Efekti novosintetisanih kompleksa platine(IV) na rast i radioosetljivost ćelija humanih malignih tumora in vitro
The effects of newly synthesized platinum(IV) complexes on growth and radiosensitization of human malignant tumor cells in vitro
Докторанд
Petrović, Marija A.Ментор
Todorović, DanijelaЧланови комисије
Popović, SuzanaAnđelković, Marija
Ristić-Fira, Aleksandra
Метаподаци
Приказ свих података о дисертацијиСажетак
Cilj ovog istraživanja je da se ispita direktno citotoksično dejstvo i potencijalni
mehanizam delovanja novosintetisanih kompleksa platine(IV) na više ćelijskih
linija humanih tumora (karcinoma pluća-A549, karcinoma dojke-MCF-7 i melanomaHTB140), kao i diferencijalna citotoksičnost u odnosu na normalne, zdrave
fibroblaste pluća-MRC-5. Rezultati su upoređeni sa efektima cisplatine (cis-Pt).
Ćelije su tretirane 24h nakon zasejavanja, a efekti analiziranih kompleksa
platine(IV) su praćeni 6h, 24h i 48h nakon tretmana koncentracijama u opsegu od 5-
100µM. Kompleksi platine(IV) pokazauju vremenski i dozno zavisnu inhibiciju rasta
ispitivanih ćelija. Inhibitorni efekti su veoma izraženi na A546 i MCF-7
ćelijskim linijama, a slabi na NTV140, zbog čega su ove ćelije isključene iz daljih
istraživanja. Indeks selektivnosti SI˃3 ukazuje na dobru selektivnost kompleksa
prema tumorskim ćelijama u odnosu na zdrave MRC-5 ćelije. Analizirani kompleksi
imaju statistički značajno antiprolifera...tivno dejstvo na A549 i MCF-7 ćelijama.
Tretman IC50 vrednostima ispitivanih kompleksa doveo je do apoptotske ćelijske
smrti. Procenat apoptotskih ćelija u tretiranim uzorcima je statistički značajno
veći u odnosu na kontrole, dostižući maksimum 48h nakon tretmana. Indukcija
apoptoze je povezana sa promenama u ekspresiji proapoptotskog Bax i antiapoptotskog
Bcl-2 prteina, kao i njihovim međusobnim odnosom. Kompleksi platine zaustavljaju
ćelijski ciklus u S fazi. Tretman A549 i MCF-7 ćelija 1Gy, 2Gy i 4Gy γ zračenja
dovodi do slabe inhibicije rasta. Pretretman ovih radiorezistentnih ćelija
analiziranim kompleksima platine povećava osetljivost ćelija na γ zračenje.
he aim of this study was to examine the direct cytotoxic effect, as well as the potential
mechanism of action of the newly synthesized platinum(IV) complexes on several human
tumour cell lines (lung cancer-A549, breast cancer-MCF-7 and melanoma-HTB140), as well
as the differential cytotoxicity compared to normal, healthy human fibroblasts-MRC-5. The
results were compared with the effects of cisplatin (cis-Pt). The cells were treated 24h after
seeding and the effects of the analysed platinum(IV) complexes were monitored 6h, 24h and
48h after treatment with concentrations in the range of 5-100µM. Platinum(IV) complexes
show a time- and dose-dependent growth inhibition of all tested cells. The inhibitory effects
are very pronounced on A546 and MCF-7 cell lines, and weak on HTB140 and therefore these
cells were excluded from further research. The selectivity index SI˃3 indicates a good
selectivity of the complex towards tumour cells compared to healthy MRC-5 cells. All analysed
...complexes showed statistically significant antiproliferative effect on A549 and MCF-7 cells.
Treatment with IC50 concentrations of the tested platinum complexes led to apoptotic cell
death. The percentage of apoptotic cells was statistically significantly higher compared to
untreated controls, reaching a maximum 48h after treatment. Induction of apoptosis is
associated with changes in the expression of proapoptotic protein Bax and antiapoptotic protein
Bcl-2, as well as their mutual relationship. Platinum(IV) complexes arrested the cell cycle in
the S phase. Treatment of A549 and MCF-7 cells with 1Gy, 2Gy and 4Gy of γ radiation results
in weak growth inhibition. Pre-treatment of these radioresistant cells with analysed
platinum(IV) complexes increases the sensitivity of cells to γ irradiation.