Acetyl tributyl citrate attenuates 5-fluorouracil-induced inflammation, oxidative stress, and apoptosis in human keratinocytes

Abstract

5-Fluorouracil (5-FU) is a commonly used chemotherapy drug that effectively destroys cancer cells. Despite its widespread use and efficacy, it also presents considerable challenges, particularly with adverse effects on rapidly dividing normal cells, such as keratinocytes. These detrimental effects are attributed to inflammatory, oxidative, and apoptotic potentials, leading to severe skin disorders. Due to the lack of specific remedies for 5-FU-induced dermatological side effects, conventional treatments are applied instead, which provide limited relief and have drawbacks. This study investigated the impact of acetyl tributyl citrate (ATBC) in 5-FU-treated human keratinocytes. The findings indicated that ATBC substantially reduced inflammation caused by 5-FU, as demonstrated by nuclear translocation of nuclear factor kappa B and expression of its downstream genes, including tumor necrosis factor, interleukin 1 beta (IL1B), and IL6. ATBC also markedly decreased oxidative stress, indicated by reactive oxygen species levels and the antioxidant gene expression such as superoxide dismutase 1 (SOD1), SOD2, and heme oxygenase 1 in 5-FU-treated cells. Furthermore, ATBC attenuated 5-FU-induced apoptosis, as determined by lactate dehydrogenase release and Annexin V/propidium iodide flow cytometry, with the potential involvement of interferon-related genes. Following this, protein kinase C delta was predicted as a possible molecular target of ATBC. These findings propose ATBC as a therapeutic agent for managing the cutaneous side effects associated with 5-FU treatment.