TY  - JOUR
AU  - Boulos, Joelle C
AU  - Omer, Ejlal A
AU  - Rigano, Daniela
AU  - Formisano, Carmen
AU  - Chatterjee, Manik
AU  - Leich, Ellen
AU  - Klauck, Sabine
AU  - Shan, Le-Tian
AU  - Efferth, Thomas
TI  - Cynaropicrin disrupts tubulin and c-Myc-related signaling and induces parthanatos-type cell death in multiple myeloma.
JO  - Acta pharmacologica Sinica
VL  - 44
IS  - 11
SN  - 1671-4083
CY  - [Basingstoke]
PB  - Springer Nature
M1  - DKFZ-2023-01239
SP  - 2265-2281
PY  - 2023
N1  - 2023 Nov;44(11):2265-2281
AB  - 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.
KW  - c-Myc (Other)
KW  - cynaropicrin (Other)
KW  - hematological malignancies (Other)
KW  - microtubules (Other)
KW  - multiple myeloma (Other)
KW  - network pharmacology (Other)
KW  - parthanatos (Other)
KW  - xenograft tumor zebrafish model (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37344563
DO  - DOI:10.1038/s41401-023-01117-3
UR  - https://inrepo02.dkfz.de/record/276989
ER  -