Speakers - CWC 2023

Abstract

Survival rates for pediatric cancers have improved enormously, although Childhood Cancer Survivors (CCS) show long-term clinical complications related to chemo/radiotherapy they have undergone, consistent with early aging. Recently, we have observed that CCS mononuclear cells (MNCs) display an altered aerobic metabolism, which concurs with the oxidative stress increment. Since oxidative insult correlates with aging, we assessed whether CCS MNCs could activate intracellular antioxidant (AO) defenses.  Biochemical, proteomic, and molecular biology analyses were conducted on mononuclear cells (MNCs) isolated from peripheral blood from CCS subjects. Analyses were performed on 96 CCS samples aged between 5-20 years and 74 healthy subjects aged between 5 and 106 years old. The expression and activity of antioxidant enzymes (catalase, glutathione reductase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase), the NRF2 and KEAP1 expression, and the content in NADPH, NADP, GSSG, GSH, malondialdehyde, and 4-hydroxy-nonenale were assessed.

CCS subjects MNCs show lower AO enzyme expression and activity than healthy age-matched and elderly subjects, resulting in low levels of NADPH and GSH, which may concur with the elevated peroxided lipid accumulation. AO enzyme failure activation appeared due to a low NRF2 and KEAP1 expression. Data suggest that premature aging in CCS may be due to an inability to activate AO defenses in response to the oxidative insult associated with altered aerobic metabolism. These biochemical and molecular alterations may contribute to the ageing phenotype of the CCS subjects.