Journal of Clinical and Aesthetic Dermatology

OCT 2017

An evidence-based, peer-reviewed journal for practicing clinicians in the field of dermatology

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35 JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY October 2017 • Volume 10 • Number 10 R E V I E W multiple mechanisms. The oil inhibits the oxidative enzyme 5-lipoxygenase and has DPPH radical scavenging activity and, in vivo, SAO was able to protect mouse livers from damage resulting from oxidative stress and the formation of reactive oxygen species. 3-7 In co-cultures of dermal fibroblasts and keratinocytes, the oil suppressed the production of numerous pro-inflammatory chemokines and cytokines produced in response to stimulation by lipopolysaccharide (LPS). Production of PGE2 was also suppressed, suggesting that SAO might be acting, at least in part, through inhibition of cyclooxygenase. 8 Additional anti-inflammatory activity in skin was reported to rely on the activation of the enzyme 11b-HSD1, which plays a role in cortisol synthesis by keratinocytes. The oil also suppressed the expression of the pro- inflammatory cytokine, IL-1b, in keratinocytes and reduced irritant dermatitis in mouse skin stimulated with haptens. 9 Recent interest in inflammatory-specific targets for the treatment of skin conditions such as psoriasis and atopic dermatitis has led to the development of a number of drugs and drug candidates that reduce levels of IL-17 and the activity of PDE4. 10-13 SAO has been shown to specifically inhibit both of these targets in various in-vitro models, 14-16 suggesting a mechanism for the activity seen in clinical studies of the oil in the treatment of these skin conditions. Alpha-santalol was found to be an inhibitor of tyrosinase, a key enzyme in the biosynthetic pathway for the skin pigment melanin. 17 This intriguing finding suggests that SAO may potentially act as an inhibitor of abnormal pigmentation associated with aging and exposure to ultraviolet light. Anti-microbial properties of album oil. The use of essential oils fell out of favor in the 1900s with the advent of sulfa drugs and other antibiotics, but interest in essential oils, such as SAO, has been re-vitalized in recent years due to their activity against antibiotic-resistant strains of bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). 18,19 Album oil has been found to be broadly active against many gram-positive strains of bacteria, including Staphylococcus (including antibiotic- resistant strains MRSA and VRSA), Streptococcus, and some gram-negative bacteria. 20–23 SAO has demonstrated potent activity against many fungal dermatophytes and yeasts including Trichophyton, Microsporum and Candida. 4, 24–29 Album oil is active against Herpes simplex viruses-1 and -2. 30,31 Beta-santalol, one of the principal components of SAO, was found to inhibit the replication of influenza virus A/HK (H3N2) in vitro at 100µg/mL. 32 The anti-microbial mechanism(s) of action of album oil have not been thoroughly elucidated but the effects seen might be partly due to the disruption of membrane integrity, a phenomenon that has been demonstrated for other essential oils. 33-35 Anti-proliferative and anti-cancer properties of sandalwood album oil. The ability of SAO to prevent the formation of tumors in mouse skin as a result of exposure to chemical carcinogens and ultraviolet light has been extensively studied in vitro and in vivo by the Dwivedi group. 36 The anti-cancer effects of album oil and its major components have also been demonstrated in bladder cancer cells and oral cancer cells. 37,38 In two papers published in 2013, Saraswati reported that alpha-santalol, the primary component of SAO, is anti-angiogenic and inhibits the growth of hepatocellular carcinoma and prostate tumors in vitro and in vivo. 39,40 A common mechanistic feature in these studies seems to be the ability of the oil to cause cell cycle arrest at G2/M and to induce apoptosis and subsequent cell death. SAO was also shown to induce autophagy and cell death in proliferating keratinocytes, suggesting that album oil may be able to prevent the progression of pre-cancerous conditions, such as actinic keratosis, to skin cancers. 41 When SAO was screened against the National Cancer Institute's NCI-60 panel of 60 human tumor cell lines, the oil inhibited the growth of all cells lines with IC50s ranging from 7 to 126μm (unpublished data, 2010, Southern Research Institute, Birmingham Alabama). Interestingly, this cytotoxicity was generally not seen when album oil was applied to non- cancerous cells. A recently published study examined the effects of essential oil from Santalum austrocalidonicum trees on human breast cancer cell lines (MCF-7) and non-tumorigenic epithelial breast cells (MCF-10A). 42 The authors demonstrated that the oil induced deoxyribonucleic acid (DNA) strand breaks in both cell lines. Unlike the MCF-10A cells, the MCF-7 cells were not able to repair the damage, and therefore, the essential oil showed a selective cytotoxicity toward the MCF-7 breast cancer cell line. It should be noted that the spectrum of components in Santalum austrocalidonicum oil differs from that seen in SAO but the general phenomenon observed might explain, in part, why sandalwood oil seems to be preferentially cytotoxic towards cancerous cell lines. A recent publication presented data showing that, in cultured keratinocytes, SAO enhanced expression of transcription factors (snail, twist) and mesenchymal factor (vimentin), all of which are related to the epithelial- mesenchymal transition (EMT). Album oil also promoted epidermal wound healing in vivo compared to vehicle control. 43 The olfactory receptor, OR2AT4, is expressed in keratinocytes and has been shown to bind to sandalwood odorants resulting in elevation of intracellular calcium levels and phosphorylation of extracellular kinases (Erk1/2) and p38 mitogen-activated kinases, promoting keratinocyte proliferation and wound healing in human skin ex vivo. 44 The relationship between OR2AT4 (or other sandalwood component receptors) and chemopreventive mechanisms in skin is speculative at this time, but these initial, intriguing findings are likely to stimulate further studies exploring the role of dermal sandalwood receptors in cellular proliferation. 45 Safety profile of sandalwood album oil. SAO has a long history of topical use as a traditional medicine and in personal care products. The dermal LD50 in rats is in excess of 5gm/kg of body weight. 46 When applied to human subjects in patch testing, neither neat sandalwood oil, nor a 10% SAO ointment, produced irritation or sensitization (unpublished data, 2013, Santalis Healthcare Corporation, San Antonio, Texas). In routine testing, a small percentage (0.1–2.4%) of people have been found to be allergic to album oil. 1 However, in many of these studies, the provenance, purity, and source of the sandalwood is not clear. For example, other species of sandalwood, such as Western Australian (Santalum spicatum) or Hawaiian sandalwood (Santalum paniculatum), contain significant percentages of farnesol, an irritant, that is not found in oil from S. album. SAO contains no known carcinogens and was not genotoxic in the Bacillus subtilis rec-assay. 47 The safety profile of album oil was reviewed

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