Malignant gliomas and especially Glioblastoma multiforme (GBM) are the most malignant and prevalent intracranial tumours, classified as grade IV by the World Health Organization (WHO). GBMs are characterized by genetic alterations affecting genes that control cell growth, migration, apoptosis, and invasion. Despite very aggressive treatment including surgery and combined radio and chemotherapy the median survival for most patients with GBM is only 1 year. Therefore there is an urgent need for the development of novel therapeutic agents [1, 2].
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain, fever and inflammation caused by various physiological or pathological conditions. Clinical trials have demonstrated that long-term NSAID use significantly reduces the risk of colorectal cancer and other tumours such as breast, lung, prostate and gastric cancer [3–5].
NSAIDs are known to inhibit a variety of cellular processes including signal transduction, transcription, and DNA repair. NSAIDs can alter cell cycle distribution, inhibit cyclins, modulate Bcl-2 family proteins and induce apoptosis [6, 7]. NSAIDs also inhibit angiogenesis, an important factor necessary for tumour growth and survival, suggesting a rationale for their potential therapeutic application as anticancer agents .
The mechanism by which NSAIDs exert their anti-inflammatory activity is primarily by inhibiting the synthesis of prostaglandins through inhibition of both cyclooxygenase isoforms (COX-1 and COX-2), the rate-limiting enzyme of the cascade. COX-1 is constitutively expressed in many tissues and plays an important role in the control of homeostasis. Conversely, COX-2 is an inducible enzyme and is activated in response to extracellular stimuli such as growth factors and pro-inflammatory cytokines [9, 10].
Several studies have shown COX and PGs play a role in cell growth, survival, migration/invasion and angiogenesis of tumour cells. Accumulating evidence suggests that the increase in overexpression of COX-2 and PGE2 in human glioma is associated with poor prognosis and tumour progression [11, 12].
Ibuprofen (IBP) belongs to the group of NSAIDs, and is a potent COX-1 and COX-2 inhibitor. Besides its widespread use in the treatment of inflammatory diseases, it has been shown that IBP may be effective in the treatment and/or prevention of cancers including prostate and colorectal cancer [13–15].
However, the effect of IBP treatment in GBM has not been widely investigated. Recent studies from our laboratory have shown novel ruthenium-containing IBP complexes have significant effects on glioma cell proliferation and apoptosis [16, 17]. In this study, we aimed to assess the potential effects of IBP on tumour cell proliferation, migration and apoptosis in T98G human glioma cells. The effect of the addition of exogenous PGE1 and PGE2 to the cells was also studied. PGE1 was compared with PGE2 as it has been reported to interact not only with the EP receptors EP3 and EP4 but also with the IP receptor, while PGE2 can interact with all four EP receptors. The cellular response to PGE1 and PGE2 depends on both the expression of receptors and the synthetic capacity of the individual tissue .
The study aimed to test the importance of PGE1 and PGE2 metabolism to the proliferative and apoptotic indices of T98G glioma cells. Since prostanoids are also involved in cell migration the effect of IBP, PGE1 and PGE2 on the migratory capacity of the cells was investigated using two migration assays.