Moses, Rachael L., Boyle, Glen M., Howard-Jones, Rachel A. ![]() ![]() ![]() ![]() |
![]() |
PDF
- Accepted Post-Print Version
Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (2MB) |
![]() |
Other (Supplement 2 MP4)
- Supplemental Material
Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (25MB) |
![]() |
Other (Supplement 1 MP4)
- Supplemental Material
Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (25MB) |
![]() |
Other (Supplement 3 MP4)
- Supplemental Material
Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (9MB) |
![]() |
Other (Supplement 4 MP4)
- Supplemental Material
Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (8MB) |
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 |
Citation Data
Cited 9 times in Scopus. View in Scopus. Powered By Scopus® Data
Actions (repository staff only)
![]() |
Edit Item |