TAE226 Inhibits Human Neuroblastoma Cell Survival

Beierle, Elizabeth A.; Trujillo, Angelica; Nagaram, Abhilasha; Golubovskaya, Vita M.; Cance, William G.; Kurenova, Elena

doi:10.1080/07357900701577475

Cited by 34 publications

(27 citation statements)

References 31 publications

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“…We found significant dose-and time-dependent cytotoxicity of TAE226 in a panel of seven human glioblastoma cell lines. These results are in concordance with previous studies in which TAE226 caused growth inhibition and apoptosis induction in different tumor entities such as glioblastoma (7), neuroblastoma (28), head and neck squamous cell carcinoma (HNSCC) (21,23), esophageal tumors (29) and breast cancer (30). However, monotherapy using a FAK inhibitor is unlikely to occur in the clinic and, thus, knowledge concerning the radiosensitizing potential of TAE226 is of great relevance.…”

Section: Discussionsupporting

confidence: 81%

Cytotoxic and radiosensitizing effects of FAK targeting in human glioblastoma cells in vitro

2015

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Abstract. Glioblastoma multiforme (GBM) is a highly aggressive and extremely lethal cancer and novel molecular therapies are required for optimized multimodal therapy regimes. While focal adhesion kinase (FAK) is regarded as a therapeutic target, its radiosensitizing potential remains to be elucidated in glioblastoma. Thus, FAK was inhibited using the pharmaco logical inhibitor TAE226 and cytotoxicity and radiosensitization of glioblastoma cells were investigated in vitro. Monolayer and suspension cell cultures of a panel of glioblastoma cell lines (A172, LN229, U87MG, U138MG, U343MG, DD-HT7607, and DD-T4) were treated with increasing TAE226 concentrations (0-10 µM) alone or in combination with X-rays (0-6 Gy). Subsequently, clonogenic cell survival, expression and the phosphorylation of FAK downstream signaling, apoptosis and autophagy were analyzed. Efficient FAK inhibition by TAE226 mediated significant cytotoxicity and reduced sphere formation in a dose-and time-dependent manner. Two out of seven glioblastoma cell lines showed radiosensitization. Apoptotic induction by TAE226 was cell line-dependent. The results demonstrated that pharmacological FAK inhibitor TAE226 efficiently reduced clonogenicity and sphere formation in glioblastoma cells without generally modifying their radiosensitivity. However, future studies are necessary to define the potential of FAK inhibition by TAE226 or other pharmacological inhibitors in combination with radiochemotherapy.

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Section: Discussionsupporting

confidence: 81%

Cytotoxic and radiosensitizing effects of FAK targeting in human glioblastoma cells in vitro

2015

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“…Importantly, TAE226 treatment significantly increased the animal survival in an intracranial glioma xenograft model. In cultured human neuroblastoma cell lines [163], TAE226 treatment resulted in a dose-dependent decrease in FAK phosphorylation and cell viability, and induced cell cycle arrest and apoptosis. In cultured breast cancer cell lines [164], TAE226 treatment induced a dosedependent cell detachment and apoptosis.…”

Section: Targeting Fak Using Specific Small Molecule Inhibitorsmentioning

confidence: 99%

“…The activity of TAE226 has been assessed in human glioma [161,162], neuroblastoma [163], breast [164], ovarian [165] and esophageal [166] cancer cell lines. In glioma cell lines [162,167], TAE226 inhibited ECM-induced autophosphorylation of FAK and IGF-I-induced phosphorylation of IGF-IR and activity of the downstream MAPK, Akt or S6K.…”

Section: Targeting Fak Using Specific Small Molecule Inhibitorsmentioning

confidence: 99%

Signal transduction by focal adhesion kinase in cancer

Zhao

Guan

2009

Cancer Metastasis Rev

546

501

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Cellular interactions with extracellular matrix play essential roles in tumor initiation, progression and metastasis. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase identified as a key mediator of signaling by integrins, a major family of cell surface receptors for extracellular matrix, as well as other receptors in both normal and cancer cells. FAK is activated by integrins through disruption of an auto-inhibitory intra-molecular interaction between its kinase domain and the amino terminal FERM domain. The activated FAK forms a binary complex with Src family kinases which can phosphorylate other substrates and trigger multiple intracellular signaling pathways to regulate various cellular functions. Subcellular localization of FAK in focal adhesions is essential for FAK signaling, which is another distinguishing feature of the kinase. Integrin-FAK signaling has been shown to activate a number of signaling pathways through phosphorylation and protein-protein interactions to promote tumorigenesis. FAK also plays a prominent role in tumor progression and metastasis through its regulation of both cancer cells and their microenvironments including cancer cell migration, invasion, epithelial to mesenchymal transition, and angiogenesis. More recently, a role for FAK in tumor initiation and progression has been demonstrated directly using xenograft as well as conditional knockout mouse models. In agreement with these experimental data, overexpression and activation of FAK have been found in a variety of human cancers. A number of small molecule inhibitors for FAK have been developed and in various phases of testing for cancer treatments. Overall, the intensive research on FAK signaling in cancer have yielded a wealth of information on this pivotal kinase and these and future studies are leading to potentially novel therapies for cancer.

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“…Recently, the same group also provided data indicating greater in vivo-therapeutic efficacy of pharmacologic FAK inhibition in N-mycpositive model systems (Beierle et al, 2010a;Beierle et al, 2010b). Efficacy of a novel small molecule dual IGF1R/FAK tyrosine kinase inhibitor (TAE226) leading to decreased FAK phosphorylation and cellular viability, cell cycle arrest and apoptosis has been described in human neuroblastoma cell lines (Beierle et al, 2008b). FAK expression was demonstrated in 51 of 70 clinical neuroblastoma samples by immunohistochemistry.…”

Section: Nervous Systemmentioning

confidence: 99%