The PARP inhibitor olaparib promotes senescence in murine macrophages.

Abstract

Cellular senescence is a multifaceted process involving cell cycle arrest, telomere shortening, and the accumulation of DNA damage associated with aging and cellular stress. It is marked by persistent cell cycle arrest and DNA damage accumulation, and plays an increasingly recognized role in age-related diseases and cancer therapy. Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, is approved for use in ovarian cancer treatment. We hypothesized that olaparib may influence senescence by inhibiting DNA damage repair, and investigated its effects on non-senescent and replicatively senescent murine macrophages (RAW 264.7 cells). Senescent cells exhibited elevated baseline levels of PARP1 expression, PARylation, and DNA damage relative to non-senescent control cells. Olaparib amplified these differences by upregulating senescence markers (SA-β-gal and p21), inhibiting proliferation, and exacerbating DNA damage. Many of its effects were more pronounced in senescent cells. At higher concentrations (10-30 µM), olaparib induced significant cytotoxicity through mixed apoptotic and necrotic mechanisms, with senescent cells exhibiting a predominantly necrotic response. Interestingly, both mitochondrial activity and cellular bioenergetics were elevated in senescent cells at baseline, and were more severely impaired by olaparib compared to non-senescent control cells. These findings underscore olaparib's enhanced cytotoxic and pro-senescent effects in senescent immune cells and suggest potential implications for its use in elderly cancer patients with an increased burden of senescent cells.