دورية أكاديمية
أعرض في EDS

Indirubin-3’-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma

التفاصيل البيبلوغرافية
العنوان: Indirubin-3’-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma
المؤلفون: Zhen Yu, Xiaojing Wei, Lanting Liu, Hao Sun, Teng Fang, Lu Wang, Ying Li, Weiwei Sui, Kefei Wang, Yi He, Yaozhong Zhao, Wenyang Huang, Gang An, Fancui Meng, Changjiang Huang, Tengteng Yu, Kenneth C. Anderson, Tao Cheng, Lugui Qiu, Mu Hao
المصدر: EBioMedicine, Vol 78, Iss , Pp 103950- (2022)
بيانات النشر: Elsevier, 2022.
سنة النشر: 2022
المجموعة: LCC:Medicine
LCC:Medicine (General)
مصطلحات موضوعية: Multiple myeloma, Proteasome inhibition, Indirubin-3’-monoxime (I3MO), PSME3 (PA28γ), PSME4 (PA200), Medicine, Medicine (General), R5-920
الوصف: Summary: Background: Multiple myeloma (MM) is still an incurable malignancy of plasma cells. Proteasome inhibitors (PIs) work as the backbone agent and have greatly improved the outcome in majority of newly diagnosed patients with myeloma. However, drug resistance remains the major obstacle causing treatment failure in clinical practice. Here, we investigated the effects of Indirubin-3’-monoxime (I3MO), one of the derivatives of Indirubin, in the treatment of MM. Methods: MM patient primary samples and human cell lines were examined. I3MO effects on myeloma treatment and the underling molecular mechanisms were investigated via in vivo and in vitro study. Findings: Our results demonstrated the anti-MM activity of I3MO in both drug- sensitive and -resistance MM cells. I3MO sensitizes MM cells to bortezomib-induced apoptosis. Mechanistically, I3MO acts as a multifaceted regulator of cell death, which induced DNA damage, cell cycle arrest, and abrogates NF-κB activation. I3MO efficiently down-regulated USP7 expression, promoted NEK2 degradation, and suppressed NF-κB signaling in MM. Our study reported that I3MO directly bound with and caused the down-regulation of PA28γ (PSME3), and PA200 (PSME4), the proteasome activators. Knockdown of PSME3 or PSME4 caused the inhibition of proteasome capacity and the overload of paraprotein, which sensitizes MM cells to bortezomib-mediated growth arrest. Clinical data demonstrated that PSME3 and PSME4 are over-expressed in relapsed/refractory MM (RRMM) and associated with inferior outcome. Interpretation: Altogether, our study indicates that I3MO is agent triggering proteasome inhibition and represents a promising therapeutic strategy to improve patient outcome in MM. Fundings: A full list of funding can be found in the acknowledgements.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2352-3964
Relation: http://www.sciencedirect.com/science/article/pii/S2352396422001347; https://doaj.org/toc/2352-3964
DOI: 10.1016/j.ebiom.2022.103950
URL الوصول: https://doaj.org/article/271b810c490745ecb2266666d34c4ea7
رقم الأكسشن: edsdoj.271b810c490745ecb2266666d34c4ea7
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:23523964
DOI:10.1016/j.ebiom.2022.103950