Inhibition of both focal adhesion kinase and fibroblast growth factor receptor 2 pathways induces anti-tumor and anti-angiogenic activities

Dao, Pascal; Jarray, Rafika; Smith, Nikaïa; Lepelletier, Yves; Coq, Johanne Le; Lietha, Daniel; Hadj-Slimane, Réda; Herbeuval, Jean-Philippe; Garbay, Christiane; Raynaud, Françoise; Chen, Huixiong

doi:10.1016/j.canlet.2014.03.007

Cited by 20 publications

(14 citation statements)

References 41 publications

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“…Anti-apoptosis is the typical characteristic for the cancer cells, therefore, induction of cancer cell apoptosis is a key end for developing antitumor drugs ( 26 ). Therefore, this study observed the nucleus morphology of the SMMC-7721 cells, and the nucleus illustrated as fragmentary and polymorphonuclear in 20, 40 µmol/l berbamine treatment, which suggests that the classical apoptotic morphology was appeared in the berbamine treatment cells.…”

Section: Discussionmentioning

confidence: 99%

Berbamine induces SMMC-7721 cell apoptosis via upregulating p53, downregulating survivin expression and activating mitochondria signaling pathway

Cao

Wang

et al. 2017

Exp Ther Med

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Hepatocellular carcinoma (HCC) is a primary malignancy in the liver, which is a global health problem. The present study aimed to observe the apoptotic effects of berbamine on SMMC-7721 cell lines and to investigate the effects of berbamine on induction of the intrinsic apoptotic pathway. The human HCC SMMC-7721 cells were cultured and cell morphology observed using a phase contrast microscope. SMMC-7721 cell apoptosis was examined by employing a flow cytometry assay. The nuclei of SMMC-7721 cells were stained with DAPI and observed by utilizing a laser fluorescence microscope. Cytochrome c (Cyto c) levels were evaluated by using immunofluorescence staining. The reverse transcription-semi-quantitative polymerase chain reaction (RT-sqPCR) and western blot analysis were used to examine the mRNA and protein levels of B-cell lymphoma 2, (Bcl-2), Bax, Bcl-2-associated X, apoptosis regulator, p53 and survivin, respectively. Berbamine inhibited SMMC-7721 cell growth at 20 and 0 µmol/l, compared with control group (0 µmol/l berbamine). DAPI results demonstrated that berbamine affected the nucleus morphology of SMMC-7721 cells. Berbamine at a concentration of 20 µmol/l (P<0.05) and 40 µmol/l (P<0.01) significantly enhanced apoptosis rate compared with control group. Berbamine triggered Cyto c release from SMMC-7721 cell nuclei to the cytoplasm. Berbamine (10, 20, 40 µmol/l) significantly enhanced Bax and p53 levels and decreased Bcl-2 and survivin levels compared with control group, according to RT-sqPCR and western blot assay findings. In conclusion, berbamine induced SMMC-7721 cell apoptosis, through upregulating p53 expression and downregulating survivin expression, which further triggered mitochondria signaling pathway-mediated apoptosis.

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Section: Discussionmentioning

confidence: 99%

Berbamine induces SMMC-7721 cell apoptosis via upregulating p53, downregulating survivin expression and activating mitochondria signaling pathway

Cao

Wang

et al. 2017

Exp Ther Med

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“…In particular, we noticed that FAK contains a cysteine residue in the Glycine-rich loop region closer to the ATP site, a feature which is not observed in most of other human kinases ( Figure 1A). The distance between Cys427 and a reversible inhibitor, such as TAE226 (PDB ID: 2JKK) 14 or PHM16 (PDB ID: 4BRX) 15 in the ATP binding site is less than 10 Å ( Figure 1B).…”

Section: Design Of Irreversible Covalent Inhibitorsmentioning

confidence: 99%

Structure-Based Design, Synthesis, and Characterization of the First Irreversible Inhibitor of Focal Adhesion Kinase

Yen‐Pon

Acebrón-García-de-Eulate

et al. 2018

ACS Chem. Biol.

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Focal Adhesion Kinase signaling pathway and its functions have been involved in the development and aggressiveness of tumor malignancy, it then presents a promising cancer therapeutic target. Several reversible FAK inhibitors have been developed and are being conducted in clinical trials. On the other hand, irreversible covalent inhibitors would bring many desirable pharmacological features including high potency and increased duration of action. Herein we report the structure-guided development of the first highly potent and irreversible inhibitor of the FAK kinase. This inhibitor showed a very potent decrease of autophosphorylation of FAK in squamous cell carcinoma. A cocrystal structure of the FAK kinase domain in complex with this compound revealed the inhibitor binding mode within the ATP binding site and confirmed the covalent linkage between the targeted Cys427 of the protein and the inhibitor.

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“…3B). Tube formation is a key step for angiogenesis in vitro 26, 27 . To investigate the angiogenic effect of 5%CS/β-TCP scaffolds on HUVECs, cells were seeded on Matrigel in the lower chamber with 5%CS/β-TCP or β-TCP in transwell inserts.…”

Section: Resultsmentioning

confidence: 99%

3D printed scaffolds of calcium silicate-doped β-TCP synergize with co-cultured endothelial and stromal cells to promote vascularization and bone formation

Deng

Jiang

et al. 2017

Sci Rep

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Synthetic bone scaffolds have potential application in repairing large bone defects, however, inefficient vascularization after implantation remains the major issue of graft failure. Herein, porous β-tricalcium phosphate (β-TCP) scaffolds with calcium silicate (CS) were 3D printed, and pre-seeded with co-cultured human umbilical cord vein endothelial cells (HUVECs) and human bone marrow stromal cells (hBMSCs) to construct tissue engineering scaffolds with accelerated vascularization and better bone formation. Results showed that in vitro β-TCP scaffolds doped with 5% CS (5%CS/β-TCP) were biocompatible, and stimulated angiogenesis and osteogenesis. The results also showed that 5%CS/β-TCP scaffolds not only stimulated co-cultured cells angiogenesis on Matrigel, but also stimulated co-cultured cells to form microcapillary-like structures on scaffolds, and promoted migration of BMSCs by stimulating co-cultured cells to secrete PDGF-BB and CXCL12 into the surrounding environment. Moreover, 5%CS/β-TCP scaffolds enhanced vascularization and osteoinduction in comparison with β-TCP, and synergized with co-cultured cells to further increase early vessel formation, which was accompanied by earlier and better ectopic bone formation when implanted subcutaneously in nude mice. Thus, our findings suggest that porous 5%CS/β-TCP scaffolds seeded with co-cultured cells provide new strategy for accelerating tissue engineering scaffolds vascularization and osteogenesis, and show potential as treatment for large bone defects.

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Inhibition of both focal adhesion kinase and fibroblast growth factor receptor 2 pathways induces anti-tumor and anti-angiogenic activities

Cited by 20 publications

References 41 publications

Berbamine induces SMMC-7721 cell apoptosis via upregulating p53, downregulating survivin expression and activating mitochondria signaling pathway

Berbamine induces SMMC-7721 cell apoptosis via upregulating p53, downregulating survivin expression and activating mitochondria signaling pathway

Structure-Based Design, Synthesis, and Characterization of the First Irreversible Inhibitor of Focal Adhesion Kinase

3D printed scaffolds of calcium silicate-doped β-TCP synergize with co-cultured endothelial and stromal cells to promote vascularization and bone formation

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