1. Academic Validation
  2. Indirubin-3'-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma

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

  • EBioMedicine. 2022 Apr;78:103950. doi: 10.1016/j.ebiom.2022.103950.
Zhen Yu 1 Xiaojing Wei 1 Lanting Liu 1 Hao Sun 1 Teng Fang 1 Lu Wang 1 Ying Li 1 Weiwei Sui 1 Kefei Wang 1 Yi He 1 Yaozhong Zhao 1 Wenyang Huang 1 Gang An 1 Fancui Meng 2 Changjiang Huang 2 Tengteng Yu 1 Kenneth C Anderson 3 Tao Cheng 1 Lugui Qiu 4 Mu Hao 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Hai he Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, PR China.
  • 2 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300301, PR China; State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300301, PR China.
  • 3 LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 4 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Hai he Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, PR China. Electronic address: qiulg@ihcams.ac.cn.
  • 5 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Hai he Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, PR China. Electronic address: haomu@ihcams.ac.cn.
Abstract

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.

Keywords

Indirubin-3’-monoxime (I3MO); Multiple myeloma; PSME3 (PA28γ); PSME4 (PA200); Proteasome inhibition.

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