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Indirubin-3'-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma
Zhen Yu1, Xiaojing Wei1, Lanting Liu1
1State 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.
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.
Insights
Indirubin-3'-monoxime (I3MO) shows anti-myeloma activity by inducing DNA damage and sensitizing cells to proteasome inhibitors. This novel agent triggers proteasome inhibition, offering a promising therapeutic strategy for multiple myeloma (MM).
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Multiple myeloma (MM) is an incurable plasma cell malignancy.
- Proteasome inhibitors (PIs) are crucial in MM treatment but face drug resistance challenges.
- Indirubin-3 extquotesingle-monoxime (I3MO) is investigated as a potential MM therapeutic agent.
Purpose of the Study:
- To investigate the anti-MM activity of I3MO.
- To elucidate the molecular mechanisms underlying I3MO's effects in MM.
- To evaluate I3MO's potential in overcoming bortezomib resistance.
Main Methods:
- In vivo and in vitro studies using MM patient samples and cell lines.
- Analysis of I3MO's impact on cell death, cell cycle, DNA damage, and NF-κB signaling.
- Investigation of I3MO's interaction with proteasome activators PA28γ (PSME3) and PA200 (PSME4).
Main Results:
- I3MO demonstrated anti-MM activity in both drug-sensitive and resistant cells.
- I3MO induced DNA damage, cell cycle arrest, and abrogated NF-κB activation.
- I3MO downregulated USP7, promoted NEK2 degradation, and suppressed NF-κB signaling.
- I3MO directly bound and downregulated proteasome activators PSME3 and PSME4, sensitizing MM cells to bortezomib.
- Overexpression of PSME3 and PSME4 in relapsed/refractory MM (RRMM) correlated with poor outcomes.
Conclusions:
- I3MO triggers proteasome inhibition, acting as a multifaceted regulator of cell death.
- I3MO sensitizes multiple myeloma cells to bortezomib by downregulating proteasome activators.
- I3MO represents a promising therapeutic strategy to improve outcomes in multiple myeloma patients.
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