Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photodamage and carcinogenesis. The transcription factor NRF2 (nuclear factor-E2-related factor 2) orchestrates major cellular defense mechanisms, and NRF2 has therefore emerged as a promising molecular target for the pharmacological prevention of human pathologies resulting from exposure to environmental toxicants including solar UV light. Pharmacological modulation of NRF2 has now attracted considerable attention as a novel approach to skin photoprotection supported by our own studies on NRF2 activation in cultured human skin cells and reconstructed epidermal skin models. The apocarotenoid bixin, an FDA-approved natural food colorant (referred to as 'annatto') originates from the seeds of the achiote tree native to tropical America, consumed since pre-Columbian times. Bixin is the only FDA approved, molecularly defined food pigment that displays potent NRF2-directed activity. Based on our published prototype data, the research pursued in this R03 research proposal will for the first time examine efficacy of bixin-based dietary activation of cutaneous NRF2 for acute skin photoprotection and suppression of chronic solar radiation-induced photocarcinogenesis. First, we will test feasibility of skin protection against acute damage (sunburn) from solar UV exposure in SKH-1 mice (Nrf2+/+ versus Nrf2-/-) by dietary supplementation using bixin (aim #1). Next, we will test feasibility of NRF2-dependent dietary suppression of solar UV-induced skin carcinogenesis using bixin supplementation in an established photocarcinogenesis model (Nrf2+/+ versus Nrf2-/- SKH-1 mice) (aim #2). Taken together, the proposed experimentation will generate crucial prototype data facilitating translational clinical research that substantiates the skin photoprotective and cancer-suppressive benefits provided by dietary consumption of this key food factor originating from the Americas.

Public Health Relevance

Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photodamage and carcinogenesis. In this R03 research project, the hypothesis is tested that protection against solar ultraviolet radiation-induced skin damage and cancer can be achieved by activation of the skin's natural antioxidant defense system. The project will test the efficacy of the specific dietary factor bixin (-a spice and FDA-approved natural food additive originating from the tropical Americas used by humans since pre-Columbian times-) that is known to activate the master regulator of the skin's own antioxidant defense system, a transcription factor called NRF2. Using bixin as a powerful dietary factor that activates NRF2, this research aims at developing a safe, efficient, and inexpensive dietary intervention that blocks solar radiation-induced skin cancer, a novel strategy protecting the general population against environmental insult from solar ultraviolet radiation. The experimental design that includes the use of specific genetically modified (Nrf2 knockout) mice will allow to draw firm mechanistic conclusions as to the crucial involvement of NRF2 in bixin-induced skin protection. It is expected that the proposed research generates crucial proof-of-concept data that can be quickly translated into nutritional strategies that strengthen the NRF2-dependent antioxidant skin defense system against sunburn and skin cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Research Grants (R03)
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Special Emphasis Panel (ZCA1)
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Riscuta, Gabriela
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University of Arizona
Schools of Pharmacy
United States
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Justiniano, Rebecca; Williams, Joshua D; Perer, Jessica et al. (2017) The B6 -vitamer Pyridoxal is a Sensitizer of UVA-induced Genotoxic Stress in Human Primary Keratinocytes and Reconstructed Epidermis. Photochem Photobiol 93:990-998
Justiniano, Rebecca; Perer, Jessica; Hua, Anh et al. (2017) A Topical Zinc Ionophore Blocks Tumorigenic Progression in UV-exposed SKH-1 High-risk Mouse Skin. Photochem Photobiol 93:1472-1482
Rojo de la Vega, Montserrat; Krajisnik, Andrea; Zhang, Donna D et al. (2017) Targeting NRF2 for Improved Skin Barrier Function and Photoprotection: Focus on the Achiote-Derived Apocarotenoid Bixin. Nutrients 9: