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Enhanced death ligand-induced apoptosis in cutaneous SCC cells by treatment with diclofenac/hyaluronic acid correlates with downregulation of c-FLIP

Actinic keratosis (AK) occurs on sun-exposed skin and may progress to invasive squamous cell carcinoma (SCC). As for its topical treatment, diclofenac/hyaluronic acid (HA) has been recently approved. The NSAID diclofenac is an inhibitor of COX-2; however, its mode of action in cutaneous epithelial c...

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Main Authors: Fecker, Lothar Friedrich (Author) , Stockfleth, Eggert (Author) , Braun, Frank K. (Author) , Rodust, Paul M. (Author) , Schwarz, Constanze (Author) , Köhler, Anja (Author) , Leverkus, Martin (Author) , Eberle, Jürgen (Author)
Format: Article (Journal)
Language:English
Published: 18 March 2010
In: The journal of investigative dermatology
Year: 2010, Volume: 130, Issue: 8, Pages: 2098-2109
ISSN:1523-1747
DOI:10.1038/jid.2010.40
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/jid.2010.40
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0022202X1534923X
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Author Notes:Lothar F. Fecker, Eggert Stockfleth, Frank K. Braun, Paul M. Rodust, Constanze Schwarz, Anja Köhler, Martin Leverkus and Jürgen Eberle
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Summary:Actinic keratosis (AK) occurs on sun-exposed skin and may progress to invasive squamous cell carcinoma (SCC). As for its topical treatment, diclofenac/hyaluronic acid (HA) has been recently approved. The NSAID diclofenac is an inhibitor of COX-2; however, its mode of action in cutaneous epithelial cancer cells is largely unknown. Here, the effects of diclofenac/HA were investigated in relation to death ligand-mediated apoptosis (TNF-α, TRAIL, and CD95 activation). Whereas diclofenac/HA only moderately induced apoptosis by itself, it resulted in pronounced enhancement of death ligand-mediated apoptosis in sensitive SCC cell lines (3/4). Apoptosis was associated with activation of initiator caspases of the extrinsic pathway (caspase-8/caspase-10). Furthermore, death ligand and diclofenac/HA-mediated apoptosis were blocked by the same caspase inhibitors, indicating related pathways. The proapoptotic effects of diclofenac/HA appeared independent of the p53 pathway. Also, upregulation of death receptors appeared less important; however, strong downregulation of c-FLIP isoforms was seen after diclofenac/HA treatment. The crucial role of c-FLIP was proven through overexpression and knockdown experiments. Thus, induction of apoptosis appears to be highly characteristic of the mode of action of diclofenac/HA, and the therapeutic effect may be related to sensitization of neoplastic keratinocytes for death ligand-induced apoptosis.
Item Description:Gesehen am 15.08.2023
Physical Description:Online Resource
ISSN:1523-1747
DOI:10.1038/jid.2010.40

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