title: A novel chemopreventive mechanism for a traditional medicine: East Indian sandalwood oil induces autophagy and cell death in proliferating keratinocytes.
abstract: One of the primary components of the East Indian sandalwood oil (EISO) is α-santalol, a molecule that has been investigated for its potential use as a chemopreventive agent in skin cancer. Although there is some evidence that α-santalol could be an effective chemopreventive agent, to date, purified EISO has not been extensively investigated even though it is widely used in cultures around the world for its health benefits as well as for its fragrance and as a cosmetic. In the current study, we show for the first time that EISO-treatment of HaCaT keratinocytes results in a blockade of cell cycle progression as well as a concentration-dependent inhibition of UV-induced AP-1 activity, two major cellular effects known to drive skin carcinogenesis. Unlike many chemopreventive agents, these effects were not mediated through an inhibition of signaling upstream of AP-1, as EISO treatment did not inhibit UV-induced Akt or MAPK activity. Low concentrations of EISO were found to induce HaCaT cell death, although not through apoptosis as annexin V and PARP cleavage were not found to increase with EISO treatment. However, plasma membrane integrity was severely compromised in EISO-treated cells, which may have led to cleavage of LC3 and the induction of autophagy. These effects were more pronounced in cells stimulated to proliferate with bovine pituitary extract and EGF prior to receiving EISO. Together, these effects suggest that EISO may exert beneficial effects upon skin, reducing the likelihood of promotion of pre-cancerous cells to actinic keratosis (AK) and skin cancer.
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, AZ, United States; Department of Pharmacology, University of Arizona, Tucson, AZ, United States. Electronic address: sdickinson@uacc.arizona.edu.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Dickinson
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, AZ, United States; Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, United States.
authors.forename: Erik R
authors.initials: ER
authors.lastname: Olson
authors.affiliation: Santalis Pharmaceuticals, Inc., San Antonio, TX, United States.
authors.forename: Corey
authors.initials: C
authors.lastname: Levenson
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, AZ, United States.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Janda
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, AZ, United States.
authors.forename: Jadrian J
authors.initials: JJ
authors.lastname: Rusche
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, AZ, United States; Department of Medicine, University of Arizona, Tucson, AZ, United States.
authors.forename: David S
authors.initials: DS
authors.lastname: Alberts
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, AZ, United States; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, United States.
authors.forename: G Timothy
authors.initials: GT
authors.lastname: Bowden
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002417:Cattle; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects*; D008519:Medicine, Traditional; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010938:Plant Oils / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects; D012717:Sesquiterpenes / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors
chemical_list: D016588:Anticarcinogenic Agents; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D010938:Plant Oils; D012717:Sesquiterpenes; D018808:Transcription Factor AP-1; C076763:sandalwood oil
keywords: Autophagy; Cell death; Sandalwood oil; Ultraviolet light