Dox is a common anti cancer agent for solid tumors
Dox is a common anti-cancer agent for solid tumors and lymphomas, producing O2− via redox cycling and leading to cardio- and neuro-toxicity. A recent study reported results of rats treated with Dox chronically at a low dose (2 mg/kg/week) . In a step-through passive avoidance test, Dox led to a significantly low memory performance compared to control rats. The number of degenerative hippocampal neurons following Dox correlated with elevated apoptosis, decreased antioxidant glutathione (GSH) levels, diminished activity of catalase, and increased level of the lipid peroxidation product, malondialdehyde (MDA) in hippocampus of treated rats in the same study . The cognitive impairment and associated neuronal apoptosis are ameliorated by food supplemented with astaxanthin, a carotenoid with antioxidant, anti-apoptotic and anti-inflammatory functions . In another study, acute and high dose administration (25 mg/kg) of Dox increased oxidative damage indexed by protein-bound HNE and protein carbonyls (PC) in both plasma and Omadacycline ic50 of mice . NOR testing revealed a cognitive impairment of mice 72 h after Dox injection. Locomotor activity was decreased by Dox even earlier, 24 h after treatment . Altered neurochemical profiles in hippocampus and decreased activity of phospholipases in brain also correlated with cognitive impairment . All of these deleterious changes were either completely or partially prevented by co-administration of MESNA, an antioxidant drug that scavenges free radicals [99,100]. γ-Glutamyl cysteine ethyl ester (GCEE), a precursor of the antioxidant GSH, restored GSH level and GSH transferase activity in Dox-treated mice brain equivalent to the saline-treated control group, reduced levels of all three oxidative stress markers of protein oxidation and lipid peroxidation in mice brain induced by Dox . BCNU triggered ROS-dependent JNK and ERK signaling and apoptosis in neurons could be inhibited by N-acetyl cysteine (NAC) . In addition, decreased GSH level and glutathione reductase activity were caused by BCNU . NAC also protected neurons in vitro and rats in vivo from cisplatin induced oxidative stress, mitochondrial dysfunction, and/or cognitive impairment . Dox generated ROS with subsequently elevated peroxisomes in neurons and mice brains . Maintaining level of peroxisomes is important to regulate cellular redox homeostasis . β-Cyclodextrin decreased this Dox-induced ROS production by up-regulating peroxisome-related autophagy (pexophagy) . Taken together, all evidences here strongly support the notion that redox homeostasis is disrupted after many chemotherapeutic agents and that oxidative stress associated with organelle dysfunction plays an important role in CICI. That is why antioxidant supplement and co-administration of antioxidant drug are very efficient methods to moderate these damages in brain . Antioxidant effectiveness in preventing oxidative damage to brain and other cellular abnormalities following chemotherapy is consistent with the notion of the role of oxidative stress associated with CICI, but this approach normally cannot be pursued in cancer therapy due, in part, to activation of glutathione-S-transferase-mediated coupling of chemotherapeutic agents to reduced GSH and subsequent removal of this complex from the cancer cell by MRP1, thereby decreasing therapeutic efficacy . In contrast, antioxidants that remain and act outside the cancer cells do not interfere with chemotherapy, but do scavenge lipid peroxidation products in plasma, preventing inflammatory cytokines from entering the brain parenchyma [2,99,108]. Moreover, highly redox-active agents that are mitochondrial manganese superoxide dismutase (MnSOD) mimetics, brain-permeable, and selective for mitochondria show great promise of cancer cell death by exacerbating the high oxidative redox state of cancer cells to cause them to undergo apoptosis . Oxidative stress mediated CICI is often accompanied by immune response and pro-inflammatory cytokine increase, including IL-1β, IL-6 and TNF-α [110,111]. IL-1β and TNF-α are important to synapse function and neural plasticity . Elevated IL-6 is associated with worsening executive function and poor self-perceived cognitive disturbance in cancer patients [113,114]. CNS excitability and CICI are associated with peripheral pro-inflammatory cytokines, modulating functions of neurons and glial cells and neurotransmitter metabolism in brain . DNA, synapses and neurites in neurons also were damaged after Dox treatment . Chemotherapeutic agents elevate peripheral cytokine levels, which could cross the BBB, lead to immune response, and increase oxidative stress and mitochondria damage in CNS .