Bulky DNA damage inducing chemotherapeutic cancer drugs such as cisplatin (CIS) and doxorubicin (DOX) are commonly used in the treatment of a variety of cancers. However, they often cause multi-organ toxicity, and the mechanisms underlying are not clear. Using cellular model, the present study showed that persistent endogenous reactive oxygen species (ROS) were stimulated after a single dose short treatment with CIS and DOX. ROS level correlated with the formation of DNA double-strand breaks (DSBs). Knockdown BRCA1, a key player involved in homologous recombination (HR), enhanced ROS accumulation. Whereas knockdown DNA-PKcs and overexpress BRCA1 to inhibit nonhomologous end-joining (NHEJ) repair pathway and restore HR can partially suppress ROS levels. These data indicated that ROS production is associated with DSB formation and repair which is likely a downstream event of DNA repair. Further studies showed that knockdown DNA repair regulators PP2A but not ATM, could partially reduce ROS too. The induction of ROS affected the level of proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Collectively, the present study reveals that DNA repair associated metabolism change and oxidative stress may be a direct cause of the severe side effects associated with genotoxic chemotherapy cancer drugs.
Keywords: Chemotherapy; Cisplatin; DNA repair; Doxorubicin; Oxidative stress.
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