Molekulski mehanizmi delovanja antitumorskog agensa iz grupe sintetskih tubulizina, tubugi 1, na odabranim model sistemima melanoma
Molecular mechanisms of the action of antitumor agent from the synthetic tubulysins’ group, tubugi 1, on selected melanoma model systems
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Tubulysins are secondary metabolites of myxobacteria that exert their antitumor activity by disrupting the organization of the mitotic spindle. In this study, the antitumor potential of synthetic analog of tubulysins, tubugi 1, was tested in mouse and human melanoma model in vitro and in vivo. Tubugi 1 showed selectivity for the malignant phenotype. In murine B16 cells, tubugi 1 induced atypical apoptosis without phosphatidylserine (PS) externalization, which was attributed to membrane lipid preservation under conditions of intense oxidative stress. Although PS plays a key role in apoptotic cell removal, this did not affect macrophage phagocytic activity in vitro. The efficacy of the experimental agent was confirmed in vivo. In addition to its direct effect on malignant cells, reduced tumor volume is ascribed to established cytotoxic phenotype, as well as the preserved phagocytic ability of macrophages. On the other hand, in A-375 cells, tubugi 1 induced a mitotic catastrophe, manifested morphologically by micronuclei formation, and biochemically by activation of caspase 2 and the nuclear factor κB (NF-κB). The described phenomenon was accompanied by intense, but transient autophagy showing cytoprotective features. With the depletion of the autophagic process, apoptosis increased, followed by an increase in proapoptotic index and caspase 3 activity. All of the events described correlated completely with the dynamic changes in signaling pathways involved in cell division and death – mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K/Akt). Finally, the results of this doctoral dissertation pointed to the important antitumor potential of the synthetic derivative of natural tubulysins, tubugi 1, in the mouse and human melanoma model.
Keywords:Melanoma; Tubulysin; Apoptosis; Mitotic catastrophe; Autophagy; Phosphatidylserine; Macrophage polarization
Source:Faculty of Biology, University of Belgrade, 2020, 1-84
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