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Tamoxifen induced cardiac damage via the IL-6/p-STAT3/PGC-1α pathway
Tingting Meng1, Dan Zhang2, Yu Zhang3
1Research Center of Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
Abstract:
Tamoxifen (TAM) is an effective anticancer drug for breast and ovarian cancer. However, increased risk of cardiotoxicity is a long-term clinical problem associated with TAM, while the underlying mechanisms remain unclear. Here, we performed experiments in cardiomyocytes and tumor-bearing or nontumor-bearing mice, and demonstrated that TAM induced cardiac injury via the IL-6/p-STAT3/PGC-1α/IL-6 feedback loop, which is responsible for reactive oxygen species (ROS) accumulation. Compared with non-tumor bearing mice, tumor-bearing mice showed stronger cardiac toxicity after TAM injection, although there was no significant difference. In vitro experiments demonstrated STAT3 phosphorylation inhibitor can increase PGC-1α expression and protect cardiomyocyte via decreasing ROS. Since tumor has higher STAT3 phosphorylation and IL-6 expression level, our research results indicated combining TAM and STAT3 inhibitor might be an effective treatment strategy which can provide both tumor killing and cardioprotective function. Further in vivo research is needed to fully elucidate the effect and mechanisms of the combination therapy of TAM and STAT3 inhibitor.
Insights
Tamoxifen causes heart damage by disrupting the IL-6/STAT3/PGC-1α loop, leading to oxidative stress. Combining Tamoxifen with a STAT3 inhibitor may offer tumor treatment and heart protection.
Area of Science:
- Cardiology
- Oncology
- Molecular Biology
Background:
- Tamoxifen (TAM) is a vital anticancer drug for breast and ovarian cancers.
- TAM-induced cardiotoxicity is a significant clinical challenge with unclear mechanisms.
- Reactive oxygen species (ROS) are implicated in cardiac dysfunction.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying TAM-induced cardiotoxicity.
- To investigate the role of the IL-6/p-STAT3/PGC-1α feedback loop in TAM cardiotoxicity.
- To explore the potential of STAT3 inhibition as a cardioprotective strategy against TAM.
Main Methods:
- In vitro studies using cardiomyocytes.
- In vivo experiments in tumor-bearing and non-tumor-bearing mice.
- Assessment of oxidative stress markers and molecular signaling pathways.
Main Results:
- TAM induces cardiac injury through the IL-6/p-STAT3/PGC-1α/IL-6 feedback loop, increasing ROS accumulation.
- Tumor-bearing mice exhibited enhanced cardiac toxicity compared to non-tumor-bearing mice.
- STAT3 phosphorylation inhibition in vitro increased PGC-1α expression and reduced ROS, protecting cardiomyocytes.
Conclusions:
- The IL-6/p-STAT3/PGC-1α feedback loop is a key mediator of TAM-induced cardiotoxicity.
- Combining TAM with a STAT3 inhibitor presents a potential therapeutic strategy for simultaneous tumor treatment and cardioprotection.
- Further in vivo studies are warranted to validate the efficacy and mechanisms of this combination therapy.
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