Apoptosis pathways as promising targets for skin cancer therapy

• Published in: British journal of dermatology (1951) Vol. 156; no. s3; pp. 18 - 24
• Main Authors: Eberle, J., Fecker, L.F., Forschner, T., Ulrich, C., Röwert-Huber, J., Stockfleth, E.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2007
• Subjects: apoptosis; Apoptosis - drug effects; Bcl-2; Cell Communication; Cell Proliferation - drug effects; COX-2; Cyclooxygenase 2 Inhibitors - therapeutic use; Humans; skin cancer; Skin Neoplasms - drug therapy; Skin Neoplasms - immunology; TRAIL
• ISSN: 0007-0963; 1365-2133
• DOI: 10.1111/j.1365-2133.2007.07855.x

Summary Apoptosis pathways provide efficient safeguard mechanisms against cancer that are mediated via cell‐intrinsic responses and immune‐mediated extrinsic signals. Intrinsic pro‐apoptotic pathways are largely controlled by p53 and Bcl‐2 proteins, whereas the extrinsic induction of apoptosis is initiated by death ligands, such as tumour necrosis factor‐alpha (TNF‐α), CD95L/FasL and TNF‐related apoptosis‐inducing ligand (TRAIL), or by granzyme B. Initiation of these pathways results in the induction of a caspase cascade leading to cell death. The inactivation of pro‐apoptotic pathways is elementary for tumourigenesis and may be responsible for therapy resistance. Thus, apoptosis‐based strategies represent important tools for the development of effective tumour therapies. The aim of these therapies is to restore p53 activity, downregulate anti‐apoptotic Bcl‐2 proteins or NF‐κB activity, and to upregulate extrinsic, death receptor‐mediated pathways. The initial results of apoptosis‐based strategies are proving promising. Also, topical treatments for actinic keratosis (AK), such as cyclo‐oxygenase‐2 inhibitors (e.g. diclofenac 3% gel), have been shown to trigger pro‐apoptotic pathways. There is hope that pro‐apoptotic strategies will lead to pronounced therapeutic success against skin cancer. Importantly, the involvement of the different pro‐apoptotic pathways in specific tumour types needs to be unravelled and understood in order to evaluate drug effectiveness, as well as to modify and optimise therapeutic approaches.