Abstract Reactive oxygen species (ROS) play a dual role in cancer biology, contributing to both tumor progression and therapeutic responses. Many chemotherapeutic agents exert their cytotoxic effects through ROS generation, although the extent and biological relevance of this process remain influenced by cellular context, including the functional status of tumor suppressor genes such as TP53. In this study, we investigated the induction of genomic damage and oxidative stress in two isogenic human colorectal cancer cell lines — HCT116TP53+/+ and HCT116TP53-/- — after exposure to four commonly used anticancer agents: oxaliplatin (OXA), irinotecan (IRI), paclitaxel (PAC), and 5-fluorouracil (5-FU). Drug concentrations were selected to ensure cell viability while inducing genotoxicity. Genome damage was assessed by micronucleus (MN) assay. ROS production was measured using the BODIPY581/591 C11 lipid peroxidation fluorescent probe. Our results showed that OXA and IRI induced both significant MN formation and robust ROS production in a dose-dependent manner, while PAC predominantly triggered genomic damage with limited ROS generation. Conversely, 5-FU exhibited marginal (or no) effect on both endpoints. Notably, with regard to the extent of ROS accumulation and MN induction, no significant differences were detected under the tested conditions between the two HCT116 cell lines. This suggests that under non-cytotoxic conditions, p53 is not a critical modulator of oxidative responses to these agents. Overall, our data reveal a drug-specific pattern of genome and oxidative damage in HCT116 colorectal cancer cells, emphasizing the importance of considering drug mechanism of action in evaluating redox responses. These insights may contribute to the development of targeted combinatorial therapies aimed at modulating oxidative stress, especially in TP53-mutated tumors.
Naldoni et al. (Sun,) studied this question.