c-Src inhibitors pyrozolo[3,4-d]pyrimidines, Si306 and pro-Si306, evade multidrug resistant phenotype and suppress invasion in glioblastoma
2019
Аутори:
Nešović, MarijaPodolski-Renić, Ana
Stanković, Tijana
Divac Rankov, Aleksandra
Nikolić, Igor
Tasić, Goran
Botta, Maurizio
Pešić, Milica
Dinić, Jelena
Остала ауторства
Matić, IvanaĐorđić Crnogorac, Marija
Тип документа:
Конференцијски прилог (Објављена верзија)
,
© 2019 by the Serbian Association for Cancer Research
Метаподаци
Приказ свих података о документуАпстракт:
Background: Glioblastoma multiforme (GBM) are the most frequent and aggressive (WHO
grade IV) brain tumors in adults. GBM have high expression of c-Src tyrosine kinase involved in
survival, migration and invasiveness of tumor cells. Thus, c-Src emerged as a potential target for
GBM therapy. Materials and methods: Antiproliferative effect of c-Src inhibitors pyrozolo[3,4-d]
pyrimidines, Si306 and its prodrug pro-Si306, was assessed in human GBM cell line U87, multidrug
resistant (MDR) U87-TxR, and primary GBM cells by MTT assay. Anti-migratory and anti-invasive
effects of c-Src inhibitors were evaluated by gelatin degradation and transwell invasion assays.
Their effect on c-Src, extracellular signal-related kinase (ERK), and focal adhesion kinase (FAK)
expression was analyzed by western-blot and flow-cytometry. Zebrafish model was used to
evaluate anti-invasive potential of pro-Si306 in U87 xenografts in vivo. Results and conclusions:
c-Src inhibitors were more efficient in cell growth inhibition compared to dasatinib, a well-known tyrosine kinase inhibitor. The potency of Si306 and pro-Si306 was not affected by the
MDR phenotype. Migratory potential of U87, U87-TxR, and primary GBM cells was significantly
decreased by both inhibitors. Si306 and pro-Si306 also compromised cells’ ability to degrade the
matrix and invade through basement membrane. Both compounds reduced phosporylation of
c-Src, and its downstream signaling components, ERK and FAK, in GBM cell lines. In vivo, pro-Si306 showed anti-invasive effect against U87 xenografts in zebrafish model. Considering their
ability to suppress migration and invasion and overcome MDR, Si306 and pro-Si306 could be
considered in GBM treatment alone or in combination with other chemotherapeutics.
Кључне речи:
glioblastoma; multidrug resistance; primary cells; invasion; migrationФинансирање / пројекти:
- Идентификација молекуларних маркера за предикцију прогресије тумора, одговора на терапију и исхода болести (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
У:
- Matić I, Đorđić Crnogorac M, editors. Abstract Book: 4th Congress of the Serbian Association for Cancer Research with International Participation SDIR-4: Bringing Science to Oncology Practice: Where is Serbia?; 2019 Oct 3-5; Belgrade, Serbia. Belgrade: Serbian Association for Cancer Research; 2019. p. 46.