ReferenceID 2651
Piperlongumine overcomes imatinib resistance by inducing proteasome inhibition in chronic myelogenous leukemia cells
J Ethnopharmacol
Ethnopharmacological relevance: Piper longum L., an herbal medicine used in India and other Asian countries, is prescribed routinely for a range of diseases, including tumor. Piperlongumine, a natural product isolated fr
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- Reference Id
- 2651
- Evidence Id
- 19241
- Core Evidence Id
- 19241
- Source Reference Id
- 5302
- Herb2 Reference Id
- HBREF006099
- Subject Paper Key
- HBIN040107_36220508
- Pubmed Id
- 36220508
- Doi
- 10.1016/j.jep.2022.115815
- Paper Title
- Piperlongumine overcomes imatinib resistance by inducing proteasome inhibition in chronic myelogenous leukemia cells
- Paper Abstract
- Ethnopharmacological relevance: Piper longum L., an herbal medicine used in India and other Asian countries, is prescribed routinely for a range of diseases, including tumor. Piperlongumine, a natural product isolated from Piper longum L., has received widespread attention due to its various pharmacological activities, such as anti-inflammatory, antimicrobial, and antitumor effects. Aim of the study: Chronic myelogenous leukemia (CML) is a hematopoietic disease caused by Bcr-Abl fusion gene, with an incidence of 15% in adult leukemias. Targeting Bcr-Abl by imatinib provides a successful treatment approach for CML. However, imatinib resistance is an inevitable issue for CML treatment. In particular, T315I mutant is the most stubborn of the Bcr-Abl point mutants associated with imatinib resistance. Therefore, it is urgent to find an alternative approach to conquer imatinib resistance. This study investigated the role of a natural product piperlongumine in overcoming imatinib resistance in CML. Materials and methods: Cell viability and apoptosis were evaluated by MTS assay and Annexin V/propidium iodide counterstaining assay, respectively. Levels of intracellular signaling proteins were assessed by Western blots. Mitochondrial membrane potential was reflected by the fluorescence intensity of rhodamine-123. The function of proteasome was detected using 20S proteasomal activity assay, proteasomal deubiquitinase activity assay, and deubiquitinase active-site-directed labeling. The antitumor effects of piperlongumine were assessed with mice xenografts. Results: We demonstrate that (i) Piperlongumine inhibits proteasome function by targeting 20S proteasomal peptidases and 19S proteasomal deubiquitinases (USP14 and UCHL5) in Bcr-Abl-WT and Bcr-Abl-T315I CML cells; (ii) Piperlongumine inhibits the cell viability of CML cell lines and primary CML cells; (iii) Proteasome inhibition by piperlongumine leads to cell apoptosis and downregulation of Bcr-Abl; (iv) Piperlongumine suppresses the tumor growth of CML xenografts. Conclusions: These results support that blockade of proteasome activity by piperlongumine provides a new therapeutic strategy for treating imatinib-resistant CML.
- Journal
- J Ethnopharmacol
- Publish Year
- 2022
- Experiment Subject
- mouse; bcr-abl-t315i cml cells; bcr-abl-wt; cml cell lines
- Experiment Type
- Cell Experiment
- Phenotype Related
- Leukemias; Hematopoietic Disease; Chronic Myelogenous Leukemia; Tumor
- Paper Title Cn
- Paper Title En
- Piperlongumine overcomes imatinib resistance by inducing proteasome inhibition in chronic myelogenous leukemia cells
- Bilingual Status
- semi_complete