Abstract
BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) have been associated with anti-tumorigenic effects in different tumor entities. For glioma, research has generally focused on diclofenac; however data on other NSAIDs, such as ibuprofen, is limited. Therefore, we performed a comprehensive investigation of the cellular, molecular, and metabolic effects of ibuprofen and diclofenac on human glioblastoma cells.MethodsGlioma cell lines were treated with ibuprofen or diclofenac to investigate functional effects on proliferation and cell motility. Cell cycle, extracellular lactate levels, lactate dehydrogenase-A (LDH-A) expression and activity, as well as inhibition of the Signal Transducer and Activator of Transcription 3 (STAT-3) signaling pathway, were determined. Specific effects of diclofenac and ibuprofen on STAT-3 were investigated by comparing their effects with those of the specific STAT-3 inhibitor STATTIC.ResultsIbuprofen treatment led to a stronger inhibition of cell growth and migration than treatment with diclofenac. Proliferation was affected by cell cycle arrest at different checkpoints by both agents. In addition, diclofenac, but not ibuprofen, decreased lactate levels in all concentrations used. Both decreased STAT-3 phosphorylation; however, diclofenac led to decreased c-myc expression and subsequent reduction in LDH-A activity, whereas treatment with ibuprofen in higher doses induced c-myc expression and less LDH-A alteration.ConclusionsThis study indicates that both ibuprofen and diclofenac strongly inhibit glioma cells, but the subsequent metabolic responses of both agents are distinct. We postulate that ibuprofen may inhibit tumor cells also by COX- and lactate-independent mechanisms after long-term treatment in physiological dosages, whereas diclofenac mainly acts by inhibition of STAT-3 signaling and downstream modulation of glycolysis.
Highlights
Glioblastomas (GBM) are characterized as highly malignant brain tumors hallmarked by infiltrating tumor cells, enhanced mitotic activity, and angiogenesis
This study indicates that both ibuprofen and diclofenac strongly inhibit glioma cells, but the subsequent metabolic responses of both agents are distinct
We postulate that ibuprofen may inhibit tumor cells by COX- and lactate-independent mechanisms after long-term treatment in physiological dosages, whereas diclofenac mainly acts by inhibition of Signal Transducer and Activator of Transcription 3 (STAT-3) signaling and downstream modulation of glycolysis
Summary
Glioblastomas (GBM) are characterized as highly malignant brain tumors hallmarked by infiltrating tumor cells, enhanced mitotic activity, and angiogenesis. Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and diclofenac may be candidates for such an approach. Traditional NSAIDs are non-selective COX-1 and -2 inhibitors. Non-selective inhibition of COX2 leads to decreased prostaglandin synthesis [10] and prostaglandin E2 was associated with tumor cell promotion [11,12]. Inhibition of tumor cell proliferation [6] and induction of apoptosis by NSAID treatment [13,14] has been described to occur via COX-independent mechanisms. Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with anti-tumorigenic effects in different tumor entities. Research has generally focused on diclofenac; data on other NSAIDs, such as ibuprofen, is limited. We performed a comprehensive investigation of the cellular, molecular, and metabolic effects of ibuprofen and diclofenac on human glioblastoma cells
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