Principal Investigator

Georg T
Wondrak
Awardee Organization

University Of Arizona
United States

Fiscal Year
2018
Activity Code
R03
Project End Date

Bixin-based dietary skin photoprotection and suppression of photocarcinogenesis

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.

Publications

  • Justiniano R, Perer J, Hua A, Fazel M, Krajisnik A, Cabello CM, Wondrak GT. A Topical Zinc Ionophore Blocks Tumorigenic Progression in UV-exposed SKH-1 High-risk Mouse Skin. Photochemistry and photobiology. 2017 Nov;93(6):1472-1482. Epub 2017 Jul 21. PMID: 28503778
  • Dickinson SE, Wondrak GT. TLR4-directed Molecular Strategies Targeting Skin Photodamage and Carcinogenesis. Current medicinal chemistry. 2018;25(40):5487-5502. PMID: 28847267
  • Rojo de la Vega M, Krajisnik A, Zhang DD, Wondrak GT. Targeting NRF2 for Improved Skin Barrier Function and Photoprotection: Focus on the Achiote-Derived Apocarotenoid Bixin. Nutrients. 2017 Dec 18;9. (12). PMID: 29258247
  • Justiniano R, Williams JD, Perer J, Hua A, Lesson J, Park SL, Wondrak GT. The B6 -vitamer Pyridoxal is a Sensitizer of UVA-induced Genotoxic Stress in Human Primary Keratinocytes and Reconstructed Epidermis. Photochemistry and photobiology. 2017 Jul;93(4):990-998. Epub 2017 Feb 28. PMID: 28083878
  • Blohm-Mangone K, Burkett NB, Tahsin S, Myrdal PB, Aodah A, Ho B, Janda J, McComas M, Saboda K, Roe DJ, Dong Z, Bode AM, Petricoin EF 3rd, Calvert VS, Curiel-Lewandrowski C, Alberts DS, Wondrak GT, Dickinson SE. Pharmacological TLR4 Antagonism Using Topical Resatorvid Blocks Solar UV-Induced Skin Tumorigenesis in SKH-1 Mice. Cancer prevention research (Philadelphia, Pa.). 2018 May;11(5):265-278. Epub 2018 Feb 1. PMID: 29437671
  • Rojo de la Vega M, Zhang DD, Wondrak GT. Topical Bixin Confers NRF2-Dependent Protection Against Photodamage and Hair Graying in Mouse Skin. Frontiers in pharmacology. 2018 Mar 27;9:287. doi: 10.3389/fphar.2018.00287. eCollection 2018. PMID: 29636694