The chemotherapeutic drug doxorubicin does not exacerbate p16 Ink4a -positive senescent cell accumulation and cardiometabolic disease development in young adult female LDLR-deficient mice.
Andrea C PostmusJanine K KruitRoos E EilersRick HavingaMirjam H KosterYoshikazu JohmuraMakoto NakanishiBart van de SluisJohan W JonkerPublished in: Toxicology and applied pharmacology (2023)
Cancer survivors who received chemotherapy, such as the anthracycline doxorubicin (DOX), have an increased risk of developing complications later in life, including the development of chronic metabolic diseases. Although the etiology of this increased risk for late metabolic complications in cancer survivors is poorly understood, a causal role of therapy-induced senescent cells has been suggested. To study the role of cellular senescence in chemotherapy-induced metabolic complications, young adult female low-density lipoprotein receptor-deficient (Ldlr -/- )-p16-3MR mice, in which p16 Ink4a -positive (p16 Ink4a+ ) senescent cells can be genetically eliminated, were treated with four weekly injections of DOX (2.5 mg/kg) followed by a high-fat high-cholesterol diet for 12 weeks. While DOX treatment induced known short-term effects, such as reduction in body weight, gonadal fat mass, and adipose tissue inflammation, it was not associated with significant long-term effects on glucose homeostasis, hepatic steatosis, or atherosclerosis. We further found no evidence of DOX-induced accumulation of p16 Ink4a+ -senescent cells at 1 or 12 weeks after DOX treatment. Neither did we observe an effect of elimination of p16 Ink4a+ -senescent cells on the development of diet-induced cardiometabolic complications in DOX-treated mice. Other markers for senescence were generally also not affected except for an increase in p21 and Cxcl10 in gonadal white adipose tissue long-term after DOX treatment. Together, our study does not support a significant role for p16 Ink4a+ -senescent cells in the development of diet-induced cardiometabolic disease in young adult DOX-treated female Ldlr -/- mice. These findings illustrate the need of further studies to understand the link between cancer therapy and cardiometabolic disease development in cancer survivors.
Keyphrases
- young adults
- induced apoptosis
- adipose tissue
- cell cycle arrest
- cancer therapy
- low density lipoprotein
- drug delivery
- body weight
- chemotherapy induced
- drug induced
- computed tomography
- cardiovascular disease
- risk factors
- diabetic rats
- endoplasmic reticulum stress
- insulin resistance
- physical activity
- stem cells
- type diabetes
- single cell
- dna damage
- cell proliferation
- pi k akt
- squamous cell carcinoma
- emergency department
- replacement therapy
- weight loss
- bone marrow
- combination therapy
- endothelial cells
- high fat diet
- radiation therapy
- glycemic control
- blood glucose