The authors of a paper published in Pharmaceuticals tested multiple drug-polyphenol combinations to find the ones with the best senolytic properties [1].
Targeting senescent cells in lung diseases
Various drugs are being used to address some of the problems associated with cellular senescence. For example, some senomorphic drugs affect the production and release of SASP-associated molecules.
In this paper, the authors focused specifically on senescent cells in lung disease. They believe cellular senescence can be a therapeutic target for such conditions as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Previous research on lung disease in animal models has found that treatments against cellular senescence, such as senolytic and senomorphic drugs, may be effective [2].
More importantly, clinical trials that investigated the combination of two senotherapeutic agents, dasatinib (a tyrosine kinase inhibitor) plus a natural polyphenol, quercetin, found them to be effective against human lung diseases [3]. Other research has shown that this combination can “induce apoptosis in senescent cells efficiently without any effect on quiescent, proliferating, or differentiated fibroblasts” [4].
In this work, the researchers aimed to find a potential new therapeutic drug-polyphenol combination with senolytic activity in human lung fibroblasts. They used therapeutics such as azithromycin, rapamycin, aspirin, metformin, and FK-506, in addition to dasatinib, in combination with chemically diverse nine natural polyphenols, such as phenolic acids (caffeic acid, chlorogenic acid, ellagic acid, ferulic acid, and gallic acid), flavonoids (epicatechin, hesperidin, and quercetin), and stilbenes (resveratrol).
Azithromycin is an antibiotic that induces autophagic and metabolic changes [5]. Rapamycin is an mTOR inhibitor. Aspirin is an antiplatelet drug that decreases the levels of the anti-apoptotic protein Bcl-xL in cells [6]. Metformin is a type 2 diabetes drug, and FK-506 (tacrolimus) is an immunosuppressive drug [7].
Two compounds are better than one
The researchers exposed lung cell lines to a senescence-inducing agent and, following the treatment, tested the effect of drugs and polyphenol combinations on lung cell lines. They didn’t observe senolytic activity when polyphenols were combined with aspirin, azithromycin, FK-506 (tacrolimus), metformin, or rapamycin.
However, a few drug-polyphenol combinations showed senolytic activity. The biggest reduction in cellular viability (49.2%) was observed in the well-known dasatinib and quercetin combination. Combining dasatinib with resveratrol and dasatinib with ellagic acid also reduced cellular viability by around 43-44%.
The authors also wanted to understand the mechanism of action of these drug-polyphenol combinations, and some evidence had suggested that cellular death by apoptosis was playing a role in this reduced cell viability. They observed that when cells were incubated with dasatinib and a polyphenol cocktail, the majority of cells entered apoptosis. They also observed a decrease in the expression of anti-apoptotic BCL-2 and an increase in pro-apoptotic caspase activity.
Additionally, they measured the levels of inflammatory markers IL-1β and IL-6 (one of the most prominent SASP cytokines [8]) following dasatinib and polyphenols incubation. The combination of dasatinib with resveratrol didn’t impact those markers. However, dasatinib with ellagic acid and dasatinib with quercetin increased their levels.
These observations were made with human lung fibroblast cells. The authors also performed these tests on epithelial cells derived from human lung carcinomas, but there was no senolytic effect, suggesting that these drug/polyphenol combinations are selective. Further research needs to be concluded to determine if this selectivity occurs in vivo, and the authors believe that ongoing clinical studies testing dasatinib and quercetin might shed some light.
Next step: preclinical and clinical trials
The authors believe that the identified senolytic combinations pave the way for testing them in human clinical trials of age-related lung diseases.
Since this study was performed on cell lines, the concentrations used by the researchers cannot be used to establish safe and effective concentrations for human trials. However, current clinical trials can serve as a base for determining safe doses for combinations that have not yet been tested.
LiteratureIn conclusion, the elimination of senescent cells through the use of senolytics has been considered as a plausible therapeutic strategy to treat age-related lung diseases and disorders, and we emerged with two new possibilities of senolytics, dasatinib plus resveratrol and dasatinib plus ellagic acid, to be evaluated in preclinical models comparing them to the standard option of dasatinib plus quercetin. Dasatinib and resveratrol associate anti-SASP activity with senolytic activity, while ellagic acid can be used in lower doses than quercetin, which may prove beneficial.
[1] de Godoy, M. C. X., Macedo, J. A., & Gambero, A. (2024). Researching New Drug Combinations with Senolytic Activity Using Senescent Human Lung Fibroblasts MRC-5 Cell Line. Pharmaceuticals (Basel, Switzerland), 17(1), 70.
[2] Hernandez-Gonzalez, F., Faner, R., Rojas, M., Agustí, A., Serrano, M., & Sellarés, J. (2021). Cellular Senescence in Lung Fibrosis. International journal of molecular sciences, 22(13), 7012.
[3] Justice, J. N., Nambiar, A. M., Tchkonia, T., LeBrasseur, N. K., Pascual, R., Hashmi, S. K., Prata, L., Masternak, M. M., Kritchevsky, S. B., Musi, N., & Kirkland, J. L. (2019). Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine, 40, 554–563.
[4] Kirkland, J. L., & Tchkonia, T. (2020). Senolytic drugs: from discovery to translation. Journal of internal medicine, 288(5), 518–536.
[5] Ozsvari, B., Nuttall, J. R., Sotgia, F., & Lisanti, M. P. (2018). Azithromycin and Roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts. Aging, 10(11), 3294–3307.
[6] Feng, M., Kim, J., Field, K., Reid, C., Chatzistamou, I., & Shim, M. (2019). Aspirin ameliorates the long-term adverse effects of doxorubicin through suppression of cellular senescence. FASEB bioAdvances, 1(9), 579–590.
[7] Kang, S. W., Kim, J., & Shin, D. Y. (2016). Inhibition of senescence and promotion of the proliferation of chondrocytes from articular cartilage by CsA and FK506 involves inhibition of p38MAPK. Mechanisms of ageing and development, 153, 7–13.
[8] Vernot J. P. (2020). Senescence-Associated Pro-inflammatory Cytokines and Tumor Cell Plasticity. Frontiers in molecular biosciences, 7, 63.
