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

Joelle C. Boulos1, Ejlal A. Omer1, Daniela Rigano2, Carmen Formisano2, Manik Chatterjee3, Ellen Leich4,5, Sabine M. Klauck6, Le-tian Shan7, Thomas Efferth1
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
Correspondence to: Thomas Efferth:,
DOI: 10.1038/s41401-023-01117-3
Received: 15 February 2023
Accepted: 28 May 2023
Advance online: 21 June 2023


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 (IC50 = 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 G2M phase along with an increase in the sub-G0G1 phase after 24 h. With prolonged treatment times, cells accumulated more in the sub-G0G1 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.

Keywords: hematological malignancies; multiple myeloma; cynaropicrin; c-Myc; microtubules; parthanatos; network pharmacology; xenograft tumor zebrafish model

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