Tea tree oil (TTO) is the essential oil steam distilled from Melaleuca alternifolia of the Myrtaceae family, a plant native from Australia. Traditionally, the oil was used by aboriginal Australian for insect bites and skin infections and rediscovered in 1920s for its topical antiseptic effects. To date, the essential oil is part of several products for skin and wound care and its safety/toxicity associated with topical uses has been rigorously examined. TTO consists largely of monoterpenes; about half are oxygenated and the rest are hydrocarbons. Out of the over 100 components of the oil, the more represented are terpinen-4-ol, -terpinene, -terpinene, 1,8-cineole, and -cymene. Currently, the composition of TTO must adhere to an international standard for “Oil ofMelaleuca terpinen-4-ol type” which sets the upper and lower limits for 14 components of the oil although it does not indicate the species of Melaleuca that must be the source of the oil (International Organization for Standardization, ISO 4730: 1996). Terpinen-4-ol, the most abundant component of the oil, is thought to be the main active constituent responsible for the several in vitro and in vivo activities reported for TTO. TTO is known for its antibacterial, antifungal, antiviral, and anti-inflammatory properties, while only recently the phytocomplex and some of its components have been screened for anticancer activities.
Studies evaluating cytotoxicity of TTO on cultured cells were initially performed to determine its potential toxic effects. TTO toxicity was tested on a wide panel of human cell cultures including cervical cancer (HeLa), acute lymphoblastic leukemia (MOLT-4), erythromyeloblastoid leukemia (K562), B cell derived from bone marrow of a patient with acute myeloid leukaemia (CTVR-1), fibroblast, and epithelial cells. In these studies TTO showed an IC50 on cell growth ranging from 20 to 2700 μg/mL.
The potential antitumoral activity of TTO was reported in a study by Calcabrini and colleagues (2004) in human melanoma M14 wild type cells and their drug-resistant counterparts, M14 adriamycin-resistant (ADR) cells. TTO, at the higher used concentrations (0.02 and 0.03%), as well as terpinen-4-ol, was able to inhibit the growth and induce caspase-dependent apoptotic cell death in both wild type and drug-resistant melanoma cells with the latter being more susceptible to the cytotoxic effect. The authors suggested that the greater sensitivity to the TTO treatment displayed by the drug-resistant cells could be ascribed to the different lipid composition of the plasma membrane since there is evidence indicating that multidrug resistance phenotype is also associated with changes in membrane lipid composition. This would suggest that, as claimed for the antimicrobial effect, the cytotoxicity of TTO might be due to the interaction of the lipophilic components of the oil with the phospholipid bilayer of cell membranes with consequent alteration of cell growth and activity. It is worth noting that an earlier study testing the cytotoxic effect of TTO on “normal” epithelial and fibroblast cells, having similar susceptibilities as basal keratinocytes to topical agents, did not report toxic effects at concentrations that were shown to affect melanoma cell survival, thus confirming a higher sensitivity of tumor cells as compared to normal cells.
Cytotoxic effect of TTO has been reported in murine mesothelioma (AE17) and melanoma (B16) cell lines though slightly different IC50 was reported, probably due to the different cell types. In this case, TTO and terpinen-4-ol induced time-dependent cancer cell cycle arrest and cell death by primary necrosis and low levels of apoptosis; differential dose-response between tumor and nontumor fibroblast cells was shown suggesting that TTO might elicit its effect by inhibiting rapidly dividing cells more readily than slower growing noncancerous cells. More recently, the ability of TTO and its major component, terpinen-4-ol, has been also reported to interfere with the migration and invasion processes of drug-sensitive and drug-resistant melanoma cells.
Two recent studies investigated the efficacy of topical TTO on aggressive, subcutaneous, chemoresistant tumors in fully immune-competent mice. The studies showed that topical treatment with 10% TTO, given once a day for 4 consecutive days, induced a significant, though temporary, regression of established subcutaneous AE17 tumors and slowed the growth of B16-F10 tumors. Use of DMSO as a penetration enhancer, at concentrations devoid of toxic effects, was necessary to induce the antitumor effect; no effects were evident when using neat TTO or solvents other than DMSO (i.e., isopropanol or acetone). Similar effects on tumor growth were obtained using a combination of the five major components of TTO (terpinen-4-ol, -terpinene, -terpinene, 1,8-cineole, and -cymene) at equivalent doses to those found in 10% TTO but not with the single components. The antitumor effect of topical TTO was accompanied by skin irritation that, unlike other topical chemotherapeutic agents, resolved quickly and completely.
A follow-up study investigated the mechanism of action underlying the antitumor activity of topical TTO reporting that topically applied 10% TTO induced a direct cytotoxicity on subcutaneous AE17 tumor cells, which was associated with nontumor specific activation of local immune response (i.e., neutrophils, dendritic, and T cells). In particular transmission electron microscopy analysis of AE17 tumor sections from mice treated topically with TTO revealed loss of cellular organization with increased intercellular spaces and accumulation of cell debris, nuclear shrinkage, chromatin condensation, mitochondria swelling and loss of cristae and membranes, significant alteration of endoplasmic reticulum, and less defined cellular membranes. These findings would suggest that, following in vivo TTO treatment, tumor cells undergo primary necrosis as previously suggested in vitro. Interestingly the topical treatment does not seem to affect the fibroblast adjacent to damaged tumor cells, nor lymphocytes within tumor sections and skeletal muscle fibers adjacent to tumor suggesting that normal cells might have higher tolerance to TTO cytotoxicity as compared to tumor cells.
Melalueca an anti cancer treatment
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