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Published on: June 28, 2019
Researching New Drug Combinations with Senolytic Activity Using Senescent Human Lung Fibroblasts MRC-5 Cell Line
Maria Carolina Ximenes de Godoy1, Juliana Alves Macedo2, Alessandra Gambero1,2
1School for Life Sciences, Pontifical Catholic University of Campinas (PUC-Campinas), Av. John Boyd Dunlop, s/n, Campinas 13034-685, SP, Brazil.
Abstract:
Therapeutically targeting senescent cells seems to be an interesting perspective in treating chronic lung diseases, which are often associated with human aging. The combination of the drug dasatinib and the polyphenol quercetin is used in clinical trials as a senolytic, and the first results point to the relief of physical dysfunction in patients with idiopathic pulmonary fibrosis. In this work, we tested new combinations of drugs and polyphenols, looking for senolytic activity using human lung fibroblasts (MRC-5 cell line) with induced senescence. We researched drugs, such as azithromycin, rapamycin, metformin, FK-506, aspirin, and dasatinib combined with nine natural polyphenols, namely caffeic acid, chlorogenic acid, ellagic acid, ferulic acid, gallic acid, epicatechin, hesperidin, quercetin, and resveratrol. We found new effective senolytic combinations with dasatinib and ellagic acid and dasatinib and resveratrol. Both drug combinations increased apoptosis, reduced BCL-2 expression, and increased caspase activity in senescent MRC-5 cells. Ellagic acid senolytic activity was more potent than quercetin, and resveratrol counteracted inflammatory cytokine release during senolysis in vitro. In conclusion, dasatinib and ellagic acid and dasatinib and resveratrol present in vitro senolytic potential like that observed for the combination in clinical trials of dasatinib and quercetin, and maybe they could be future alternatives in the senotherapeutic field.
Insights
New drug combinations, dasatinib with ellagic acid or resveratrol, show senolytic potential for chronic lung diseases. These findings offer promising alternatives for senotherapeutics in aging-related conditions.
Area of Science:
- Biomedical Science
- Cellular Biology
- Aging Research
Background:
- Chronic lung diseases are linked to cellular senescence and aging.
- Dasatinib and quercetin are currently used in clinical trials as senolytics for idiopathic pulmonary fibrosis.
- Investigating novel senolytic drug combinations is crucial for developing new therapeutic strategies.
Purpose of the Study:
- To identify new senolytic drug combinations targeting senescent human lung fibroblasts (MRC-5 cells).
- To evaluate the senolytic efficacy of dasatinib combined with various natural polyphenols.
- To compare the senolytic activity of novel combinations with existing treatments.
Main Methods:
- Induced senescence in human lung fibroblasts (MRC-5 cell line).
- Tested combinations of dasatinib with nine natural polyphenols (including ellagic acid and resveratrol).
- Assessed senolytic activity by measuring apoptosis, BCL-2 expression, caspase activity, and inflammatory cytokine release.
Main Results:
- Identified dasatinib and ellagic acid, and dasatinib and resveratrol as effective senolytic combinations.
- These combinations increased apoptosis, reduced BCL-2 expression, and elevated caspase activity in senescent cells.
- Ellagic acid demonstrated higher potency than quercetin, and resveratrol mitigated inflammatory cytokine release.
Conclusions:
- Dasatinib and ellagic acid, and dasatinib and resveratrol exhibit significant in vitro senolytic potential.
- These combinations show comparable efficacy to dasatinib and quercetin used in clinical trials.
- Novel senolytic combinations may offer future therapeutic alternatives for senotherapeutics in lung diseases.
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