Activation of NRF2 by topical apocarotenoid treatment mitigates radiation-induced dermatitis
| Autor: | Jessica Perer, Cody J. Schmidlin, Donna D. Zhang, Georg T. Wondrak, Montserrat Rojo de la Vega |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Keratinocytes DNA damage NF-E2-Related Factor 2 Clinical Biochemistry Human skin medicine.disease_cause Biochemistry environment and public health NRF2 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine ROS reactive oxygen species medicine GSH glutathione Animals Humans Viability assay Radiosensitivity lcsh:QH301-705.5 Skin Cancer Gene knockdown lcsh:R5-920 Radiotherapy Chemistry Organic Chemistry Radiation-Induced Dermatitis Bixin RT radiation therapy respiratory system Radiation-induced dermatitis NRF2 nuclear factor (erythroid-derived 2)-like 2 Oxidative Stress 030104 developmental biology lcsh:Biology (General) Cancer research Quality of Life IR ionizing radiation Radiodermatitis lcsh:Medicine (General) 030217 neurology & neurosurgery Oxidative stress Research Paper |
| Zdroj: | Redox Biology Redox Biology, Vol 37, Iss, Pp 101714-(2020) |
| ISSN: | 2213-2317 |
| Popis: | Radiation therapy is a frontline treatment option for cancer patients; however, the effects of radiotherapy on non-tumor tissue (e.g. radiation-induced dermatitis) often worsen patient quality of life. Previous studies have implicated the importance of redox balance in preventing dermatitis, specifically in reference to modulation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) signaling pathway. Due to the cytoprotective functions of transcriptional target genes of NRF2, we investigated how modulation of NRF2 expression could affect DNA damage, oxidative stress, and cell viability in response to radiotherapy. Specifically, it was noted that NRF2 knockdown sensitized human skin keratinocytes to ionizing radiation; likewise, genetic ablation of NRF2 in vivo increased radiosensitivity of murine epidermis. Oppositely, pharmacological induction of NRF2 via the apocarotenoid bixin lowered markers of DNA damage and oxidative stress, while preserving viability in irradiated keratinocytes. Mechanistic studies indicated that topical pretreatment using bixin as an NRF2 activator antagonized initial DNA damage by raising cellular glutathione levels. Additionally, topical application of bixin prevented radiation-induced dermatitis, epidermal thickening, and oxidative stress in the skin of SKH1 mice. Overall, these data indicate that NRF2 is critical for mitigating the harmful skin toxicities associated with ionizing radiation, and that topical upregulation of NRF2 via bixin could prevent radiation-induced dermatitis. Graphical abstract Topical application of bixin induces epidermal NRF2 signaling, preventing IR-induced DNA damage, oxidative stress, and cell death, all of which contribute to cutaneous radiation damage. Thus, induction of NRF2 via topical bixin application could represent a novel strategy for the prevention of radiation-induced dermatitis.Image 1 Highlights • The apocarotenoid bixin prevents IR-induced damage via the NRF2 signaling pathway. • Topical application of bixin prevents radiation-induced dermatitis in vivo. • NRF2 is a critical mediator of bixin protection against IR-induced cutaneous damage. • Glutathione upregulation contributes to bixin protection against IR-induced ROS and genotoxic stress. |
| Databáze: | OpenAIRE |
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