Pyrazolo[3,4-d]pyrimidine derivatives, Si306 and pro-Si306, inhibit the growth of sensitive and multidrug resistant glioblastoma
2020
Authors:
Dinić, JelenaPodolski-Renić, Ana
Nešović, Marija
Stepanović, Ana
Divac Rankov, Aleksandra
Dragoj, Miodrag
Nikolić, Igor
Tasić, Goran
Pešić, Milica
Document Type:
Conference object (Published version)
,
© 2020 by the COST Action CA17104
Metadata
Show full item recordAbstract:
Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. Main characteristics of GBM include high
proliferation rate, infiltrating nature, and resistance to chemotherapy and radiation. GBM have high expression of c-Src
tyrosine kinase which has a key role in regulating survival, proliferation, angiogenesis and invasiveness of tumor cells. Thus,
c-Src emerged as a potential target for GBM therapy. Anticancer properties of c-Src tyrosine kinase inhibitors Si306 and its
prodrug pro-Si306, pyrazolo[3,4-d]pyrimidines were assessed in human GBM cell line U87, its multidrug resistant (MDR)
counterpart U87-TxR, and human primary GBM culture. Si306 and pro-Si306 triggered ROS generation and DNA damage
in sensitive and MDR GBM cell lines, as well as primary GBM cells. Both compounds induced a prominent cell death in
primary GBM culture, while the effect on GBM cell lines was predominantly antiproliferative, characterized by decrease in
Ki-67 expression and cell cycle disturbance. Moreover, the investigated compounds made primary GBM culture more prone
to anoikis. In addition, Si306 and pro-Si306 showed strong antiproliferative effect in U87 xenografts in zebrafish embryo
model. The antiglioblastoma effects of investigated c-Src inhibitors were more prominent when compared to dasatinib, a
well-known tyrosine kinase inhibitor. The presence of the MDR phenotype did not diminish the activity of the compounds.
The investigated pyrazolo[3,4-d]pyrimidines displayed significant anticancer potential in GBM which makes them good
candidates for further development regarding treatment of this cancer type.
In:
- Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug resistant tumours: Annual conference 3rd MC meeting and 4th WGs meeting; 2020 Feb 27-28; Belgrade, Serbia. COST Action CA17104; 2020. p. 35.