Apoptosis pathways as promising targets for skin cancer therapy.
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-alpha), 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-kappaB 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.
Eberle
J
J
Department of Dermatology, Charité, Skin Cancer Center Charité, University Hospital of Berlin, Berlin, Germany. juergen.eberle@charite.de
Fecker
L F
LF
Forschner
T
T
Ulrich
C
C
Röwert-Huber
J
J
Stockfleth
E
E
D017209:Apoptosis / Q000187:drug effects*; D002450:Cell Communication; D049109:Cell Proliferation / Q000187:drug effects*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D006801:Humans; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology
D052246:Cyclooxygenase 2 Inhibitors