Mini-reviewTargeting apoptosis pathways by Celecoxib in cancer
Section snippets
Celecoxib is a selective COX-2 inhibitor with anti-neoplastic activity
The non-steroidal anti-inflammatory drug (NSAID) Celecoxib (Celebrex®, Onsenal®, Pfizer, New York, USA) belongs to the drug family of COXIBs and constitutes a potent and specific inhibitor of the human cyclooxygenase-2 (COX-2). COX-2 is constitutively overexpressed in many human premalignant, malignant and metastatic epithelial tumors, e.g. colorectal, lung, breast, prostate, and head/neck cancer [1], [2], [3], [4]. Upregulated expression of COX-2 is an early event during carcinogenesis, and is
Role of COX-2
The pro-apoptotic effects of Celecoxib had first been attributed to its inhibitory action on COX-2. It had been suggested that by inhibiting COX-2 Celecoxib would interfere with prostaglandin (PG)-mediated upregulation of anti-apoptotic proteins [52], [53] (Fig. 2). However, later it became increasingly clear that the pro-apoptotic effects of Celecoxib do not critically rely on COX-2 inhibition. This assumption was supported by the following findings: (i) numerous reports demonstrated that
Relevance for the clinical use in anti-cancer treatment
As outlined above, Celecoxib and its derivative DMC that lacks COX-2 inhibitory action are unique among the COXIB drug family as they potently induce apoptosis in tumor cells and endothelial cells. Even more important, the molecular requirements for Celecoxib-induced apoptosis differ from those of most DNA-damaging anti-neoplastic drugs and ionizing radiation. This suggests a putative benefit for the therapeutic use of Celecoxib alone or in combination with chemotherapy, radiotherapy, or
Conclusions
The selective COX-2 inhibitor Celecoxib is a potent anti-cancer agent. Among the COXIB-family members, Celecoxib has the unique capacity to induce apoptotic cell death in tumor and endothelial cells, making Celecoxib a lead compound for anti-cancer drug development. Although inhibition of COX-2 can contribute to its cytotoxic effects, Celecoxib is a prototype of drugs that induce cell death independently from COX-2 mainly by activation of an intrinsic, mitochondria-dependent apoptosis pathway.
Conflict of interest
Pharmacia/Pfizer kindly provided Celecoxib for the studies performed in the authors laboratory.
Acknowledgements
The work in the authors laboratory was supported by grants from the German Research Foundation (DFG; IRTG1302/1), the Wilhelm-Sander-Stiftung 2005.143.1, and the Deutsche Krebshilfe/ Mildred-Scheel-Stiftung (107388).
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