In Vitro Anti-skin Cancer Properties and Mechanisms of Action of Xanthones from the Mangosteen Pericarp

Author: JingJing Wang

Wang, JingJing, 2012 In Vitro Anti-skin Cancer Properties and Mechanisms of Action of Xanthones from the Mangosteen Pericarp, Flinders University, School of Medicine

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The incidence of skin cancer has increased more than 600% worldwide since the 1940s, and Australians have the highest incidence in the world, with at least 2 in 3 Australians diagnosed with skin cancer before the age of 70. The current chemotherapy is not effective, with new drugs in high demand. Plants are important sources for anti-cancer drugs. Mangosteen (Garcinia mangostana Linn.) is a tropical tree from South East Asia and its fruit pericarp is a well-known traditional medicine. This study investigated the potential anti-skin cancer activity of the crude extract and major xanthone compounds from the pericarp of mangosteen by investigating the cytotoxicity and underlying cellular and molecular mechanisms. Two types of human skin cancer cell lines were used as in vitro models: melanoma SK-MEL-28 and squamous cell carcinoma A-431. There were five major research outcomes. (i) Development of a methodology for extraction of mangosteen based on chemical composition and antioxidant activity. (ii) Demonstration of anti-proliferative activity towards skin cancer cell lines. The crude extract and six xanthone compounds tested had significant anti-cancer activities, with IC50 values ranging from 2.39 to 7.61 [mu]g/ml. The activity was selective against skin cancer cells with less effect on human normal skin fibroblast CCD-1064Sk and the keratinocyte HaCaT cell lines. IC50 values of the xanthones were similar to, or much lower than, those of two most commonly used commercial drugs (5-fluorouracil and dacarbazine). (iii) Identification of cellular and molecular pathways. The anti-cancer action of xanthone compounds was found to be via activation of caspases together with the loss of mitochondrial membrane potential and inhibition of Akt and NFκB survival pathways. In melanoma SK-MEL-28 cells, downregulation of BRAF V600E mutation expression was observed after treatment with some xanthones, e.g. a maximum 6.8-fold decrease in the level of BRAF V600E relative to the untreated control. (iv) Identification of synergistic effects. Synergistic effects between α-mangostin and the other individual compounds were observed. However, no synergistic effect was found between xanthone compounds and commercial drugs under the tested conditions in the current study. (v) Evaluation of anti-metastatic activity of α-mangostin. Skin cancers, especially melanoma, have a high potential to metastasise. α-Mangostin exhibited significant inhibitive activity of invasion and migration at non-toxic doses on both skin cancer cell lines tested. The anti-metastatic activity of α-mangostin was associated with downregulation of mRNA expression of MMP-2 and MMP-9 through inhibiting NFκB and Akt pathways. This study provides important scientific evidence of the potential antioxidant and antiproliferative activity of extracts and xanthone compounds from the pericarp of mangosteen, and increases understanding of their underlying mechanisms. These findings can contribute to the development of novel plant-derived antioxidant strategies in the treatment of skin cancers.

Keywords: skin cancer,mangosteen,xanthones,cytotoxicity,apoptosis,survival pathway,metastasis

Subject: Medicine thesis, Medical Biotechnology thesis

Thesis type: Doctor of Philosophy
Completed: 2012
School: School of Medicine
Supervisor: Prof. Wei Zhang; Dr. Barbara Sanderson