Abstract
Sulforaphane (SFN) is a naturally-occurring isothiocyanate best known for its role as an indirect antioxidant. Notwithstanding, in different cancer cell lines, SFN may promote the accumulation of reactive oxygen species (ROS) and cause cell death e.g. by apoptosis. Osteosarcoma often becomes chemoresistant, and new molecular targets to prevent drug resistance are needed. Here, we aimed to determine the effect of SFN on ROS levels and to identify key biomarkers leading to ROS unbalance and apoptosis in the p53-null MG-63 osteosarcoma cell line. MG-63 cells were exposed to SFN for up to 48 h. At 10 μM concentration or higher, SFN decreased cell viability, increased the%early apoptotic cells and increased caspase 3 activity. At these higher doses, SFN increased ROS levels, which correlated with apoptotic endpoints and cell viability decline. In exposed cells, gene expression analysis revealed only partial induction of phase-2 detoxification genes. More importantly, SFN inhibited ROS-scavenging enzymes and impaired glutathione recycling, as evidenced by inhibition of glutathione reductase (GR) activity and combined inhibition of glutathione peroxidase (GPx) gene expression and enzyme activity. In conclusion, SFN induced oxidative stress and apoptosis via a p53-independent mechanism. GPx expression and activity were found associated with ROS accumulation in MG-63 cells and are potential biomarkers for the efficacy of ROS-inducing agents e.g. as co-adjuvant drugs in osteosarcoma.
Highlights
Osteosarcoma is the most frequent primary solid malignancy of the bone and shows higher incidence in children, adolescents and young adults [1], [2]
In different cancer cell lines it has been reported that activation of apoptosis by SFN is highly dependent on reactive oxygen species (ROS) generation, as the apoptotic effect could be counteracted with ectopic catalase (Cat) expression [22], [23], [24], [25], [26]
In a study by Matsui and colleagues, SFN was shown to act as a sensitiser to TRAIL-induced apoptosis through DR5 receptor increased expression, in two p53 null osteosarcoma cell lines, including MG-63 [17]
Summary
Osteosarcoma is the most frequent primary solid malignancy of the bone and shows higher incidence in children, adolescents and young adults [1], [2]. Recent studies have shown that cells with low mitochondrial respiratory chain activity are mostly protected from SFN-induced DNA breakage, G2/M phase arrest, disruption of mitochondrial membrane potential and apoptosis [23], [26], [27]. These observations reinforced the notion that the mitochondrial respiratory chain is the main site for SFN-induced ROS production and subsequent ROS-induced cellular alterations. The development of drugs targeting ROS-sensitive cancer cells shows much potential to chemotherapy [28], [29]
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