Are there attacking points in the eicosanoid cascade for chemotherapeutic options in benign meningiomas?

Abstract

ENINGIOMAS are usually benign tumors that arise from the leptomeningeal cells of the arachnoid membrane surrounding the brain and spinal cord. However, recurrence after seemingly complete surgical removal occurs in eight to 15% of cases, and tumor control rates achieved with radiotherapy are only 80%. 20,35,36,53 Moreover, a surgical cure is not always achievable in meningiomas involving the skull base or vital neurovascular structures. Results achieved with chemotherapeutic treatments in the past were not convincing, and even drugs such as temozolomide-which have shown high efficacy against malignant brain tumors-have failed to inhibit the growth of refractory meningiomas in Phase II studies. 7,26,39,45 The development of novel treatment strategies based on molecular information has not yet been successfully translated into common clinical practice.Arachidonic acid is a v6 polyunsaturated fatty acid that is converted into biologically active lipid compounds called eicosanoids. Eicosanoids constitute a large family of biologically active lipid mediators produced by two enzyme classes: the cyclooxygenases (COX-1 and COX-2) and the lipoxygenases (5-LO, 12-LO, and 15-LO). Both classes catalyze the same enzymatic reaction that occurs in the synthesis of PG 2 and PGH 2 , which are successively metabolized to PGE 2 , PGD 2 , PGF 2 , thromboxane A 2 , and prostacyclin PGI 2 (Fig. 1 Object. The current treatment for recurrent or malignant meningiomas with adjuvant therapies has not been satisfactory, and there is an intense interest in evaluating new molecular markers to act as therapeutic targets. Enzymes of the arachidonic acid (AA) cascade such as cyclooxygenase (COX)-2 or 5-lipoxygenase (5-LO) are upregulated in a number of epithelial tumors, but to date there are hardly any data about the expression of these markers in meningiomas. To find possible targets for chemotherapeutic intervention, the authors evaluated the expression of AA derivatives at different molecular levels in meningiomas.Methods. One hundred and twenty-four meningioma surgical specimens and normal human cortical tissue samples were immunohistochemically and cytochemically stained for COX-2, COX-1, 5-LO, and prostaglandin E receptor 4 (PTGER4). In addition, Western blot and polymerase chain reaction (PCR) analyses were performed to detect the presence of eicosanoids in vivo and in vitro.Results. Sixty (63%) of 95 benign meningiomas, 21 (88%) of 24 atypical meningiomas, all five malignant meningiomas, and all normal human cortex samples displayed high COX-2 immunoreactivity. All cultured specimens and IOMM-Lee cells stained positive for COX-2, COX-1, 5-LO, and PTGER4. The PCR analysis demonstrated no changes in eicosanoid expression among meningiomas of different World Health Organization grades and in normal human cortical and dura mater tissue.Conclusions. Eicosanoid derivatives COX-1, COX-2, 5-LO, and PTGER4 enzymes show a high universal expression in meningiomas but are not upregulated in normal human cortex and dura tissue. This finding of the ...

The molecular genetics and tumor pathogenesis of meningiomas and the future directions of meningioma treatments

“…95 Celecoxib decreased tumor microvascularity, increased cell apoptosis, and decreased Cox-2 and VEGF expression in vivo in a mouse xenograph model. 96 In addition to Cox-2, Pfister et al 92 identified a number of other potential therapeutic targets involved in eicosanoid formation that are highly expressed in meningiomas, including the enzymes Cox-1, 5-LO, and PTGER4. Future clinical trials are necessary to determine the potential efficacy of Cox-2 inhibitors and other nonsteroidal antiinflammatory drugs in treating meningiomas.…”

Immunohistochemical analysis of cyclooxygenase‐2 and brain fatty acid binding protein expression in grades I‐II meningiomas: Correlation with tumor grade and clinical outcome after radiotherapy

“…Pfister et al . proposed that over‐production of arachidonic acid derivatives is fundamental in meningioma pathogenesis . Arachidonic acid metabolism via COX and the lipoxygenase pathway can lead to acute inflammatory response and the production of a number of metabolites that have a critical role in tumor initiation, growth and dissemination.…”

Evidence of ubiquitous in vivo and in vitro expression of pro-apoptotic Smac/DIABLO protein in meningioma cell lines

“…Smac/DIABLO negatively regulates the caspase inhibitory properties of XIAP (X-linked IAP) by ONCOLOGY REPORTS 21: 1181-1188, 2009 Evidence of ubiquitous in vivo and in vitro expression of proapoptotic Smac/DIABLO protein in meningioma cell lines binding into the same pockets in XIAP which are used to bind caspases; when XIAP binds Smac/DIABLO, the caspases are displaced and primed to affect the execution phase of apoptosis (16). It is of utmost importance to identify possible key players in this orchestra when aiming for clinical application of new chemotherapeutic agents (17). With this study we provide crucial information on several apoptotic proteins in meningiomas of different WHO grades, as these pro-and antiapoptotic enzymatic complexes in this tumor entity have not been previously studied in detail.…”