Molekulski mehanizmi delovanja antitumorskog agensa iz grupe sintetskih tubulizina, tubugi 1, na odabrani model sistemima melanoma
Molecular mechanisms of the action of antitumor agent from the synthetic tubulysinsʼ group, tubugi 1, on selected melanoma model systems
Author
Drača, DijanaMentor
Maksimović-Ivanić, DanijelaCommittee members
Markelić, MilicaMijatović, Sanja
Golić, Igor
Maksimović-Ivanić, Danijela
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Show full item recordAbstract
Tubulizini su sekundarni metaboliti miksobakterija koji svoju antitumorsku aktivnost ostvaruju
narušavanjem organizacije deobnog vretena. U ovoj studiji ispitivan je antitumorski potencijal
sintetskog analoga tubulizina, tubugi 1, in vitro i in vivo na modelu mišjeg i humanog melanoma.
Tubugi 1 je pokazao selektivnost prema malignom fenotipu. U mišjim B16 ćelijama, tubugi 1 je
indukovao atipičnu apoptozu bez eksternalizacije fosfatidilserina (PS), što je pripisano očuvanosti
lipida membrane u uslovima intenzivnog oksidativnog stresa. Iako PS ima ključnu ulogu u uklanjaju
apoptotskih ćelija, ovo se nije odrazilo na fagocitnu aktivnost makrofaga in vitro. Delotvornost
eksperimentalnog agensa potvrdjena je in vivo. Smanjeni volumen tumora je, pored direktnog
uticaja na maligne ćelije, rezultat i indukcije citotoksičnog fenotipa, kao i očuvane fagocitne
sposobnosti makrofaga. Sa druge strane, kod A-375 ćelija tubugi 1 je indukovao mitotsku
katastrofu, morfološki manifestovanu mikronukleaci...jama, a biohemijski – aktivacijom kaspaze 2 i
nukleusnog faktora κB (NF-κB). Opisani fenomen bio je praćen intenziviranom, ali prolaznom
autofagijom citoprotektivnog karaktera. Sa jenjavanjem autofagnog procesa, jačala je apoptoza
praćena porastom proapoptotskog indeksa i aktivnosti kaspaze 3. Svi opisani događaji u potpunosti
su korelirali sa dinamičnim promenama u signalnim putevima uključenim u ćelijsku deobu i smrt –
mitogenom-aktivirane protein kinaze (MAPK) i fosfatidilinozitol 3-kinaze (PI3K/Akt). U celini,
rezultati ove doktorske disertacije ukazaju na značajan antitumorski potencijal sintetskog derivata
prirodnih tubulizina, tubugi 1, pokazan na modelu mišjeg i humanog melanoma
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, manifest...ed 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.
Faculty:
Универзитет у Београду, Биолошки факултетDate:
07-10-2020Projects:
- Molecular mechanisms of physiological and pharmacological control of inflammation and cancer (RS-MESTD-Basic Research (BR or ON)-173013)