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American Association for Cancer Research, Cancer Research, 8_Supplement(72), p. 5550-5550, 2012

DOI: 10.1158/1538-7445.am2012-5550

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Abstract 5550: Ingenol mebutate induces an early and inflammatory wound healing response in a human in vitro 3-D skin model

Journal article published in 2012 by Thomas Litman, Maria H. Høyer-Hansen, John R. Zibert
This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

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Abstract

Abstract Ingenol mebutate (IM, ingenol-3-angelate, PEP005) is a promising new agent for topical treatment of actinic keratosis (AK), a pre-malignant condition that if left untreated can develop into squamous cell carcinoma. A dual mechanism of action of IM has been suggested; this involves direct lesional cell death and PKC activation dependent, immune modulatory effects. The aim of this study was to investigate the mode of action of IM. We have previously compared IM's penetration through normal skin to a 3-D reconstructed human skin (RHS) model (EpiDermFT™, MatTek). A 10-fold higher permeability was found in RHS, which likely reflects the increased permeability of AK lesions. Therefore, we studied the effects of 0.05% IM gel in this model at different time points (0.5, 6, 24, and 96 h). The response parameters measured included cytotoxicity (MTT assay), cytokine secretion, as well as global transcriptomic profiling (Affymetrix GeneChip® Human Gene 1.0 ST arrays). Multivariate analysis, including principal component analysis, unsupervised hierarchical clustering, and gene ontology enrichment, revealed that the major effects of IM comprised: cell death, inflammation and a wound healing response. This was indicated by differential expression of e.g. CASP14, HAS2, several MMPs, SERPINs, ILs, and CCL20. We also observed regulation of many skin-specific genes, related both to epidermis development, such as keratinocyte differentiation, and to fibroblasts in dermis, reflecting the nature of the RHS. Furthermore, a transcription factor binding site (TFBS) analysis suggested ERK2 and PKC as relevant targets for IM. This is in accord with the drug's transient immune modulatory effect. Indeed, a specific, inflammatory response was observed already after 30 min treatment, and several genes, including MMP10 and IL1R2, displayed a time-dependent increase in expression, reaching a maximum at 24h returning to normal at 96h. A sustained effect was observed for more than 300 genes, most of which were down-regulated following IM treatment. In conclusion, IM displays pleiotropic effects, of which many are regulated on a transcriptional level. Our data suggest transient activation of in particular PKC and ERK2, with a link to cytokine release and wound healing response. The inflammatory reaction may subsequently contribute to the cell death observed after 24h treatment with IM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5550. doi:1538-7445.AM2012-5550