The novel norcantharidin derivative DCZ5417 suppresses multiple myeloma progression by targeting the TRIP13–MAPK–YWHAE signaling pathway
-
Published:2023-11-27
Issue:1
Volume:21
Page:
-
ISSN:1479-5876
-
Container-title:Journal of Translational Medicine
-
language:en
-
Short-container-title:J Transl Med
Author:
Wang Yingcong, Dong Sanfeng, Hu Ke, Xu Li, Feng Qilin, Li Bo, Wang Guangli, Chen Gege, Zhang Bibo, Jia Xinyan, Xu Zhijian, Gao Xuejie, Zhang Hui, Xie Yongsheng, Lu Meiling, Chang Shuaikang, Song Dongliang, Wu Xiaosong, Jia Qi, Zhu Huabin, Zhou Jinfeng, Zhu Weiliang, Shi JumeiORCID
Abstract
Abstract
Background
Multiple myeloma (MM), an incurable disease owing to drug resistance, requires safe and effective therapies. Norcantharidin (NCTD), an active ingredient in traditional Chinese medicines, possesses activity against different cancers. However, its toxicity and narrow treatment window limit its clinical application. In this study, we synthesized a series of derivatives of NCTD to address this. Among these compounds, DCZ5417 demonstrated the greatest anti-MM effect and fewest side effects. Its anti-myeloma effects and the mechanism were further tested.
Methods
Molecular docking, pull-down, surface plasmon resonance-binding, cellular thermal shift, and ATPase assays were used to study the targets of DCZ5417. Bioinformatic, genetic, and pharmacological approaches were used to elucidate the mechanisms associated with DCZ5417 activity.
Results
We confirmed a highly potent interaction between DCZ5417 and TRIP13. DCZ5417 inhibited the ATPase activity of TRIP13, and its anti-MM activity was found to depend on TRIP13. A mechanistic study verified that DCZ5417 suppressed cell proliferation by targeting TRIP13, disturbing the TRIP13/YWHAE complex and inhibiting the ERK/MAPK signaling axis. DCZ5417 also showed a combined lethal effect with traditional anti-MM drugs. Furthermore, the tumor growth-inhibitory effect of DCZ5417 was demonstrated using in vivo tumor xenograft models.
Conclusions
DCZ5417 suppresses MM progression in vitro, in vivo, and in primary cells from drug-resistant patients, affecting cell proliferation by targeting TRIP13, destroying the TRIP13/YWHAE complex, and inhibiting ERK/MAPK signaling. These results imply a new and effective therapeutic strategy for MM treatment.
Funder
National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Subject
General Biochemistry, Genetics and Molecular Biology,General Medicine
Reference30 articles.
1. Kuiper R, Broyl A, de Knegt Y, van Vliet MH, van Beers EH, van der Holt B, el Jarari L, Mulligan G, Gregory W, Morgan G, et al. A gene expression signature for high-risk multiple myeloma. Leukemia. 2012;26:2406–13. 2. Kumar SK, Rajkumar V, Kyle RA, van Duin M, Sonneveld P, Mateos MV, Gay F, Anderson KC. Multiple myeloma. Nat Rev Dis Primers. 2017;3:17046. 3. Waxman AJ, Mink PJ, Devesa SS, Anderson WF, Weiss BM, Kristinsson SY, McGlynn KA, Landgren O. Racial disparities in incidence and outcome in multiple myeloma: a population-based study. Blood. 2010;116:5501–6. 4. Huang SY, Yao M, Tang JL, Lee WC, Tsay W, Cheng AL, Wang CH, Chen YC, Shen MC, Tien HF. Epidemiology of multiple myeloma in Taiwan: increasing incidence for the past 25 years and higher prevalence of extramedullary myeloma in patients younger than 55 years. Cancer. 2007;110:896–905. 5. Drayson M, Tang LX, Drew R, Mead GP, Carr-Smith H, Bradwell AR. Serum free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma. Blood. 2001;97:2900–2.
|
|