Antitumorski potencijal novosintetiziranih heterobimetalnih kompleksa

master's thesis

• Title (english): Anticancer potential of newly synthesized heterobimetallic complexes
• Author: Lea Milić
• Mentor: Anamaria Brozović (mentor)
• Mentor: Maja Matulić (komentor)
• Committee member: Maja Matulić (predsjednik povjerenstva)
• Committee member: Inga Urlić (član povjerenstva)
• Committee member: Petra Peharec Štefanić (član povjerenstva)
• Committee member: Sofia Ana Blažević (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2022-12-22, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology

Abstract

Ferocen (bis(η5-ciklopentadienil)željezo(II)) vrlo je značajan pripadnik skupine metalocena, organometalnih
spojeva čiji se derivati intenzivno proučavaju kao potencijalni kandidati u liječenju tumora. Jedna od
obećavajućih strategija je sinteza heterobimetalnih kompleksa koji uz ferocen u svojoj strukturi imaju i
drugi metal čime bi se potencijalno mogli prevladati nedostatci široko korištenog kemoterapeutika cisplatine.
U ovom diplomskom radu istraženo je biološko djelovanje dva novosintetizirana heterobimetalna kompleksa
nikla s aminoferocenskim ligandima. Navedeni kompleksi su odabrani za daljnja ispitivanja od prvotnih
20 sintetiziranih spojeva s ferocenom zbog stabilnosti i značajne toksičnosti kod stanica karcinoma
vrata maternice HeLa ispitanih metodom MTT. Istom metodom ispitana je citotoksičnost odabranih
kompleksa kod tumorskih linija stanica MES-OV, RPMI-7951 i MDA-MB-435 te na normalnoj liniji
stanica. Oba su kompleksa pokazala manju toksičnost kod normalnih, u odnosu na tumorske linije
stanica što ukazuje na njihovo selektivno djelovanje. Pomoću specifičnih inhibitora i prekursora
sinteze glutationa pokazano je da glutation ne sudjeluje u odgovoru stanice na stres potaknut s oba
kompleksa. Protočnom citometrijom pokazano je da oba kompleksa potiču nakupljanje stanica u
fazama G0/G1 i S ciklusa stanice te uzrokuju apoptozu. Metodom Western blot utvrđeno je da
tretmani kompleksima ne uzrokuju cijepanje proteina PARP-1, specifičnog biljega apoptoze te da
povećanjem koncentracije oba kompleksa dolazi do smanjenja ekspresije antiapoptotskog proteina
Bcl-2.

Abstract (english)

Ferrocene (bis(η5-cyclopentadienyl)iron(II)) is an important member of metallocenes, organometallic
compounds whose derivatives are intensively studied as potential candidates for tumor treatment. A
promising strategy that could potentially overcome the disadvantages of the widely used
chemotherapeutic agent cisplatin is the synthesis of heterobimetallic complexes that, in addition to
ferrocene, have another metal in their structure. In this graduation thesis, the biological activity of two
newly synthesized heterobimetallic complexes of nickel with aminoferrocene ligands was examined.
The mentioned complexes were selected for further testing from the original 20 synthesized
compounds with the ferrocenyl moiety, due to their stability and significant toxicity for human
cervical carcinoma HeLa cells as tested by the MTT assay. Using the same method, the cytotoxicity of
the selected complexes was tested on tumor cell lines MES-OV, RPMI-7951, MDA-MB-435 and on a
normal cell line. Both complexes were less toxic for normal than for tumor cell lines, which indicates
their selective action. Using specific inhibitors and precursors of glutathione synthesis, it was shown
that glutathione was not involved in cell stress response caused by both complexes. Flow cytometry
showed that both complexes stimulated the accumulation of cells in the G0/G1 and S phase of the cell
cycle and caused apoptosis. Using the Western blot method, it was determined that treatments with
the selected complexes did not cause cleavage of the PARP-1 protein, a specific marker of apoptosis,
and that increasing the concentration of both complexes led to a decrease in the expression of the
antiapoptotic protein Bcl-2.

• Keywords: tumor; ferocen; glutation; ciklus stanice; smrt stanice
• Keywords (english): tumor; ferrocen; glutathion; cell cycle; cell death
• Language: croatian
• URN:NBN: urn:nbn:hr:217:336448
• Study programme: Title: Molecular Biology; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra molekularne biologije (magistar/magistra molekularne biologije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2023-08-22
• Created on: 2023-04-05 10:24:00