Dual inhibition of mTORC1/2 by DCZ0358 induces cytotoxicity in multiple myeloma and overcomes the protective effect of the bone marrow microenvironment. (1st May 2018)

• Record Type: Journal Article
• Authors: Gao, Lu; Li, Bo; Yang, Guang; Liu, Peng; Lan, Xiucai; Chang, Shuaikang; Tao, Yi; Xu, Zhijian; Xie, Bingqian; Sun, Xi; Wang, Yingcong; Hu, Liangning; Yu, Dandan; Xie, Yongsheng; Bu, Wenxuan; Wu, Xiaosong; Zhu, Weiliang; Shi, Jumei
• Is Part Of: Cancer letters. Volume 421(2018)
• Page Start: 135
• Page End: 144
• Publication Date: 2018-05-01
• Subjects: mTOR -- Multiple myeloma -- Bone marrow microenvironment -- Apoptosis; MM multiple myeloma -- BM bone marrow -- EDU 5-ethynyl-2′-deoxyuridine -- PBMC peripheral blood mononuclear cell -- H&E hematoxylin-eosin -- ALT glutamic-pyruvic transaminase -- AST glutamic-oxalacetic transaminase -- Cr creatinine -- BUN urea nitrogen; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.02.009
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Interaction of multiple myeloma (MM) cells with the bone marrow (BM) microenvironment promotes the proliferation, survival and chemoresistance of MM. The mTOR pathway plays a key role in these undesirable BM microenvironment-mediated events. We synthesized a novel alkaloid compound, DCZ0358, that effectively inhibits mTOR signaling via dual mTORC1/2 inhibition and exhibits potent anti-MM activity in cultured and primary MM cells, as well as a MM xenograft model but has little effect on normal cells. Importantly, we show that this compound can block the BM stromal cell-mediated activation of mTOR/Akt signaling and antagonizes the protective effect of the BM microenvironment. Moreover, DCZ0358 abrogates the bortezomib-triggered activation of Akt, leading to the synergism of DCZ0358 and bortezomib in MM cells. Taken together, our results provide the proof-of-concept for clinical evaluation of DCZ0358, alone or in combination, as an anti-MM agent in MM therapy. Highlights: The activity of the mTOR kinase is inhibited by DCZ0358. The BM stromal cell-mediated activation of mTOR/Akt signaling is blocked by DCZ0358. DCZ0358 potently targets myeloma cells within the protective BM microenvironment. The bortezomib-triggered activation of Akt is abrogated by DCZ0358. DCZ0358 is synergistic with bortezomib.