Therapeutic potential of cyclooxygenase-3 inhibitors in the management of glioblastoma

Abstract

In this study we investigated the expression of COX-1, COX-2 and COX-3 mRNA in C6 glioblastoma and normal brain tissues and the effects of acetaminophen, indomethacin or metamizole treatments on the development of C6 glioblastoma in relation with COX inhibition. Glioblastoma cells were inoculated intracerebrally into frontal lobe of adult male Wistar albino rats. 10 days after inoculation, rats were treated with 150 mg/kg acetaminophen, 10 mg/kg indomethacin or 150 mg/kg metamizole. The tumor size was measured histologically and total RNA was isolated from tumor or normal brain tissue and mRNA levels of COX isoforms were determined by qRT-PCR. Our results showed the presence of COX-1, COX-2 and COX-3 expressions in both C6 glioblastoma and normal brain tissues. In tumor tissues COX-3 expression was significantly higher than normal brain tissue (p < 0.05) while there was no significant difference in COX-1 and COX-2 expressions. Acetaminophen and indomethacin decreased the tumor size by 71 and 43 % by inhibiting COX-3 mRNA expression around 87 and 91 % respectively. For the first time our study proposes a possible relationship between COX-3 mRNA expression and C6 glioblastoma development. We also suggested that the inhibition of COX-3 enzyme may be responsible for decrease in tumor size in part, the mechanism by which acetaminophen and indomethacin decreased rat C6 glioblastoma growth. However, the molecular events responsible for COX-3 effects on tumor development are still unresolved as these drugs exert their anti-cancer effect via both COX-3 dependent and independent mechanisms.

Cyclooxygenase-2 in glioblastoma multiforme

“…The mammalian COX has two isozymes [COX-1 and COX-2 (or PTGS1 and PTGS2 )], both of which were discovered during the early 1990s. COX-3 was reported as a third form, but proved to be a truncated COX-1 lacking enzymatic activity in humans [16], although it might show some pathological activity in rodents, such as C6 glioblastoma development in rat models [17]. NSAIDs are nonselective COX inhibitors, such as aspirin, ibuprofen, and naproxen, whereas most commonly used selective COX-2 inhibitors (COXIBs) include celecoxib, rofecoxib, valdecoxib, and NS398 (Figure 2).…”

Eicosanoids in carcinogenesis

“…All Cox enzymes (Cox-1, Cox-2 and Cox-3) have been found to be expressed in glioblastoma and normal brain tissues but Cox-3 expression was significant higher in cancerous versus normal tissues [131]. Inhibiting Cox-3 with acetaminophen decreased glioblastoma tumor size by 71% in a rat model and by 43% using indomethacin.…”

Paracetamol – An old drug with new mechanisms of action

“…20 Another feature of COX-3 is the localization of expression. 36 Initially, Chandrasekharan et al (2002) assumed that the enzyme was expressed in the cerebral cortex and heart. However, the expression of COX-3 mRNA rather appears to take place in the pituitary gland and the hypothalamus, which seems to be in good agreement with the finding of sites associated with fever.…”

“…However, the expression of COX-3 mRNA rather appears to take place in the pituitary gland and the hypothalamus, which seems to be in good agreement with the finding of sites associated with fever. 16,[36][37][38] Similar to NSAIDs, paracetamol can enter the central nervous system across the bloodbrain barrier, which allows it to reach the effective concentration in the brain to inhibit COX-3, which could also explain why paracetamol is often more effective against headache and fever than some other NSAIDs. 39 Interestingly, some literature reveals that COX-3 may be capable of inducing a remission in chronic inflammatory conditions and may be involved in the growth of cervical, ovarian, leukemia, and colon cancer.…”