Superoxide induces protein oxidation in plasma and TNF-α elevation in macrophage culture: Insights into mechanisms of neurotoxicity following doxorubicin chemotherapy

Abstract

Chemotherapy-induced cognitive impairment (CICI) is a quality of life-altering consequence of chemotherapy experienced by a large percentage of cancer survivors. Approximately half of FDA-approved anti-cancer drugs are known to produce ROS. Doxorubicin (Dox), a prototypical ROS-generating chemotherapeutic agent, generates superoxide (O2−•) via redox cycling. Our group previously demonstrated that Dox, which does not cross the BBB, induced oxidative damage to plasma proteins leading to TNF-α elevation in the periphery and, subsequently, in brain following cancer chemotherapy. We hypothesize that such processes play a central role in CICI. The current study tested the notion that O2−• is involved and likely responsible for Dox-induced plasma protein oxidation and TNF-α release. Addition of O2−• as the potassium salt (KO2) to plasma resulted in significantly increased oxidative damage to proteins, indexed by protein carbonyl (PC) and protein-bound HNE levels. We then adapted this protocol for use in cell culture. Incubation of J774A.1 macrophage culture using this KO2-18crown6 protocol with 1 and 10 μM KO2 resulted in dramatically increased levels of TNF-α produced. These findings, together with our prior results, provide strong evidence that O2−• and its resulting reactive species are critically involved in Dox-induced plasma protein oxidation and TNF-α release.

C60 fullerene and its nanocomplexes with anticancer drugs modulate circulating phagocyte functions and dramatically increase ROS generation in transformed monocytes

“…Our results are consistent with numerous literature data. Approximately half of FDA-approved anticancer drugs (including Dox and Cis) are known to produce ROS that are critically involved in toxic side effects of these drugs (Keeney et al 2015 ). Reactivity reserve in cells treated with anticancer drugs in response to PMA was absent.…”

Acute treatment with doxorubicin affects glutamate neurotransmission in the mouse frontal cortex and hippocampus

“…Despite DOX's, or its major metabolite's, inability to traverse the blood brain barrier, DOX treatment has been reported to increase tumor necrosis factor-α (TNF) in serum from 1 h to 24 h post-injection. TNF could then infiltrate the brain, causing CNS effects by TNF-initiated production of reactive oxygen and nitrogen species (Gaman et al, 2016; Gutierrez et al, 1993; Joshi et al, 2007; Joshi et al, 2010; Keeney et al, 2015; Tangpong et al, 2006; Tangpong et al, 2007). Tangpong et al provides support for this mechanism by reporting increased levels of TNF in brain homogenates at 3 h post-injection, heavily localized to neurons in the cortex and hippocampus (Tangpong et al, 2006).…”

DNA damage in the oligodendrocyte lineage and its role in brain aging

“…The amyloid-independent nature of this oxidative stress hypothesis is well exemplified by the adverse effect of chemotherapy on cognition (Ahles and Saykin, 2007; Ricard et al, 2009). Conventional chemotherapy drugs, such as adriamycin (doxorubicin), do not cross the blood brain barrier, but can nonetheless cause peripheral inflammation and transfer the subsequent oxidative stress in the brain (Joshi et al, 2010; Keeney et al, 2015). …”