Please use this identifier to cite or link to this item:
http://doi.org/10.25358/openscience-9395
Authors: | Boulos, Joelle C. Omer, Ejlal A. Rigano, Daniela Formisano, Carmen Chatterjee, Manik Leich, Ellen Klauck, Sabine M. Shan, Le-tian Efferth, Thomas |
Title: | Cynaropicrin disrupts tubulin and c-Myc-related signaling and induces parthanatos-type cell death in multiple myeloma |
Online publication date: | 24-Aug-2023 |
Year of first publication: | 2023 |
Language: | english |
Abstract: | 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. |
DDC: | 570 Biowissenschaften 570 Life sciences |
Institution: | Johannes Gutenberg-Universität Mainz |
Department: | FB 09 Chemie, Pharmazie u. Geowissensch. |
Place: | Mainz |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-9395 |
Version: | Published version |
Publication type: | Zeitschriftenaufsatz |
License: | CC BY |
Information on rights of use: | https://creativecommons.org/licenses/by/4.0/ |
Journal: | Acta pharmacologica Sinica Version of Record (VoR) |
Publisher: | Springer Nature |
Publisher place: | Basingstoke |
Issue date: | 2023 |
ISSN: | 1745-7254 |
Publisher DOI: | 10.1038/s41401-023-01117-3 |
Appears in collections: | DFG-491381577-H |
Files in This Item:
File | Description | Size | Format | ||
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cynaropicrin_disrupts_tubulin-20230815123736975.pdf | 8.54 MB | Adobe PDF | View/Open |