Nonmelanoma skin cancer (NMSC) is the most common malignancy in the United States presenting a public health burden of considerable magnitude. Chemoprevention strategies that involve pharmacological suppression of skin photocarcinogenesis have shown promise in preclinical and clinical studies, but more efficacious agents are needed. Recent research indicates that oncogene expression in premalignant and cancerous cells may represent a specific molecular vulnerability that can be targeted by personalized genetic or pharmacological intervention without impairing viability of cells that do not express the specific oncogene, a mode of conditional cytotoxicity referred to as 'synthetic-lethal'. Our recent research has identified artemisinins, an important class of redox-anti-malarials in clinical use worldwide, as synthetic- lethal anticancer agents that target disruption of cellular iron homeostasis, a common alteration of transformed cells that causes hypersensitivity to cytotoxic oxidative stress. In continuation of our current research aiming at elucidating molecular mechanisms underlying targeted inactivation of nonmelanoma and melanoma skin cancer cells by artemisinins, we propose pilot experimentation that tests the hypothesis that artemisinin-based topical intervention can suppress skin photocarcinogenesis by synthetic-lethal elimination of premalignant and malignant cutaneous keratinocytes. First, skin pharmacokinetics (cutaneous absorption profile) of artemisinin-derivatives will be established using an ex-vivo mouse skin chamber model (aim #1). Second, feasibility of artemisinin-based topical suppression of photocarcinogenesis will then be tested in the SKH-1 murine model of solar ultraviolet B-induced squamous cell carcinoma (aim #2). Critical proof-of-principle data will be generated guiding the rational design of future mechanistic and preclinical studies that validate synthetic-lethal approaches for photochemoprevention.

Public Health Relevance

Nonmelanoma skin cancer (NMSC) is the most common malignancy in the United States creating an urgent need for more efficacious strategies antagonizing skin carcinogenesis. Our studies pursue a novel mechanism of pharmacological intervention that kills precancerous and cancerous human skin cells without causing toxic effects in normal skin cells. In this pilot project, we will first optimize skin delivery of prototpe agents (called 'artemisinins') that harness this novel molecular mechanism and then test for the first time feasibility of artemisinin-based suppression of sun light-induced skin cancer in an animal model of the disease, representing a potentially significant advance in the development of novel treatment options suppressing skin cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
5R03CA167580-02
Application #
8450745
Study Section
Special Emphasis Panel (ZCA1-SRLB-2 (J1))
Program Officer
Perloff, Marjorie
Project Start
2012-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$75,750
Indirect Cost
$25,750
Name
University of Arizona
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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:
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
Tao, Shasha; Rojo de la Vega, Montserrat; Quijada, Hector et al. (2016) Bixin protects mice against ventilation-induced lung injury in an NRF2-dependent manner. Sci Rep 6:18760
Long, Min; Tao, Shasha; Rojo de la Vega, Montserrat et al. (2015) Nrf2-dependent suppression of azoxymethane/dextran sulfate sodium-induced colon carcinogenesis by the cinnamon-derived dietary factor cinnamaldehyde. Cancer Prev Res (Phila) 8:444-54
Davis, Angela L; Qiao, Shuxi; Lesson, Jessica L et al. (2015) The quinone methide aurin is a heat shock response inducer that causes proteotoxic stress and Noxa-dependent apoptosis in malignant melanoma cells. J Biol Chem 290:1623-38
Park, Sophia L; Justiniano, Rebecca; Williams, Joshua D et al. (2015) The Tryptophan-Derived Endogenous Aryl Hydrocarbon Receptor Ligand 6-Formylindolo[3,2-b]Carbazole Is a Nanomolar UVA Photosensitizer in Epidermal Keratinocytes. J Invest Dermatol 135:1649-1658
Tao, Shasha; Park, Sophia L; Rojo de la Vega, Montserrat et al. (2015) Systemic administration of the apocarotenoid bixin protects skin against solar UV-induced damage through activation of NRF2. Free Radic Biol Med 89:690-700
Williams, Joshua D; Bermudez, Yira; Park, Sophia L et al. (2014) Malondialdehyde-derived epitopes in human skin result from acute exposure to solar UV and occur in nonmelanoma skin cancer tissue. J Photochem Photobiol B 132:56-65
Tao, Shasha; Zheng, Yi; Lau, Alexandria et al. (2013) Tanshinone I activates the Nrf2-dependent antioxidant response and protects against As(III)-induced lung inflammation in vitro and in vivo. Antioxid Redox Signal 19:1647-61

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