Activation of NRF2 by topical apocarotenoid treatment mitigates radiation-induced dermatitis

Abstract

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.

NF-E2-Related Factor 2 (Nrf2) Ameliorates Radiation-Induced Skin Injury

“…However, the protein kinase mediating S40 phosphorylation remains unclear and needs further study. Taken together, these results, along with those of other studies (14,37), clearly demonstrate that Nrf2 plays a pivotal role during the process of RISI. Pharmacological induction or activation of Nrf2 has been widely studied to prevent or protect against radiation-induced dermatitis in preclinical research both in vitro and in vivo (14,37).…”

“…Previous studies have suggested that the antioxidant capacity of Nrf2 is mediated through ROS-eliminating enzymes, and Nrf2 is thought to protect against stress-induced cell death (13). Pharmacological induction of Nrf2 before radiation exposure is thought to prevent radiation-induced dermatitis (14). The role of Nrf2 in high-dose radiation-induced skin injury remains unknown, and there is no strong evidence that exogenous supplementation with Nrf2 is capable of attenuating RISI.…”

Multispectroscopic, virtual and in vivo insights into the photoaging defense mediated by the natural food colorant bixin

“…Earlier, the cytoprotective activity of bixin in keratinocytes and fibroblasts via the activation of the NRF2 pathway (master switch of the cellular antioxidant response) has been reported. 51 Here, statistically significant difference in cellular viability was observed between NC vs. V groups ( p < 0.001) and V vs. BIX 1, BIX 2, and BIX 3 groups ( p < 0.001) emphasizing the cytoprotective role of bixin in UV treated HDF cells (Fig. 2A).…”

Quantitative Proteomics Identifies Reduced NRF2 Activity and Mitochondrial Dysfunction in Atopic Dermatitis

“…Most importantly, Nrf2 knockout mice showed increased numbers of neutrophils in the skin upon J o u r n a l P r e -p r o o f induction of contact dermatitis, which was a consequence of oxidative stress and enhanced chemokine production (Helou et al, 2019). They were also more sensitive to radiation-induced dermatitis (Schmidlin et al, 2020). Nrf2 is also a key regulator of the epidermal barrier, which activates a "rescue" pathway in LOR-deficient mice.…”