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Topical application of RTA 408 lotion activates Nrf2 in human skin and is well-tolerated by healthy human volunteers
BACKGROUND: Topical application of the synthetic triterpenoid RTA 408 to rodents elicits a potent dermal cytoprotective phenotype through activation of the transcription factor Nrf2. Therefore, studies were conducted to investigate if such cytoprotective properties translate to human dermal cells, a...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501113/ https://www.ncbi.nlm.nih.gov/pubmed/26170027 http://dx.doi.org/10.1186/s12895-015-0029-7 |
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author | Reisman, Scott A. Goldsberry, Angela R. Lee, Chun-Yue I. O’Grady, Megan L. Proksch, Joel W. Ward, Keith W. Meyer, Colin J. |
author_facet | Reisman, Scott A. Goldsberry, Angela R. Lee, Chun-Yue I. O’Grady, Megan L. Proksch, Joel W. Ward, Keith W. Meyer, Colin J. |
author_sort | Reisman, Scott A. |
collection | PubMed |
description | BACKGROUND: Topical application of the synthetic triterpenoid RTA 408 to rodents elicits a potent dermal cytoprotective phenotype through activation of the transcription factor Nrf2. Therefore, studies were conducted to investigate if such cytoprotective properties translate to human dermal cells, and a topical lotion formulation was developed and evaluated clinically. METHODS: In vitro, RTA 408 (3–1000 nM) was incubated with primary human keratinocytes for 16 h. Ex vivo, RTA 408 (0.03, 0.3, or 3 %) was applied to healthy human skin explants twice daily for 3 days. A Phase 1 healthy volunteer clinical study with RTA 408 Lotion (NCT02029716) consisted of 3 sequential parts. In Part A, RTA 408 Lotion (0.5 %, 1 %, and 3 %) and lotion vehicle were applied to individual 4-cm(2) sites twice daily for 14 days. In Parts B and C, separate groups of subjects had 3 % RTA 408 Lotion applied twice daily to a 100-cm(2) site for 14 days or a 500-cm(2) site for 28 days. RESULTS: RTA 408 was well-tolerated in both in vitro and ex vivo settings up to the highest concentrations tested. Further, RTA 408 significantly and dose-dependently induced a variety of Nrf2 target genes. Clinically, RTA 408 Lotion was also well-tolerated up to the highest concentration, largest surface area, and longest duration tested. Moreover, significant increases in expression of the prototypical Nrf2 target gene NQO1 were observed in skin biopsies, suggesting robust activation of the pharmacological target. CONCLUSIONS: Overall, these data suggest RTA 408 Lotion is well-tolerated, activates Nrf2 in human skin, and appears suitable for continued clinical development. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12895-015-0029-7) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4501113 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-45011132015-07-15 Topical application of RTA 408 lotion activates Nrf2 in human skin and is well-tolerated by healthy human volunteers Reisman, Scott A. Goldsberry, Angela R. Lee, Chun-Yue I. O’Grady, Megan L. Proksch, Joel W. Ward, Keith W. Meyer, Colin J. BMC Dermatol Research Article BACKGROUND: Topical application of the synthetic triterpenoid RTA 408 to rodents elicits a potent dermal cytoprotective phenotype through activation of the transcription factor Nrf2. Therefore, studies were conducted to investigate if such cytoprotective properties translate to human dermal cells, and a topical lotion formulation was developed and evaluated clinically. METHODS: In vitro, RTA 408 (3–1000 nM) was incubated with primary human keratinocytes for 16 h. Ex vivo, RTA 408 (0.03, 0.3, or 3 %) was applied to healthy human skin explants twice daily for 3 days. A Phase 1 healthy volunteer clinical study with RTA 408 Lotion (NCT02029716) consisted of 3 sequential parts. In Part A, RTA 408 Lotion (0.5 %, 1 %, and 3 %) and lotion vehicle were applied to individual 4-cm(2) sites twice daily for 14 days. In Parts B and C, separate groups of subjects had 3 % RTA 408 Lotion applied twice daily to a 100-cm(2) site for 14 days or a 500-cm(2) site for 28 days. RESULTS: RTA 408 was well-tolerated in both in vitro and ex vivo settings up to the highest concentrations tested. Further, RTA 408 significantly and dose-dependently induced a variety of Nrf2 target genes. Clinically, RTA 408 Lotion was also well-tolerated up to the highest concentration, largest surface area, and longest duration tested. Moreover, significant increases in expression of the prototypical Nrf2 target gene NQO1 were observed in skin biopsies, suggesting robust activation of the pharmacological target. CONCLUSIONS: Overall, these data suggest RTA 408 Lotion is well-tolerated, activates Nrf2 in human skin, and appears suitable for continued clinical development. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12895-015-0029-7) contains supplementary material, which is available to authorized users. BioMed Central 2015-07-14 /pmc/articles/PMC4501113/ /pubmed/26170027 http://dx.doi.org/10.1186/s12895-015-0029-7 Text en © Reisman et al. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Reisman, Scott A. Goldsberry, Angela R. Lee, Chun-Yue I. O’Grady, Megan L. Proksch, Joel W. Ward, Keith W. Meyer, Colin J. Topical application of RTA 408 lotion activates Nrf2 in human skin and is well-tolerated by healthy human volunteers |
title | Topical application of RTA 408 lotion activates Nrf2 in human skin and is well-tolerated by healthy human volunteers |
title_full | Topical application of RTA 408 lotion activates Nrf2 in human skin and is well-tolerated by healthy human volunteers |
title_fullStr | Topical application of RTA 408 lotion activates Nrf2 in human skin and is well-tolerated by healthy human volunteers |
title_full_unstemmed | Topical application of RTA 408 lotion activates Nrf2 in human skin and is well-tolerated by healthy human volunteers |
title_short | Topical application of RTA 408 lotion activates Nrf2 in human skin and is well-tolerated by healthy human volunteers |
title_sort | topical application of rta 408 lotion activates nrf2 in human skin and is well-tolerated by healthy human volunteers |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501113/ https://www.ncbi.nlm.nih.gov/pubmed/26170027 http://dx.doi.org/10.1186/s12895-015-0029-7 |
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