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Defining regorafenib as a senomorphic drug: therapeutic potential in the age-related lung disease emphysema
Jung-Jin Park1, Kwangseok Oh1, Gun-Wu Lee1
1Department of Biochemistry, Chungbuk National University College of Medicine, Cheongju, 28644, Korea.
Abstract:
Senescence, a hallmark of aging, is a factor in age-related diseases (ARDs). Therefore, targeting senescence is widely regarded as a practicable method for modulating the effects of aging and ARDs. Here, we report the identification of regorafenib, an inhibitor of multiple receptor tyrosine kinases, as a senescence-attenuating drug. We identified regorafenib by screening an FDA-approved drug library. Treatment with regorafenib at a sublethal dose resulted in effective attenuation of the phenotypes of βPIX knockdown- and doxorubicin-induced senescence and replicative senescence in IMR-90 cells; cell cycle arrest, and increased SA-β-Gal staining and senescence-associated secretory phenotypes, particularly increasing the secretion of interleukin 6 (IL-6) and IL-8. Consistent with this result, slower progression of βPIX depletion-induced senescence was observed in the lungs of mice after treatment with regorafenib. Mechanistically, the results of proteomics analysis in diverse types of senescence indicated that growth differentiation factor 15 and plasminogen activator inhibitor-1 are shared targets of regorafenib. Analysis of arrays for phospho-receptors and kinases identified several receptor tyrosine kinases, including platelet-derived growth factor receptor α and discoidin domain receptor 2, as additional targets of regorafenib and revealed AKT/mTOR, ERK/RSK, and JAK/STAT3 signaling as the major effector pathways. Finally, treatment with regorafenib resulted in attenuation of senescence and amelioration of porcine pancreatic elastase-induced emphysema in mice. Based on these results, regorafenib can be defined as a novel senomorphic drug, suggesting its therapeutic potential in pulmonary emphysema.
Insights
Regorafenib, a drug targeting multiple receptor tyrosine kinases, effectively reduces cellular senescence and its associated secretory phenotypes. This senomorphic drug shows therapeutic potential for age-related diseases like pulmonary emphysema.
Area of Science:
- Cellular senescence and aging research
- Drug discovery and repurposing
- Molecular mechanisms of aging
Background:
- Cellular senescence is a key factor in aging and age-related diseases (ARDs).
- Targeting senescence offers a promising strategy to mitigate aging effects and ARDs.
- Identifying existing drugs that can modulate senescence is a practical approach.
Purpose of the Study:
- To identify drugs that can attenuate cellular senescence.
- To investigate the senomorphic potential of regorafenib, a known kinase inhibitor.
- To explore the therapeutic applications of regorafenib in age-related conditions, specifically pulmonary emphysema.
Main Methods:
- Screening of an FDA-approved drug library to identify senescence-attenuating compounds.
- Treatment of IMR-90 cells with regorafenib to assess attenuation of induced and replicative senescence phenotypes.
- Proteomics analysis and phospho-receptor/kinase arrays to elucidate molecular targets and signaling pathways.
- In vivo studies in mice to evaluate regorafenib's effect on senescence progression and emphysema.
Main Results:
- Regorafenib effectively attenuated senescence phenotypes, including cell cycle arrest, SA-β-Gal staining, and secretion of IL-6 and IL-8.
- In vivo, regorafenib slowed senescence progression in mouse lungs.
- Identified shared targets including GDF15 and SERPINE1, and receptor tyrosine kinases (PDGFRA, DDR2) as regorafenib targets, implicating AKT/mTOR, ERK/RSK, and JAK/STAT3 pathways.
- Regorafenib treatment ameliorated emphysema in a mouse model.
Conclusions:
- Regorafenib is identified as a novel senomorphic drug capable of attenuating cellular senescence.
- Regorafenib demonstrates therapeutic potential for age-related diseases, particularly pulmonary emphysema.
- The study highlights regorafenib's multifaceted mechanism involving kinase inhibition and pathway modulation.
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