Abstract
ABSTRACT Objectives In cancer survivors, chemotherapy-associated adverse neurological effects are described as side effects in non-targeted tissue. We investigated the role of redox-imbalance in neuronal damage by a relative low dose of Docetaxel (DTX). Methods The neuroblastoma cells (SH-SY5Y cells) were exposed to DTX at a dose of 1.25 nM for 6 h. Antioxidant defenses (i.e. ascorbic acid, glutathione, and catalase) and lipid oxidation products (i.e. F2-isoprostanes) were evaluated. To investigate cell ultrastructure and tubulin localisation, transmission electron microscopy (TEM) and immunofluorescence techniques were applied. Results In the SH-SY5Y cells, DTX induced a significant reduction of total glutathione (P < 0.001) and ascorbic acid (P < 0.05), and an increase in both total F2-Isoprostanes (P < 0.05) and catalase activity (P < 0.05), as compared to untreated cells. Additionally, TEM showed a significant increase in cells with apoptotic characteristics. Immunolocalisation of tubulin showed a compromised cytoskeletal organisation. Discussion The investigated sublethal dose of DTX, to which non-targeted cells may be exposed throughout the duration of chemotherapy treatment, induces a redox imbalance resulting in a specific modulation of the antioxidant response. This study provides new insights into DTX-induced cellular mechanisms useful for evaluating whether the concomitant use of antioxidants associated with chemotherapy mitigates chemotherapy side effects in cancer survivors.
Highlights
An oxidant/antioxidant imbalance is implicated in tumour progression [1] and is relevant to the side effects of chemotherapy drugs [2]
Neuroblastoma SH-SY5Y cell toxicity induced by DTX
The SH-SY5Y cell line was treated with DTX at different doses ranging from the lower non-lethal doses (0.1 nM) to the lethal dose (10 μM) for different times of incubation (6, 12, 24, 48, and 72 h), data not shown
Summary
An oxidant/antioxidant imbalance is implicated in tumour progression [1] and is relevant to the side effects of chemotherapy drugs [2]. As long-term side effects of chemotherapy, an array of cognitive impairments and alterations in brain structure and function, such as changes in the hippocampus, neurogenesis [4], white matter [5,6], and cerebral blood supply [7], have been described. Such chemotherapy-induced cognitive impairment (CICI) [8], called chemobrain or chemofog [9,10], continues for up to 10 years after chemotherapy treatment [11]. Cytokine modulation has been reported to play a key role in the pathophysiology of chemobrain [12], CICI has been related both to increased production of free radicals [13]
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