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DCZ0814 induces apoptosis and G0/G1 phase cell cycle arrest in myeloma by dual inhibition of mTORC1/2

Authors Kong Y, Li B, Chang S, Gao L, Xu Z, He W, Yang G, Xie B, Chen G, Hu L, Lu K, Wang Y, Wu X, Zhu W, Shi J

Received 14 November 2018

Accepted for publication 17 March 2019

Published 27 May 2019 Volume 2019:11 Pages 4797—4808

DOI https://doi.org/10.2147/CMAR.S194202

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 2

Editor who approved publication: Dr Xueqiong Zhu


Yuanyuan Kong,1,* Bo Li,2,* Shuaikang Chang,1 Lu Gao,1 Zhijian Xu,2 Wan He,1 Guang Yang,1 Bingqian Xie,1 Gege Chen,1 Liangning Hu,1 Kang Lu,1 Yingcong Wang,1 Xiaosong Wu,1 Weiliang Zhu,2 Jumei Shi1

1Department of Hematology, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China; 2CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People’s Republic of China

*These authors contributed equally to this work

Purpose:
The present study investigates the effect of DCZ0814 in multiple myeloma (MM) cells, and determines the molecular mechanism of its antitumor activity against MM.
Methods: The effects of DCZ0814 were evaluated in vitro using human MM cell lines (ARP1 and OCI-MY5) and in vivo in a murine xenograft MM model. Cell viability was measured with the CCK-8 assay and mitochondrial membrane potential (MMP) was assessed with the JC-1 dye. Apoptosis and cell cycle distribution were examined by flow cytometry. Inhibition of mTORC1 and mTORC2 was assessed by western blot analysis, and the synergistic effect of DCZ0814 and known MM drugs was assessed by calculating the combination index value, using the CalcuSyn software.
Results: DCZ0814 effectively inhibited proliferation in MM cells, an effect that was associated with the induction of apoptosis, G0/G1 cell cycle arrest, MMP reduction and reactive oxygen species (ROS) generation. Meanwhile, DCZ0814 repressed the mTOR signaling via dual mTORC1/C2 inhibition and overcame the protective effect of the bone marrow (BM) microenvironment in myeloma cells. In addition, co-treatment with DCZ0814 and other anti-MM agents induced synergistic effects. Finally, the efficacy of the DCZ0814 treatment was confirmed in an MM xenograft mouse model.
Conclusion: DCZ0814 exhibits potent anti-MM activity and abrogates the activation of the mTOR/Akt signaling pathway mediated by the BM stroma-derived cytokines. Our results provide a theoretical basis for the development of novel therapeutic strategies in MM using DCZ0814 as a natural product combination compound.

Keywords: DCZ0814, multiple myeloma, mTOR, bone marrow microenvironment, apoptosis
 

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