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Novel epoxy-tiglianes stimulate skin keratinocyte wound healing responses and re-epithelialization via protein kinase C activation

Moses, Rachael L., Boyle, Glen M., Howard-Jones, Rachel A. ORCID: https://orcid.org/0000-0001-7200-3110, Errington, Rachel J. ORCID: https://orcid.org/0000-0002-8016-4376, Johns, Jenny P., Gordon, Victoria, Reddell, Paul, Steadman, Robert ORCID: https://orcid.org/0000-0002-1303-2496 and Moseley, Ryan ORCID: https://orcid.org/0000-0002-2812-6735 2020. Novel epoxy-tiglianes stimulate skin keratinocyte wound healing responses and re-epithelialization via protein kinase C activation. Biochemical Pharmacology 178 , 114048. 10.1016/j.bcp.2020.114048

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Abstract

Epoxy-tiglianes are a novel class of diterpene esters. The prototype epoxy-tigliane, EBC-46 (tigilanol tiglate), possesses potent anti-cancer properties and is currently in clinical development as a local treatment for human and veterinary cutaneous tumors. EBC-46 rapidly destroys treated tumors and consistently promotes wound re-epithelialization at sites of tumor destruction. However, the mechanisms underlying these keratinocyte wound healing responses are not completely understood. Here, we investigated the effects of EBC-46 and an analogue (EBC-211) at 1.51 nM-151 µM concentrations, on wound healing responses in immortalized human skin keratinocytes (HaCaTs). Both EBC-46 and EBC-211 (1.51 nM-15.1 µM) accelerated G0/G1-S and S-G2/M cell cycle transitions and HaCaT proliferation. EBC-46 (1.51-151 nM) and EBC-211 (1.51 nM-15.1 µM) further induced significant HaCaT migration and scratch wound repopulation. Stimulated migration/wound repopulation responses were even induced by EBC-46 (1.51 nM) and EBC-211 (1.51-151 nM) with proliferation inhibitor, mitomycin C (1 μM), suggesting that epoxy-tiglianes can promote migration and wound repopulation independently of proliferation. Expression profiling analyses showed that epoxytiglianes modulated keratin, DNA synthesis/replication, cell cycle/proliferation, motility/migration, differentiation, matrix metalloproteinase (MMP) and cytokine/chemokine gene expression, to facilitate enhanced responses. Although epoxy-tiglianes down-regulated established cytokine and chemokine agonists of keratinocyte proliferation and migration, enhanced HaCaT responses were demonstrated to be mediated via protein kinase C (PKC) phosphorylation and significantly abrogated by pan-PKC inhibitor, bisindolylmaleimide-1 (BIM-1, 1 μM). By identifying how epoxy-tiglianes stimulate keratinocyte healing responses and re-epithelialization in treated skin, our findings support the further development of this class of small molecules as potential therapeutics for other clinical situations associated with impaired re-epithelialization, such as non-healing skin wounds.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Medicine
Additional Information: Research dataset available at https://doi.org/10.17632/gd8nxrt8z9.2
Publisher: Elsevier
ISSN: 0006-2952
Date of First Compliant Deposit: 21 May 2020
Date of Acceptance: 19 May 2020
Last Modified: 09 Nov 2023 17:20
URI: https://orca.cardiff.ac.uk/id/eprint/131879

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