Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse

Abstract

Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a pro-inflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells non-specifically, often with adverse reactions. In accord with prior work, we show that several chemotherapeutic drugs induce senescence of primary murine and human cells. Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic inflammation. Eliminating TIS cells reduced several short- and long-term effects of the drugs, including bone marrow suppression, cardiac dysfunction, cancer recurrence and physical activity and strength. Consistent with our findings in mice, the risk of chemotherapy-induced fatigue was significantly greater in humans with increased expression of a senescence marker in T-cells prior to chemotherapy. These findings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anti-cancer treatments.

Expression of p16INK4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

“…The quantity of this subset increases during aging (thus the correlation of p16 INK4a to age) and p16 INK4a also serves as a biomarker that identifies chondrocytes with greater potential for secreting factors that drive tissue dysfunction (thus the correlation of p16 INK4a to SASP markers). The utility of p16 INK4a as a biomarker of molecular age in other cell types has been demonstrated by assessing the impact of lifestyle modifications such as smoking or exercise (Liu et al., 2009), predicting the risk for particular negative outcomes after chemotherapy (Demaria et al., 2017), and screening the quality of potential donor organs (Koppelstaetter et al., 2008). For chondrocytes, screening patients for low p16 INK4a expression may improve the outcomes of autologous chondrocyte implantation procedures, as the success of this procedure requires avoidance of senescence to ensure sufficient expansion and subsequent re‐differentiation of the chondrocytes (Ashraf et al., 2016).…”

Elimination of p19ARF‐expressing cells protects against pulmonary emphysema in mice

“…We used the anti‐apoptotic Bcl‐2 family inhibitor, ABT‐263, in the PPE‐induced emphysema model. ABT‐263, or its related molecule ABT‐737, has been shown to alleviate senescence‐associated pathologies (Chang et al, 2016; Childs et al, 2016; Demaria et al, 2017; Yosef et al, 2016; Zhu et al, 2016, 2015 ), but it may not be effective in all cell types (Schafer et al, 2017). In the PPE‐induced emphysema model, an 8‐week treatment with ABT‐263 resulted in a partial decrease in p19 ARF ‐expressing cell numbers, with a concomitant reduction in INK4a expression in lung tissues.…”

Oxidation resistance 1 is a novel senolytic target

“…This hypothesis is supported by recent studies demonstrating that the genetic clearance of SCs prolongs the lifespan of mice and delays the onset of several age‐related diseases and disorders in both progeroid and naturally aged mice (Baker et al., 2011, 2016). Therefore, the pharmacological clearance of SCs with a small molecule, a senolytic agent that can selectively kill SCs, is potentially a novel anti‐aging strategy and a new treatment for chemotherapy‐ and radiotherapy‐induced side effects (Baar et al., 2017; Chang et al., 2016; Childs et al., 2016; Demaria et al., 2017; Jeon et al., 2017; Ogrodnik et al., 2017; Pan et al., 2017; Schafer et al., 2017; Yosef et al., 2016; Zhu et al., 2015). …”