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Titolo: Identification & characterization of natural and synthetic compounds as new anticancer agents
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Data di pubblicazione: 23-mar-2016
Abstract: This thesis collects the work I have done during the three-year PhD Course. During my first year I have started a path that has allowed me to acquire different techniques devoted to set up and maintain primary cell cultures and cancer derived cell lines as well as to evaluate the cytotoxicity of potential novel synthetic inhibitors of human cancer cells. Part of the second and all the third year was spent at the University of Cape Town, South Africa, in the laboratory of prof. Ariel Katz under the supervision of proff. Roger Hunter and Catherine H. Kaschula investigating the anticancer activity of Z-ajoene, a garlic compound. Overall, the main aim of all the my research project was to identify and characterize natural or synthetic compounds as new antineoplastic agents. The results obtained are divided according to the research topics addressed: Anticancer activity of new Phenanthroline compounds (Part I); The garlic compound Z-ajoene as anticancer agents (Part II). Studies referring to the Part have been carried out at the University of Cagliari and were focalized on the evaluation of new Cu(II) -phenanthroline complexes as a potent antineoplastic agents against various solid and suspension tumours. The [Cu(1,10-phenanthrolin -5,6-diol)2(OH2)](ClO4)2 complex appears to be the most potent compound against human leukemia, prostate and lung cancer cell lines. The results obtained on the biological activity of this class of compounds, providing valuable information for the design of new anticancer drugs, have been published in the Journal of Inorganic Biochemistry (2014). As for the Part II of my research, I focused on the mechanisms underlying the anti-tumoral activity of garlic compound Z-ajoene on human triple –negative breast cancer cells. The results indicate that Z-ajoene localizes in the ER of MDA-MB-231 cells where it activates the unfolded protein response (UPR) and ER stress. These findings have been published in the Molecular Carcinogenesis journal (2015) Moreover, immunofluorescence studies support the concept that the Z-ajoene main target is a ER-resident chaperon protein (PDI), whose functional alteration may well be the cause of the cytotoxic effect. Another molecular target of Z-ajoene is the cytoskeleton protein Vimentin. Z-ajoene interacts with Vimentin through a S–thiolation causing the disruption of Vimentin filaments and therefore an alteration of the cell morphology. Given that Vimentin is known to participate to the early stage of the metastatic process, I also investigated the potential effect of Z-ajoene at non-cytotoxic concentrations in a specific cell assay and found that it effectively inhibits cell migration, both in the absence and presence of a chemotactic agent. The metastatic inhibition induced by Z-ajoene seems caused by modification of several signaling pathways as expression of Axl and Src proteins, and phosphorylation of β–catenin were changed. Although following inhibition of cell migration, a reduction of Vimentin expression was to be expected, Z-ajoene treatment surprisingly induced an upregulation of Vimentin. We interpreted this result as a consequence of Z-ajoene binding to Vimentin which unable this protein to perform its physiologic functions (manuscripts in preparation). Altogether, the data of my in vitro study indicate that Z-ajoene is a promising chemotherapeutic agent simultaneously acting on different molecular targets, also able to affect the metastatic process in cells derived from highly invasive breast tumors. Due to its potential use in the clinic, preclinical evaluation in xenograft mouse models of cancer are ongoing.
Handle: http://hdl.handle.net/11584/266770
Tipologia:8.2 Tesi di dottorato (ePrints)

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