The Differential Effect of Senolytics on SASP Cytokine Secretion and Regulation of EMT by CAFs
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View abstract on PubMed
Summary
This summary is machine-generated.Senolytic drugs targeting senescent cells in the tumor microenvironment can have opposing effects. Some senolytics may paradoxically promote tumor progression and resistance to therapy.
Area Of Science
- Oncology
- Cellular Biology
- Pharmacology
Background
- The tumor microenvironment (TME) is crucial for tumor progression and therapy response.
- Cellular senescence and its associated secretory phenotype (SASP) can influence tumorigenesis.
- Senolytic therapy aims to eliminate senescent cells, offering a novel anticancer strategy.
Purpose Of The Study
- To investigate the differential effects of two senolytic drugs, navitoclax and dasatinib/quercetin, on cancer-associated fibroblasts (CAFs) and their role in epithelial-mesenchymal transition (EMT).
- To assess potential side effects of senolytic therapy beyond senescent cell depletion.
Main Methods
- Treatment of cancer-associated fibroblasts (CAFs) with navitoclax or dasatinib/quercetin.
- Quantification of senescent cell reduction.
- Analysis of senescence-associated secretory phenotype (SASP) components, specifically IL-6 secretion.
- Assessment of epithelial-mesenchymal transition (EMT) and cell migration in MC38 colorectal cancer cells.
Main Results
- Both navitoclax and dasatinib/quercetin effectively reduced senescent CAFs.
- Dasatinib/quercetin, unlike navitoclax, increased IL-6 secretion from CAFs.
- This increase in IL-6 correlated with enhanced migration and EMT in MC38 cancer cells.
Conclusions
- Senolytic drugs can have distinct, even opposing, effects on CAFs and tumor-promoting processes.
- Certain senolytics may possess side effects that promote tumorigenesis, independent of their senolytic activity.
- Extensive preclinical evaluation of senolytics is necessary to understand their multifaceted impact on tumor progression and therapy resistance before clinical application.
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