Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo

Nešović, Marija; Rankov, Aleksandra Divac; Podolski-Renić, Ana; Nikolić, Igor; Tasić, Goran; Mancini, Arianna; Schenone, Silvia; Pešić, Milica; Dinić, Jelena

doi:10.3390/cancers12061570

Cited by 15 publications

(25 citation statements)

References 81 publications

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“…In this study, we aimed to evaluate the pro-oxidative effect of Si306 and pro-Si306 in GBM cells. In addition, our earlier studies showed that Si306 and pro-Si306 were twice as efficient in inhibiting GBM cell growth compared to dasatinib and were equally effective in sensitive and multidrug-resistant GBM cells [20,22,25]. We showed that Si306 and pro-Si306 suppress the activity of P-glycoprotein, a membrane efflux transporter whose overexpression is responsible for glioblastoma resistance to therapy and has an important role in the bloodbrain barrier.…”

Section: Introductionmentioning

confidence: 82%

“…We showed that Si306 and pro-Si306 suppress the activity of P-glycoprotein, a membrane efflux transporter whose overexpression is responsible for glioblastoma resistance to therapy and has an important role in the blood-brain barrier. Si306 and its prodrug also significantly reduced the invasive potential of several primary GBM cultures, as well as GBM xenografts in zebrafish embryo model [25].…”

Section: Introductionmentioning

confidence: 92%

“…Attached cells were grown until confluence prior to further studies. The glioblastoma origin of the established primary culture, named GBM-6, was confirmed as previously described [25]. The passage number of GBM-6 was kept low to prevent genetic and epigenetic changes in cells [28], to ensure the translational potential of obtained results [29].…”

Section: Primary Glioblastoma Culturementioning

confidence: 99%

“…Novel TK inhibitors with pyrazolo [3,4-d]pyrimidine scaffold are ATP-competitive TK inhibitors with good efficacy regarding the inhibition of SFKs [18,19], and their activity against neuroblastoma and glioblastoma has been demonstrated in vitro and in vivo [20][21][22][23][24][25]. Specifically, a pyrazolo [3,4-d]pyrimidine derivative, Si306 (Figure 1), strongly suppressed U87 glioblastoma xenograft growth in nude mice in combination with radiotherapy, and the findings indicated efficient delivery of Si306 to the brain [26].…”

Section: Introductionmentioning

confidence: 99%

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Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells

et al. 2021

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Background: Glioblastoma (GBM) highly expresses Src tyrosine kinase involved in survival, proliferation, angiogenesis and invasiveness of tumor cells. Src activation also reduces reactive oxygen species (ROS) generation, whereas Src inhibitors are able to increase cellular ROS levels. Methods: Pro-oxidative effects of two pyrazolo[3,4-d]pyrimidine derivatives—Src tyrosine kinase inhibitors, Si306 and its prodrug pro-Si306—were investigated in human GBM cells U87 and patient-derived GBM-6. ROS production and changes in mitochondrial membrane potential were assessed by flow cytometry. The expression levels of superoxide dismutase 1 (SOD1) and 2 (SOD2) were studied by Western blot. DNA damage, cell death induction and senescence were also examined in GBM-6 cells. Results: Si306 and pro-Si306 more prominently triggered ROS production and expression of antioxidant enzymes in primary GBM cells. These effects were followed by mitochondrial membrane potential disruption, double-strand DNA breaks and senescence that eventually led to necrosis. Conclusion: Src kinase inhibitors, Si306 and pro-Si306, showed significant pro-oxidative potential in patient-derived GBM cells. This feature contributes to the already demonstrated anti-glioblastoma properties of these compounds in vitro and in vivo and encourages clinical investigations.

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Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 92%

Section: Primary Glioblastoma Culturementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells

et al. 2021

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“…Cells in the logarithmic growth stage were inoculated into 96-well plates in groups and performed as described. 17 For The Transwell migration and invasion assay, the Transwell chamber was pretreated with Matrigel (Corning, NY, United States) and dried at 37 C for 1 hour. Other procedures were the same as for the Transwell migration assay.…”

Section: Methodsmentioning

confidence: 99%

B4GalT1 Regulates Apoptosis and Autophagy of Glioblastoma In Vitro and In Vivo

Wang

Xie

2020

Technol Cancer Res Treat

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Our study was designed to investigate the role of B4GalT1 in glioblastoma, in vitro and in vivo, to detect whether B4GalT1 knockdown could regulate the development of glioblastoma, and further observe the relationship between B4GalT1 knockdown and the apoptosis and autophagy of glioblastoma. To begin, we looked at TCGA and GEPIA systems to predict the potential function of B4GalT1. Western blot and RT-PCR were used to analyze the expression, or mRNA level, of B4GalT1 at different tissue or cell lines. Next, the occurrence and development of glioblastoma, in vitro and in vivo, was observed by using B4GalT1 knocked down by lentivirus. Finally, the apoptosis and autophagy of glioblastoma was observed in vitro and in vivo. Results show that B4GalT1 was a highly variable gene, and GEPIA and TCGA systems show B4GalT1 expression in GBM tumor tissue was higher than in normal tissue. Pair-wise gene correlation analysis revealed a probable relationship between B4GalT1 and autophagy related proteins. The B4GalT1 expression and mRNA level were increased in tumor cells, or U87 cells. B4GalT1 knocked down by lentivirus could inhibit glioblastoma development, in vitro and in vivo, by reducing tumor weight and volume, increasing survival, and weakening tumor cells proliferation, migration, invasion. B4GalT1 knockdown could increase apoptosis and autophagy of glioblastoma in vitro and in vivo. Our study demonstrates that B4GalT1 may be able to regulate apoptosis and autophagy of glioblastoma. Bax, Bcl-2, cleaved caspase-3, Beclin-1, and LC3 s may be the downstream target factors of B4GalT1 in apoptosis and autophagy, which may provide a new strategy to reduce glioblastoma development by regulating apoptosis and autophagy.

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Early investigation of a novel SI306 theranostic prodrug for glioblastoma treatment

Vagaggini,

Petroni,

D'Agostino

et al. 2024

Drug Development Research

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Glioblastoma multiforme (GBM) is one of the most aggressive malignancies with a high recurrence rate and poor prognosis. Theranostic, combining therapeutic and diagnostic approaches, arises as a successful strategy to improve patient outcomes through personalized medicine.Src is a non‐receptor tyrosine kinase (nRTK) whose involvement in GBM has been extensively demonstrated. Our previous research highlighted the effectiveness of the pyrazolo[3,4‐d]pyrimidine SI306 and its more soluble prodrug CMP1 as Src inhibitors both in in vitro and in vivo GBM models.In this scenario, we decided to develop a theranostic prodrug of SI306, ProSI‐DOTA(68Ga) 1, which was designed to target GBM cells after hydrolysis and follow‐up on the disease's progression and improve the therapy's outcome.First, the corresponding nonradioactive prodrug 2 was tested to evaluate its ADME profile and biological activity. It showed good metabolic stability, no inhibition of CYP3A4, suboptimal aqueous solubility, and slight gastrointestinal and blood‐brain barrier passive permeability. Compound 2 exhibited a drastic reduction of cell vitality after 72 h on two different GBM cell lines (GL261 and U87MG). Then, 2 was subjected to complexation with the radionuclide Gallium‐68 to give ProSI‐DOTA(68Ga) 1. The cellular uptake of 1 was evaluated on GBM cells, highlighting a slight but significant time‐dependent uptake. The data obtained from our preliminary studies reflect the physiochemical properties of 1. The use of an alternative route of administration, such as the intranasal route, could overcome the physiochemical limitations and enhance the pharmacokinetic properties of 1, paving the way for its future development.

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Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo

Cited by 15 publications

References 81 publications

Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells

Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells

B4GalT1 Regulates Apoptosis and Autophagy of Glioblastoma In Vitro and In Vivo

Early investigation of a novel SI306 theranostic prodrug for glioblastoma treatment

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