Cynaropicrin disrupts tubulin and c-Myc-related signaling and induces parthanatos-type cell death in multiple myeloma  

作　　者：Joelle C.Boulos Ejlal A.Omer Daniela Rigano Carmen Formisano Manik Chatterjee Ellen Leich Sabine M.Klauck Le-tian Shan Thomas Efferth 

机构地区：[1]Department of Pharmaceutical Biology,Institute of Pharmaceutical and Biomedical Sciences,Johannes Gutenberg University,Staudinger Weg 5,55128,Mainz,Germany [2]Department of Pharmacy,University of Naples“Federico II”,Naples,Italy [3]University Hospital Würzburg,Translational Oncology,Comprehensive Cancer Center Mainfranken,Würzburg,Germany [4]Julius Maximilian University,Institute of Pathology,Würzburg,Germany [5]Comprehensive Cancer Center Mainfranken,Translational Oncology,University Hospital of Würzburg,Würzburg,Germany [6]Division of Cancer Genome Research,German Cancer Research Center(DKFZ),German Cancer Consortium(DKTK),National Center for Tumor Diseases(NCT),Heidelberg,Germany [7]The First Affiliated Hospital,Zhejiang Chinese Medical University,Hangzhou,310053,China

出　　处：《Acta Pharmacologica Sinica》2023年第11期2265-2281,共17页中国药理学报（英文版）

基　　金：funded by a private donation of Marc Strobel,Frankfurt,Germany;by the Deutsche Krebshilfe(process number:70112693 to EL)。

摘　　要：The majority of blood malignancies is incurable and has unforeseeable remitting-relapsing paths in response to different treatments. Cynaropicrin, a natural sesquiterpene lactone from the edible parts of the artichoke plant, has gained increased attention as a chemotherapeutic agent. In this study, we investigated the effects of cynaropicrin against multiple myeloma (MM) cells in vitro and assessed its in vivo effectiveness in a xenograft tumor zebrafish model. We showed that cynaropicrin exerted potent cytotoxicity against a panel of nine MM cell lines and two leukemia cell lines with AMO1 being the most sensitive cell line (IC_(50 )= 1.8 ± 0.3 µM). Cynaropicrin (0.8, 1.9, 3.6 µM) dose-dependently reduced c-Myc expression and transcriptional activity in AMO1 cells that was associated with significant downregulation of STAT3, AKT, and ERK1/2. Cell cycle analysis showed that cynaropicrin treatment arrested AMO1 cells in the G_(2)M phase along with an increase in the sub-G_(0)G_(1) phase after 24 h. With prolonged treatment times, cells accumulated more in the sub-G_(0)G_(1) phase, implying cell death. Using confocal microscopy, we revealed that cynaropicrin disrupted the microtubule network in U2OS cells stably expressing α-tubulin-GFP. Furthermore, we revealed that cynaropicrin promoted DNA damage in AMO1 cells leading to PAR polymer production by PARP1 hyperactivation, resulting in AIF translocation from the mitochondria to the nucleus and subsequently to a novel form of cell death, parthanatos. Finally, we demonstrated that cynaropicrin (5, 10 µM) significantly reduced tumor growth in a T-cell acute lymphoblastic leukemia (T-ALL) xenograft zebrafish model. Taken together, these results demonstrate that cynaropicrin causes potent inhibition of hematopoietic tumor cells in vitro and in vivo.

关 键 词：hematological malignancies multiple myeloma cynaropicrin C-MYC MICROTUBULES parthanatos network pharmacology xenograft tumor zebrafish model 

分 类 号：R965[医药卫生—药理学]