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Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling

Authors :
Ana Carolina B. da C. Rodrigues
Suellen L. R. Silva
Ingrid R. S. B. Dias
Rafaela G. A. Costa
Maiara de S. Oliveira
Milena B. P. Soares
Rosane B. Dias
Ludmila F. Valverde
Clarissa A. G. Rocha
Emily M. Johnson
Cristina Pina
Daniel P. Bezerra
Source :
Cell Death Discovery, Vol 10, Iss 1, Pp 1-16 (2024)
Publication Year :
2024
Publisher :
Nature Publishing Group, 2024.

Abstract

Abstract Acute myeloid leukaemia (AML) is a haematological malignancy characterised by the accumulation of transformed myeloid progenitors in the bone marrow. Piplartine (PL), also known as piperlongumine, is a pro-oxidant small molecule extracted from peppers that has demonstrated antineoplastic potential in solid tumours and other haematological malignancies. In this work, we explored the potential of PL to treat AML through the use of a combination of cellular and molecular analyses of primary and cultured leukaemia cells in vitro and in vivo. We showed that PL exhibits in vitro cytotoxicity against AML cells, including CD34+ leukaemia-propagating cells, but not healthy haematopoietic progenitors, suggesting anti-leukaemia selectivity. Mechanistically, PL treatment increased reactive oxygen species (ROS) levels and induced ROS-mediated apoptosis in AML cells, which could be prevented by treatment with the antioxidant scavenger N-acetyl-cysteine and the pancaspase inhibitor Z-VAD(OMe)-FMK. PL treatment reduced NFKB1 gene transcription and the level of NF-κB p65 (pS536), which was depleted from the nucleus of AML cells, indicating suppression of NF-κB p65 signalling. Significantly, PL suppressed AML development in a mouse xenograft model, and its combination with current AML treatments (cytarabine, daunorubicin and azacytidine) had synergistic effects, indicating translational therapeutic potential. Taken together, these data position PL as a novel anti-AML candidate drug that can target leukaemia stem/progenitors and is amenable to combinatorial therapeutic strategies.

Details

Language :
English
ISSN :
20587716
Volume :
10
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Cell Death Discovery
Publication Type :
Academic Journal
Accession number :
edsdoj.45153271df08471280ba301d8a84973f
Document Type :
article
Full Text :
https://doi.org/10.1038/s41420-024-01909-4