai Wang  1 ,  Xiaosong Wu  1 ,  Weiliang Zhu  3 ,  Jumei Shi  4  5
Affiliations
  • 1. Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China.
  • 2. 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.
  • 3. 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. [email protected].
  • 4. Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China. [email protected].
  • 5. Tongji University Cancer Center, Tongji University, Shanghai, 200092, China. [email protected].
PMID: 32517809 DOI: 10.1186/s13046-020-01597-9
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.

Keywords
Cell cycle; DNA damage response; Drug-resistance; Multiple myeloma.
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