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Published on: June 7, 2018
Bevacizumab-Induced Mitochondrial Dysfunction, Endoplasmic Reticulum Stress, and ERK Inactivation Contribute to
Yue Li1, Wei Tian2, Dongsheng Yue1
1Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin 300060, China.
Abstract:
The molecular mechanisms underlying the cardiotoxicity associated with bevacizumab, a first-line immunotherapeutic agent used to treat lung cancer, are not fully understood. Here, we examined intracellular signal transduction in cardiomyocytes after exposure to different doses of bevacizumab in vitro. Our results demonstrated that bevacizumab significantly and dose-dependently reduces cardiomyocyte viability and increases cell apoptosis. Bevacizumab treatment also led to mitochondrial dysfunction in cardiomyocytes, as evidenced by the decreased ATP production, increased ROS production, attenuated antioxidative enzyme levels, and reduced respiratory complex function. In addition, bevacizumab induced intracellular calcium overload, ER stress, and caspase-12 activation. Finally, bevacizumab treatment inhibited the ERK signaling pathway, which, in turn, significantly reduced cardiomyocyte viability and contributed to mitochondrial dysfunction. Together, our results demonstrate that bevacizumab-mediated cardiotoxicity is associated with mitochondrial dysfunction, ER stress, and ERK pathway inactivation. These findings may provide potential treatment targets to attenuate myocardial injury during lung cancer immunotherapy.
Insights
Bevacizumab causes heart damage in lung cancer patients by harming cardiomyocytes, leading to mitochondrial dysfunction and ER stress. Targeting the ERK pathway may prevent this cardiotoxicity.
Area of Science:
- Cardiology
- Oncology
- Molecular Biology
Background:
- Bevacizumab is a key immunotherapy for lung cancer.
- Its cardiotoxicity mechanisms remain unclear.
- Understanding these mechanisms is crucial for patient safety.
Purpose of the Study:
- To investigate the molecular mechanisms of bevacizumab-induced cardiotoxicity.
- To examine the effects of bevacizumab on cardiomyocyte signaling pathways.
- To identify potential therapeutic targets for mitigating heart damage.
Main Methods:
- In vitro study of cardiomyocytes exposed to varying bevacizumab doses.
- Assessment of cardiomyocyte viability, apoptosis, and mitochondrial function.
- Analysis of intracellular calcium levels, ER stress markers, and ERK signaling.
Main Results:
- Bevacizumab reduced cardiomyocyte viability and increased apoptosis in a dose-dependent manner.
- Mitochondrial dysfunction was observed, including decreased ATP, increased ROS, and impaired respiratory function.
- Bevacizumab induced calcium overload, ER stress, and caspase-12 activation, while inhibiting the ERK pathway.
Conclusions:
- Bevacizumab-induced cardiotoxicity involves mitochondrial dysfunction, ER stress, and ERK pathway inactivation.
- These findings highlight potential therapeutic targets for managing myocardial injury in cancer patients.
- Further research can focus on developing strategies to protect the heart during bevacizumab treatment.
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