Uloga inhibitora SRC tirozin-kinaze u prevazilaženju urođeno rezistentnog i invanzivnog fenotipa glioblastoma
The role of SRC tyrosine kinase inhibitors in overcoming the intrinsically resistant and invasive phenotype of glioblastoma
Докторанд
Nešović, Marija D.Ментор
Nedeljković, NadeždaЧланови комисије
Dinić, JelenaPešić, Milica
Divac Rankov, Aleksandra
Adžić, Marija
Метаподаци
Приказ свих података о дисертацијиСажетак
Glioblastomi su najagresivniji primarni tumora mozga, koje odlikuje visoka aktivnost Src
tirozin-kinaze. Stoga, ovaj enzim, koji reguliše preživljavanje i invazivnost tumorskih ćelija,
predstavlja potencijalnu metu za razvoj ciljane terapije. U ovom radu je ispitano dejstvo Src
tirozin-kinaznih inhibitora, Si306 i njegovog proleka pro-Si306 na invazivni potencijal humanih
ćelijskih linija glioblastoma (U87 i U87-TxR) i tri primarne ćelijske kulture glioblastoma, kao i na
višestruku rezistenciju na lekove posredovanu ekspresijom P-glikoproteina u U87-TxR ćelijskoj
liniji. P-glikoprotein je ATP vezujući transporter, koji ima protektivnu ulogu u krvno-moždanoj
barijeri, dok na membrani tumorskih ćelija sprečava prodiranje brojnih lekova i tako umanjuje
njihovu efikasnost.
Značajan efekat Si306 i pro-Si306 na ćelijski rast glioblastoma dobijen je u
mikromolarnom opsegu koncentracija 1-20 μM. Sposobnost ćelija glioblastoma da razgrade
vanćelijski matriks je bila značajno smanjena primenom S...rc tirozin-kinaznih inhibitora. Oba
inhibitora su uticala na ekspresiju komponenti Src signalnog puta i pokazala anti-invazivni
potencijal in vitro. In vivo, inhibitori su sprečili invadiranje U87 ćelija u ksenograft modelu
embriona zebrice. Pored svoje primarne uloge, Src tirozin-kinazni inhibitori su pokazali
sposobnost da umanje aktivnost P-glikoproteina i povećaju efikasnost paklitaksela kod U87-TxR
ćelija.
Uzimajući u obzir rezultate ovog rada, Si306 i pro-Si306 predstavljaju kandidate za
buduća klinička ispitivanja na glioblastomima kod kojih su terapeutske mogućnosti ograničene.
Prolek pro-Si306 je pokazao sličnu efikasnost kao i Si306, što ukazuje na opravdanost njegove
upotrebe zbog povoljnijih farmakokinetičkih svojstava u odnosu na sam lek.
Glioblastoma, as the most aggressive brain tumor, displays high activity of Src tyrosine
kinase. Thus, this enzyme that participates in the survival, migration, and invasiveness of tumor
cells emerged as a potential target for glioblastoma therapy. The effects of Src inhibitors, Si306
and its prodrug pro-Si306, on invasive potential in human glioblastoma cell lines (U87 and U87-
TxR) and three primary glioblastoma cell cultures were investigated in this study. Another
phenomenon investigated was multidrug resistance mediated by the overexpression of Pglycoprotein
in the resistant glioblastoma cell line U87-TxR. This ATP-binding cassette
membrane transporter has a protective role in the blood-brain barrier, while it limits drug delivery
through tumor membrane and decreases their efficacy.
Si306 and pro-Si306 have shown significant effects on cell growth of glioblastoma cells
applied in concentrations range 1-20 μM. The ability of glioblastoma cells to degrade the
extracellular matrix wa...s considerably compromised after application of Src tyrosine kinase
inhibitors. Both compounds affected Src signaling pathway members and showed their antiinvasive
potential in vitro. In addition, Si306 and pro-Si306 displayed an anti-invasive effect
against U87 xenografts in the zebrafish embryo model in vivo. Moreover, the tested compounds
were found to inhibit the activity of P-glycoprotein, and enhance the efficacy of paclitaxel in Pglycoprotein
overexpressing cells.
Considering the results of this study, clinical testing of Si306 and pro-Si306 in
glioblastoma with limited treatment options is anticipated in the near future. The prodrug showed
similar efficacy to the drug, implying the rationality of its use in clinical settings.