Cyclooxygenase 2 (COX-2) is frequently found up-regulated during pathological conditions and in cancer, where it is thought to support carcinogenesis and tumor angiogenesis. The development of newer-generation non-steroidal anti-inflammatory drugs (NSAIDs) able to more selectively inhibit cyclooxygenase 2 (COX-2) raised expectations that these agents might be beneficial for cancer prevention and therapy. However, while chemopreventive effects of some selective COX-2 inhibitors have been established, it has remained unpersuasive whether these new NSAIDs, such as celecoxib, rofecoxib or etoricoxib, are able to exert cancer therapeutic effects, i.e., whether they would be beneficial for the treatment of advanced cancers that are already grown and established. This issue was further complicated by findings that celecoxib was able to exert pronounced pro-apoptotic effects in vitro and in vivo in the absence of any apparent involvement of COX-2. In fact, newly synthesized close structural analogs of the celecoxib molecule revealed that it was possible to separate COX-2 inhibitory function from the ability to trigger apoptosis; for example, the analog 2,5-dimethyl-celecoxib (DMC) has lost COX-2 inhibitory function, yet exerts increased cytotoxic potency. This review will summarize pertinent results from the exploratory therapeutic use of NSAIDs, in particular celecoxib, in preclinical and clinical studies of malignant glioma. Several COX-2 independent targets will be presented, and it will be discussed how DMC has helped to delineate their relevance for the surmised COX-2 independent tumoricidal effects of celecoxib.
Keywords: Celecoxib, cyclooxygenase, dimethyl-celecoxib, glioblastoma, glioma, NSAIDs, rofecoxib, valdecoxib, COX-2 Inhibitors, Malignant Glioma Therapy, non-steroidal anti-inflammatory drugs, etoricoxib, apoptosis, 2,5-dimethyl-celecoxib, prostaglandin H synthase, arachidonic acid, prostaglandin H2, prostacyclin, thromboxane A2, aspirin, ibuprofen, naproxen, indomethacin, sulindac, osteoarthritis, rheumatoid arthritis, adenomatous colorectal polyps, nimesulide, diclofenac, meloxicam, temozolomide, stereotactic radiosurgery, fluorescence-guided surgery, central nervous system, prostaglandin synthases, brain metastases, radiosensitization, tumor vasculature density, anti-angiogenic drugs, glioblastoma multiforme, topoisomerase I inhibitor irinotecan, cancer therapy, flurbiprofen, unmethylated-celecoxib, cyclin-dependent kinases, beta-catenin signaling, 3-Phosphoinositide-Dependent Protein Kinase-1, Akt phosphorylation, Carbonic Anhydrases, acetazolamide, Endoplasmic Reticulum Stress, yin-yang mechanism, nelfinavir, sarcoplasmic/ endoplasmic reticulum calcium ATPase
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