Presently largely irreversible lung disease like idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease were one of the first conditions targeted for the development of senolytic therapies to clear senescent cells. A range of evidence supports a prominent role for an increased burden of senescent cells in airway and lung tissues in these conditions. Here, researchers discuss a more recent approach to senolytic therapy, employing a proteolysis-targeting chimera approach to make the cell break down one of the proteins involved in senescent cell survival. Senescent cells, unlike normal cells, are primed to undergo the programmed cell death of apoptosis. They are only held back from that fate by the activity of a few proteins, including BCLXL, which is the target here. When levels of BCLXL are dramatically reduced, senescent cells undergo apoptosis while normal cells are largely unaffected.
Ageing and cellular senescence significantly contribute to the progression of age-related diseases, particularly chronic obstructive pulmonary disease (COPD). Cellular senescence refers to the cessation of cell division in response to stress and damage. While senescent cells remain metabolically active, they secrete pro-inflammatory factors that drive disease progression. Senolytic therapies aim to selectively target and eliminate these senescent cells by inducing their apoptosis. This study examines the senolytic potential of BCLXL-PROTAC, a novel proteolysis-targeting chimera designed to degrade BCLXL, in small airway epithelial cells and fibroblasts from patients with COPD.
Treatment of COPD small airway epithelial cells and fibroblasts with BCLXL-PROTAC led to their apoptosis through the activation of caspase 3, along with a reduction in senescence markers such as p21CIP1, p16INK4a, and senescence-associated β-galactosidase. The effects of BCLXL-PROTAC were selective for senescent cells and did not affect non-COPD cells. The clearance of COPD small airway epithelial cells and fibroblasts by BCLXL-PROTAC was associated with an increase in the proliferation marker Ki67 and enhanced cell proliferation. Additionally, in precision-cut lung slices obtained from COPD patients, BCLXL-PROTAC significantly reduced p21CIP1 expression in the airway epithelium, validating its effectiveness in a more complex tissue environment.
These findings demonstrate that BCLXL-PROTAC is a potent and selective senolytic agent that may promote lung cell rejuvenation, supporting its potential as a novel therapeutic strategy for age-related diseases, including COPD.
Link: https://doi.org/10.1111/acel.70487
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