Targeting apoptosis pathways by Celecoxib in cancer

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.