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

Autor: Rodrigues ACBDC; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil.; College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UB8 3PH, UK., Silva SLR; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil., Dias IRSB; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil., Costa RGA; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil., Oliveira MS; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil., Soares MBP; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil.; SENAI Institute for Innovation in Advanced Health Systems, SENAI CIMATEC, Salvador, Bahia, 41650-010, Brazil., Dias RB; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil.; Department of Propaedeutics and Integrated Clinical, Faculty of Dentistry, Federal University of Bahia (UFBA), Salvador, Bahia, 40301-155, Brazil., Valverde LF; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil., Rocha CAG; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil.; Department of Propaedeutics and Integrated Clinical, Faculty of Dentistry, Federal University of Bahia (UFBA), Salvador, Bahia, 40301-155, Brazil.; Center for Biotechnology and Cell Therapy, D'Or Institute for Research and Education (IDOR), Salvador, Bahia, 41253-190, Brazil., Johnson EM; College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UB8 3PH, UK., Pina C; College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UB8 3PH, UK. cristina.pina@brunel.ac.uk.; Centre for Genome Engineering and Maintenance, Brunel University London, Uxbridge, UB8 3PH, UK. cristina.pina@brunel.ac.uk., Bezerra DP; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil. daniel.bezerra@fiocruz.br.
Jazyk: angličtina
Zdroj: Cell death discovery [Cell Death Discov] 2024 Mar 19; Vol. 10 (1), pp. 147. Date of Electronic Publication: 2024 Mar 19.
DOI: 10.1038/s41420-024-01909-4
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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