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Induction of Tumor-Selective Cytotoxicity by Myrtus communis L. Extract and its Bioactive Metabolite 1, 8-cineole

Yasenya Kasikci*, Ayfer Pazarbasi, Seray Karacay, Durmus Kaya A, Gülay Duran G, Akinchan Kumar, Bertan Yılmaz M, Hinrich Gronemeyer

Breast cancer is the most common type of cancer in women. Despite current treatments, new treatments should be investigated. The antioxidant and apoptotic activities of plant metabolites have attracted increasing interest in the molecular pharmacology. Here, we investigated the anti-proliferative and apoptotic potential of Myrtus communis L. extracts, used in traditional medicine. To monitor cancer-selective activities, the extract and its most prominent components were assayed in parallel with human MCF7 breast cancer and normal MCF10A mammary epithelial cells. Indeed, we observed a potential therapeutic window of concentrations with significantly higher toxicity for the tumor cells. GC-MS confirmed the presence of α-pinene, 1,8-cineole, linalool as major components. Analyzing these pure terpenoids revealed exclusive toxicity of 1,8-cineole for MCF7 cells, whereas no toxicity was seen for MCF10A cells. In contrast, both α-pinene and linalool did not exhibit tumor selectivity but were toxic for the tumor and normal cells. These data suggest that the anti-proliferative activity of the oil may be mediated by 1,8-cineole with the other components counteracting this potential therapeutic activity, which apperantely acted preferentially on epithelial cells. To gain mechanistic insight, we tested by RT-qPCR whether the essential oil affected apoptosis mediators. Indeed, BCL2 expression was dramatically down-regulated in MCF7 while it was up regulated in MCF10A. Minor differences were observed for BAX, while APAF1 expression was up-regulated in MCF7 and down-regulated in MCF10A. Our data suggest that in M. communis extracts, 1,8-cineole mediates tumor-selective apoptosis by deregulating BCL2 and APAF1.