The potential of c-Src inhibitors Si306 and pro-Si306 for suppressing invasion and overcoming multidrug resistance in glioblastoma
2019
Authors:
Nešović, MarijaPodolski-Renić, Ana
Stanković, Tijana
Divac Rankov, Aleksandra
Fallacara, Anna Lucia
Schenone, Silvia
Botta, Maurizio
Pešić, Milica
Dinić, Jelena
Document Type:
Conference object (Published version)
,
© 2019 by the COST Action CM1407
Metadata
Show full item recordAbstract:
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. Cytotoxicity of c-Src inhibitors pyrozolo[3,4-d]pyrimidines, Si306 and its prodrug pro-Si306,
was investigated in human GBM cell line U87 and its multidrug resistant (MDR) counterpart
U87-TxR by MTT assay. Anti-migratory and anti-invasive effects of Si306 and pro-Si306 were
assessed by wound healing, gelatin degradation and transwell invasion assays. The effect of cSrc inhibitors on P-glycoprotein (P-gp) activity in U87-TxR cells was analyzed by flow cytometry. Their ability to reverse paclitaxel resistance in MDR cells was also assessed. Zebrafish model was used to evaluate anti-invasive potential of pro-Si306 on U87 xenografts in vivo. Novel c-Src inhibitors were significantly more efficient in cell growth inhibition compared to the well-known tyrosine kinase inhibitor dasatinib. The efficacy of Si306 and pro-Si306 was not affected by the MDR phenotype.
Migratory potential of U87 and U87-TxR cells was significantly decreased by both inhibitors.
The ability of cells to degrade the matrix and invade through basement membrane was also
significantly impaired upon treatment with Si306 and its prodrug. Assessment of intracellular
accumulation of fluorescent P-gp substrate showed that both compounds inhibited P-gp activity
in U87-TxR cells. Si306 and pro-Si306 also enhanced the paclitaxel efficacy in resistant
glioblastoma. 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 proSi306 could be considered in GBM treatment alone or in combination with other
chemotherapeutics.
Funding / projects:
- Identification of predictive molecular markers for cancer progression, response to therapy and disease outcome (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
In:
- COST Action CM1407: Challenging organic syntheses inspired by naturefrom natural products chemistry to drug discovery: Meeting dedicated to Early career Investigators; 2019 Feb 18-19; Brussels, Belgium. COST Action CM1407; 2019. p. 9.