Defining regorafenib as a senomorphic drug: therapeutic potential in the age-related lung disease emphysema

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.

Regorafenib prevents the development of emphysema in a murine elastase model

“…Regorafenib, a well-known inhibitor of multi-receptor tyrosine kinases, is approved for therapy of metastatic colorectal cancer, and is also used as the second-line treatment in patients with hepatocellular carcinoma ( 15 , 16 ). The findings of our previous study demonstrated a therapeutic effect of regorafenib in a PPE-induced animal model of emphysema (which might be in part due to the attenuation of senescence) ( 14 ). In the present study, we asked whether regorafenib has a preventive effect on the development of PPE-induced emphysema in mice.…”

“…In our previous study, regorafenib, a multi-receptor tyrosine kinase inhibitor drug, was identified as a potential senomorphic agent capable of exerting a therapeutic effect in porcine pancreatic elastase (PPE)-induced emphysema in mice ( 14 ). A key element of the experimental setup for that purpose was to administer regorafenib after the development of emphysematous phenotypes.…”

FRMD6 determines the cell fate towards senescence: involvement of the Hippo-YAP-CCN3 axis

“…Based on our previous study, which demonstrated that silencing beta p21-activated kinase interacting exchange factor (βPIX), a focal adhesion protein, triggers cellular senescence [19], we sought to identify a novel senescence regulator. To this end, we analyzed previous data from tandem mass tag (TMT)-labeling proteomic analysis [20] and found 4643 differentially expressed proteins following βPIX depletion (Fig. 1a and Table S1).…”

Targeting accelerated pulmonary ageing to treat chronic obstructive pulmonary disease‐induced neuropathological comorbidities

“…Moreover, a recent study by Park et al identified the effectiveness of a sublethal dose of regorafenib in attenuating cellular senescence in human lung fibroblast cells (IMR‐90 cells). Treatment with regorafenib successfully mitigated the βPIX knockdown‐ and doxorubicin‐induced senescence and replicative senescence and reduced SA‐β‐Gal staining and the SASP profile (Park et al, 2023 ). In complementary studies, the potential of regorafenib was shown in a porcine pancreatic elastase (PPE)‐induced model of emphysema.…”

“…In complementary studies, the potential of regorafenib was shown in a porcine pancreatic elastase (PPE)‐induced model of emphysema. Treatment with regorafenib (5 mg·kg −1 ) attenuated the senescence profile with reduced SA‐β‐Gal staining and p16 INK4a expression and improved PPE‐induced emphysema in mice (Oh et al, 2023 ; Park et al, 2023 ). To the best of our knowledge, there is no experimental data on the effects of regorafenib on the circadian rhythm in a disease setting.…”