Cancer Letters

Cancer Letters

Volume 332, Issue 2, 28 May 2013, Pages 313-324
Cancer Letters

Mini-review
Targeting apoptosis pathways by Celecoxib in cancer

https://doi.org/10.1016/j.canlet.2011.01.012Get rights and content

Abstract

Celecoxib is a paradigmatic selective inhibitor of cyclooxygenase-2 (COX-2). This anti-inflammatory drug has potent anti-tumor activity in a wide variety of human epithelial tumor types, such as colorectal, breast, non-small cell lung, and prostate cancers. Up to now, the drug found application in cancer prevention in patients with familial adenomatous polyposis. Moreover, the use of Celecoxib is currently tested in the prevention and treatment of pancreatic, breast, ovarian, non-small cell lung cancer and other advanced human epithelial cancers.

Induction of apoptosis contributes to the anti-neoplastic activity of Celecoxib. In most cellular systems Celecoxib induces apoptosis independently from its COX-2 inhibitory action via a mitochondrial apoptosis pathway which is however, not inhibited by overexpression of Bcl-2. In addition, Celecoxib exerts antagonistic effects on the anti-apoptotic proteins Mcl-1 and survivin. Consequently, the use of Celecoxib may be of specific value for the treatment of apoptosis-resistant tumors with overexpression of Bcl-2, Mcl-1, or survivin as single drug or in combination with radiotherapy, chemotherapy, or targeted pro-apoptotic drugs that are inhibited by survivin, Bcl-2 or Mcl-1. As COX-2 inhibition has been associated with cardiovascular toxicity, the value of drug derivatives without COX-2 inhibitory action should be validated for prevention and treatment of human epithelial tumors to reduce the risk for heart attack or stroke. However, its additional COX-2 inhibitory action may qualify Celecoxib for a cautious use in COX-2-dependent epithelial tumors, where the drug could additionally suppress COX-2-mediated growth and survival promoting signals from the tumor and the stromal cells.

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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