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Published on: May 15, 2019
Cardiovascular Toxicity of Proteasome Inhibitors in Multiple Myeloma Therapy
Yi Zheng1, Shan Huang1, Bingxin Xie1
1Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin China.
Abstract:
The treatment for multiple myeloma has advanced significantly over the past few decades. Proteasome inhibitors have become the cornerstone of the treatment of multiple myeloma. However, proteasome inhibitors have shown cardiovascular complications such as hypertension, pulmonary hypertension, heart failure, arrhythmias, ischaemic heart disease and thromboembolism. Detection, monitoring and management of proteasome inhibitor-related cardiovascular toxicity are essential to improve clinical outcomes for patients. Proposed mechanisms of proteasome inhibitor-related cardiovascular toxicity are apoptosis, prolonged inhibition of the ubiquitin-proteasome system, accumulation of improperly folded proteins within cardiomyocytes and higher protein phosphatase 2A activity. To better understand the mechanisms underlying cardiotoxicity, further in vitro and in vivo experiments are required to investigate these hypotheses. Combined use of metformin or angiotensin II receptor blockers with the proteasome inhibitor, carfilzomib, showed an emerging role as a prophylactic therapy because they can preserve heart function in multiple myeloma patients. Metformin is expected to be an effective therapeutic intervention for the management of carfilzomib-induced cardiotoxicity. There has been evidence that three compounds, apremilast, rutin, and dexrazoxane, can reverse carfilzomib-induced cardiotoxicity in rats. The future transition from animal experiments to clinical trials is worth waiting for.
Insights
Proteasome inhibitors are key in multiple myeloma treatment but cause heart problems. Early detection and new therapies like metformin show promise for managing this cardiovascular toxicity.
Area of Science:
- Cardiology
- Oncology
- Pharmacology
Background:
- Proteasome inhibitors are a cornerstone in multiple myeloma treatment.
- These drugs can cause significant cardiovascular complications, including hypertension, heart failure, and thromboembolism.
- Effective management of proteasome inhibitor-related cardiotoxicity is crucial for patient outcomes.
Purpose of the Study:
- To review the cardiovascular complications associated with proteasome inhibitors in multiple myeloma.
- To explore the proposed mechanisms underlying proteasome inhibitor-induced cardiotoxicity.
- To discuss emerging prophylactic and therapeutic strategies for managing this toxicity.
Main Methods:
- Literature review of proteasome inhibitor-related cardiovascular toxicity.
- Analysis of proposed mechanisms including apoptosis and protein accumulation.
- Evaluation of potential interventions such as metformin and specific compounds.
Main Results:
- Proteasome inhibitors are linked to various cardiovascular issues like hypertension and heart failure.
- Potential mechanisms involve cardiomyocyte apoptosis and protein handling disruptions.
- Metformin and angiotensin II receptor blockers show prophylactic potential against carfilzomib cardiotoxicity.
- Apremilast, rutin, and dexrazoxane demonstrated efficacy in reversing carfilzomib-induced cardiotoxicity in rat models.
Conclusions:
- Cardiovascular toxicity is a significant concern with proteasome inhibitor therapy for multiple myeloma.
- Understanding the underlying mechanisms is essential for developing targeted interventions.
- Further research, including clinical trials, is needed to validate prophylactic and therapeutic strategies like metformin and other compounds.
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