Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling
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 po...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-03-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-024-01909-4 |
| _version_ | 1797247462358908928 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ana Carolina B. da C. Rodrigues |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T19:59:05Z |
| format | Article |
| id | doaj.art-45153271df08471280ba301d8a84973f |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-24T19:59:05Z |
| publishDate | 2024-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-45153271df08471280ba301d8a84973f2024-03-24T12:10:32ZengNature Publishing GroupCell Death Discovery2058-77162024-03-0110111610.1038/s41420-024-01909-4Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signallingAna Carolina B. da C. Rodrigues0Suellen L. R. Silva1Ingrid R. S. B. Dias2Rafaela G. A. Costa3Maiara de S. Oliveira4Milena B. P. Soares5Rosane B. Dias6Ludmila F. Valverde7Clarissa A. G. Rocha8Emily M. Johnson9Cristina Pina10Daniel P. Bezerra11Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA)Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA)Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA)Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA)Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA)Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA)Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA)Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA)Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA)College of Health, Medicine and Life Sciences, Brunel University LondonCollege of Health, Medicine and Life Sciences, Brunel University LondonGonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA)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.https://doi.org/10.1038/s41420-024-01909-4 |
| spellingShingle | 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 Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling Cell Death Discovery |
| title | Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling |
| title_full | Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling |
| title_fullStr | Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling |
| title_full_unstemmed | Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling |
| title_short | Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling |
| title_sort | piplartine eliminates cd34 aml stem progenitor cells by inducing oxidative stress and suppressing nf κb signalling |
| url | https://doi.org/10.1038/s41420-024-01909-4 |
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