Synergistic effect of STAT3‑targeted small interfering RNA and AZD0530 against glioblastoma in�vitro and in�vivo

Liu, Qingjun; Wang, Leibo; Li, David; Zhao, Jingxia; Shen, Chen; Li, Jialin

doi:10.3892/mmr.2019.10596

Cited by 3 publications

(4 citation statements)

References 34 publications

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“…Pre-clinical trials from 2018, 2019, and 2023 testing new formulations with saracatinib in clear-cell renal carcinoma (ccRCCs) [80], glioblastoma [81], and castration-resistant prostate cancer (CRPC) [82], respectively, were also performed. Specifically, combined therapy with saracatinib and GDC-0941 (an inhibitor of PI3K) inhibits cell growth, and invasion, and promotes cell death in renal tumour cell lines [80].…”

Section: Saracatinib Returns To Cancer Treatmentmentioning

confidence: 99%

“…Specifically, combined therapy with saracatinib and GDC-0941 (an inhibitor of PI3K) inhibits cell growth, and invasion, and promotes cell death in renal tumour cell lines [80]. For glioblastoma, in vitro and in vivo trials demonstrated that a combination of Lentivirus vectors containing siRNAtargeted STAT3 (LV-STAT3 siRNA) and AZD0530 has a synergistic effect, inhibiting proliferation and inducing the apoptosis of glioblastoma cells and tumour size reduction [81]. Encouraging in vitro results were also produced in the pre-clinical trial performed in CRPC cells, where the combined therapy of saracatinib and enzalutamide (a second-generation hormonal drug given to men with CRPR) resulted in a reduction in DNA replication and the subsequent increase of apoptosis in a subset of CRPC cells, including those positive for androgen receptor-full length and androgen receptor splice variants (AR-FL+/AR-V+) [82].…”

Section: Saracatinib Returns To Cancer Treatmentmentioning

confidence: 99%

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Dual Drug Repurposing: The Example of Saracatinib

Ramos,

Vale

2024

IJMS

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Saracatinib (AZD0530) is a dual Src/Abl inhibitor initially developed by AstraZeneca for cancer treatment; however, data from 2006 to 2024 reveal that this drug has been tested not only for cancer treatment, but also for the treatment of other diseases. Despite the promising pre-clinical results and the tolerability shown in phase I trials, where a maximum tolerated dose of 175 mg was defined, phase II clinical data demonstrated a low therapeutic action against several cancers and an elevated rate of adverse effects. Recently, pre-clinical research aimed at reducing the toxic effects and enhancing the therapeutic performance of saracatinib using nanoparticles and different pharmacological combinations has shown promising results. Concomitantly, saracatinib was repurposed to treat Alzheimer’s disease, targeting Fyn. It showed great clinical results and required a lower daily dose than that defined for cancer treatment, 125 mg and 175 mg, respectively. In addition to Alzheimer’s disease, this Src inhibitor has also been studied in relation to other health conditions such as pulmonary and liver fibrosis and even for analgesic and anti-allergic functions. Although saracatinib is still not approved by the Food and Drug Administration (FDA), the large number of alternative uses for saracatinib and the elevated number of pre-clinical and clinical trials performed suggest the huge potential of this drug for the treatment of different kinds of diseases.

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Section: Saracatinib Returns To Cancer Treatmentmentioning

confidence: 99%

Section: Saracatinib Returns To Cancer Treatmentmentioning

confidence: 99%

Dual Drug Repurposing: The Example of Saracatinib

Ramos,

Vale

2024

IJMS

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“…For example, AZD0530 is a dual inhibitor of Src family kinases/Abl, inhibiting Src activation and preventing cell growth by inducing G1/S cell cycle arrest (Nygaard et al, 2015). The combined treatment of LV-STAT3 siRNA and AZD0530 shows better effects in inhibiting the proliferation and inducing the apoptosis of GBM cells than using LV-STAT3 siRNA or AZD0530 alone (Liu et al, 2019). Similarly, Pang and colleagues used self-assembling fluorescent virus-like particle/RNAi nano-complexes to downregulate the hepatocyte growth factor receptor gene, inhibiting the DNA repair mechanism.…”

Section: Co-delivery Of Small Interfering Rna and Anti-cancer Compoundsmentioning

confidence: 99%

Small Interfering RNA for Gliomas Treatment: Overcoming Hurdles in Delivery

Teng

et al. 2022

Front. Cell Dev. Biol.

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Gliomas are central nervous system tumors originating from glial cells, whose incidence and mortality rise in coming years. The current treatment of gliomas is surgery combined with chemotherapy or radiotherapy. However, developing therapeutic resistance is one of the significant challenges. Recent research suggested that small interfering RNA (siRNA) has excellent potential as a therapeutic to silence genes that are significantly involved in the manipulation of gliomas’ malignant phenotypes, including proliferation, invasion, metastasis, therapy resistance, and immune escape. However, it is challenging to deliver the naked siRNA to the action site in the cells of target tissues. Therefore, it is urgent to develop delivery strategies to transport siRNA to achieve the optimal silencing effect of the target gene. However, there is no systematic discussion about siRNAs’ clinical potential and delivery strategies in gliomas. This review mainly discusses siRNAs’ delivery strategies, especially nanotechnology-based delivery systems, as a potential glioma therapy. Moreover, we envisage the future orientation and challenges in translating these findings into clinical applications.

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“…A combined therapy increased the apoptotic rate of GBM cells in vitro and decreased tumor growth in vivo more efficiently as compared with the single treatments. However, saracatinib in vivo was less effective, possibly because of drug metabolism and tumor drug resistance, highlighting how much more needs to be done to improve drug therapy [ 115 ].…”

Section: Targeting Src In Glioblastomamentioning

confidence: 99%

SRC Kinase in Glioblastoma: News from an Old Acquaintance

Cirotti

Contadini

Barilá

2020

Cancers

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Glioblastoma multiforme (GBM) is one of the most recalcitrant brain tumors characterized by a tumor microenvironment (TME) that strongly supports GBM growth, aggressiveness, invasiveness, and resistance to therapy. Importantly, a common feature of GBM is the aberrant activation of receptor tyrosine kinases (RTKs) and of their downstream signaling cascade, including the non-receptor tyrosine kinase SRC. SRC is a central downstream intermediate of many RTKs, which triggers the phosphorylation of many substrates, therefore, promoting the regulation of a wide range of different pathways involved in cell survival, adhesion, proliferation, motility, and angiogenesis. In addition to the aforementioned pathways, SRC constitutive activity promotes and sustains inflammation and metabolic reprogramming concurring with TME development, therefore, actively sustaining tumor growth. Here, we aim to provide an updated picture of the molecular pathways that link SRC to these events in GBM. In addition, SRC targeting strategies are discussed in order to highlight strengths and weaknesses of SRC inhibitors in GBM management, focusing our attention on their potentialities in combination with conventional therapeutic approaches (i.e., temozolomide) to ameliorate therapy effectiveness.

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Synergistic effect of STAT3‑targeted small interfering RNA and AZD0530 against glioblastoma in�vitro and in�vivo

Cited by 3 publications

References 34 publications

Dual Drug Repurposing: The Example of Saracatinib

Dual Drug Repurposing: The Example of Saracatinib

Small Interfering RNA for Gliomas Treatment: Overcoming Hurdles in Delivery

SRC Kinase in Glioblastoma: News from an Old Acquaintance

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