Piperlongumine overcomes imatinib resistance by inducing proteasome inhibition in chronic myelogenous leukemia cells. (30th January 2023)

• Record Type: Journal Article
• Authors: Lan, Xiaoying; Hu, Min; Jiang, Liling; Wang, Jiamin; Meng, Yi; Chen, Xinmei; Liu, Aochu; Ding, Wa; Zhang, Haichuan; Zhou, Huan; Liu, Bingyuan; Peng, Guanjie; Liao, Siyan; Chen, Xin; Liu, Jinbao; Shi, Xianping
• Is Part Of: Journal of ethnopharmacology. Volume 301(2023)
• Publication Date: 2023-01-30
• Subjects: Piperlongumine -- CML -- Bcr-abl -- Proteasome -- USP14 -- UCHL5; CML chronic myelogenous leukemia -- IM imatinib -- TKI tyrosine kinase inhibitor -- UPS Ubiquitin-proteasome system; Ethnopharmacology -- Periodicals; Pharmacognosy -- Periodicals; Herbs -- Periodicals; Herbs -- Periodicals; Pharmacognosy -- Periodicals; Pharmacognosie -- Périodiques; Herbes -- Périodiques; 615.1
• DOI: 10.1016/j.jep.2022.115815
• Languages: English
• ISSNs: 0378-8741

Abstract

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. Graphical abstract: Image 1 Highlights: Piperlongumine exhibits potent anti-cancer activities in CML in vitro and in vivo . Piperlongumine inhibits activities of 20S proteasome, USP14, and UCHL5. Piperlongumine induces apoptosis and suppresses Bcr-Abl signaling in CML cells. Proteasome inhibition as potential approach for overcoming imatinib resistance.