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Type of thesis
Biological evaluation of a novel lysosomotropic compound with improved anticancer activity compared to chloroquine
Scientific disciplinary sector
Istituto di Scienze della Vita - TRANSLATIONAL MEDICINE
relatore Dott. GRIMALDI, BENEDETTO
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A drug discovery screening for lysosomotropic agents identified ARNX1741 as a compound able to prevent lysosomal acidification. Because the potential use of lysosomotropic compounds in inhibiting the viability of cancer cells, this work evaluated the in vitro anticancer properties of ARNX1741 in comparison with chloroquine (CQ), a lysosomal inhibitor molecule currently evaluated in many anticancer trials.<br>In particular, I focused my studies on comparing the activity of ARNX1741 and CQ in killing cancer cells and in blocking autophagy. In addition, biochemical and molecular approaches were adopted for identifying similarities and differences between the biological pathways engaged by the two compounds.<br>Collectively, my results indicated that ARNX1741 has an improved in vitro anticancer activity than CQ against a number of human cancer cells with diverse origin. Opposite to CQ, ARNX1741 ability in killing breast cancer cells did not depend on ERBB2 overexpression. In addition, ARNX1741 showed a high anticancer potency against diverse uveal melanoma cell lines, including cells with alterations of chromosome 3 that are associated with a high metastatic rate.<br>Combined immunofluorescence microscopy, proteomic, immunoblot and transcriptional studies revealed that the two compounds similarly block autophagy but strongly differ for the alteration of cholesterol metabolism. Indeed, ARNX1741, but not CQ, impairs cholesterol trafficking inhibiting its transport outside lysosomes and generates a depletion of intracellular cholesterol.<br>Cell viability and molecular analysis from cells growth in presence or absence of exogenous cholesterol further indicated that ARNX1741-mediated impairment of cholesterol metabolism contributes to the anticancer effect of this compound.<br>Collectively, my data identified ARNX1741 as a suitable chemical scaffold for the development of novel lysosomotropic anticancer agents. In addition, ARNX1741 represents a valuable pharmacological tool for unraveling the role of lysosome-mediated cholesterol trafficking and autophagy in supporting the viability of cancer cells.
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