Showing papers on "Growth factor receptor inhibitor published in 2018"

Connective tissue growth factor induces renal fibrosis via epidermal growth factor receptor activation

Abstract: Connective tissue growth factor (CCN2/CTGF) is a matricellular protein that is overexpressed in progressive human renal diseases, mainly in fibrotic areas. In vitro studies have demonstrated that CCN2 regulates the production of extracellular matrix (ECM) proteins and epithelial-mesenchymal transition (EMT), and could therefore contribute to renal fibrosis. CCN2 blockade ameliorates experimental renal damage, including diminution of ECM accumulation. We have reported that CCN2 and its C-terminal degradation product CCN2(IV) bind to epidermal growth factor receptor (EGFR) to modulate renal inflammation. However, the receptor involved in CCN2 profibrotic actions has not been described so far. Using a murine model of systemic administration of CCN2(IV), we have unveiled a fibrotic response in the kidney that was diminished by EGFR blockade. Additionally, in conditional CCN2 knockout mice, renal fibrosis elicited by folic acid-induced renal damage was prevented, and this was linked to inhibition of EGFR pathway activation. Our in vitro studies demonstrated a direct effect of CCN2 via the EGFR pathway on ECM production by fibroblasts and the induction of EMT in tubular epithelial cells. Our studies clearly show that the EGFR regulates CCN2 fibrotic signalling in the kidney, and suggest that EGFR pathway blockade could be a potential therapeutic option to block CCN2-mediated profibrotic effects in renal diseases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Role of fibroblast growth factor receptor-2 splicing in normal and cancer cells.

Abstract: Types 1-4 of fibroblast growth factor receptors (FGFR) are all expressed in various cancers Because of its prominent role in carcinogenesis and cancer progression, FGFR-2, is being considered as a novel target in cancer treatment Owing to the alternative splicing of its extracellular domain, FGFR-2 exists in two variants: IIIb and IIIc FGFR-2 IIIb is mainly expressed in normal epithelial cells, as well as in oral mucosal, esophageal, gastric, colorectal, pancreatic, pulmonary, breast, endometrial, cervical, and prostate cancers The IIIc variant of FGFR is expressed in mesenchymal cells, and during epithelial-mesenchymal transition (EMT), is expressed in colorectal, pancreatic, bladder, cervical, and prostate cancers The FGFR IIIb and IIIc variants bind different forms of FGFs and exert autocrine and/or paracrine effects in cancers Recent reports indicate that switching from IIIb to IIIc variants correlates with the aggressiveness of the cancers via EMT Here, we discuss the expression, role, and regulatory mechanisms of IIIb and IIIc variants of FGFR in cancers

TGF-β1 promotes cell barrier function upon maturation of corneal endothelial cells.

Abstract: Human corneal endothelial cells (HCECs) easily become fibroblastic-like when cultured, rendering them unsuitable for tissue engineering of the cornea. Transforming growth factor β (TGF-β) could be a key factor in this phenomenon; however, TGF-β is also known to maintain the endothelium in a quiescent state in vivo. This work aimed to compare the effects of TGF-β1 on the phenotype of HCECs during the proliferation and maturation phases. Our results show that addition of TGF-β1 during the active proliferation phase produced fibroblastic HCECs and loss of the cell junction markers ZO-1 and n-cadherin, independent from the presence of epidermal growth factor (EGF). By contrast, addition of TGF-β1 in maturation media containing few mitogens led to an endothelial phenotype and functional cell junctions as HCECs developed a high trans-endothelial resistance. Furthermore, addition of AG-1478, an epithelial growth factor receptor inhibitor, enhanced the gain of the endothelial phenotype and cell barrier function. Overall, these results show that TGF-β1 can be used to promote the formation of a typical leaky endothelial barrier during the maturation phase of cultured HCECs. A two-phase culture of HCECs using distinct proliferation and maturation media could also be key for developing ideal HCEC culture conditions.

Inhibition of epidermal growth factor receptor by ferulic acid and 4-vinylguaiacol in human breast cancer cells

Abstract: To examine the potential of ferulic acid and 4-vinylguaiacol for inhibiting epidermal growth factor receptor (EGFR) in human breast cancer cells in vitro. Ferulic acid and 4-vinylguaiacol limit the EGF (epidermal growth factor)-induced breast cancer proliferation and new DNA synthesis. Western blot analysis revealed both ferulic acid and 4-vinylguaiacol exhibit sustained inhibition of EGFR activation through down-regulation of Tyr 1068 autophosphorylation. Molecular docking analysis shows ferulic acid forming hydrogen bond interaction with Lys 745 and Met 793 whereas, 4-vinylguaiacol forms two hydrogen bonds with Phe 856 and exhibits stronger hydrophobic interactions with multiple amino acid residues at the EGFR kinase domain. Ferulic acid and 4-vinylguaiacol could serve as a potential structure for the development of new small molecule therapeutics against EGFR.

Histological transformation after acquired resistance to epidermal growth factor tyrosine kinase inhibitors.

Abstract: Non-small-cell lung cancer patients with sensitive epidermal growth factor receptor mutations generally respond well to tyrosine kinase inhibitors (TKIs). However, acquired resistance will eventually develop place after 8–16 months. Several mechanisms contribute to the resistance including T790M mutation, c-Met amplification, epithelial mesenchymal transformation and PIK3CA mutation; however, histological transformation is a rare mechanism. The patterns and mechanisms underlying histological transformation need to be explored. We searched PubMed, EMBASE and search engines Google Scholar, Medical Matrix for literature related to histological transformation. Case reports, cases series, and clinical and basic medical research articles were reviewed. Sixty-one articles were included in this review. Cases of transformation to small-cell lung cancer, squamous cell carcinoma, large-cell neuroendocrine carcinoma and sarcoma after TKI resistance have all been reported. As the clinical course differed dramatically between cases, a new treatment scheme needs to be recruited. The mechanisms underlying histological transformation have not been fully elucidated and probably relate to cancer stem cells, driver genetic alterations under selective pressure or the heterogeneity of the tumor. When TKI resistance develops, we recommend that patients undergo a second biopsy to determine the reason, guide the next treatment and predict the prognosis.

In silico evaluation of the resistance of the T790M variant of epidermal growth factor receptor kinase to cancer drug Erlotinib.

Abstract: Epidermal growth factor receptor kinase is implicated in cancer development due to either overexpression or activation variants in its functional intracellular kinase domain. Threonine to methionin...

Reversible Macular Lesions in the Setting of Oral Pan-Fibroblast Growth Factor Inhibitor for the Treatment of Bladder Cancer:

Abstract: The tyrosine kinase inhibitor, JNJ-42756493, is an oral pan-fibroblast growth factor receptor inhibitor being studied as an antineoplastic agent. It is currently the subject of a phase II clinical ...

Analysis and Prospect of Targeted Therapy for Head and Neck Tumors

Abstract: Head and neck tumors account for 30% of malignant tumors in the body, which is a key topic in the world. The comparative data of radiotherapy, surgical therapy or chemotherapy for the treatment of these diseases are given. The treatment of epidermal growth factor receptor inhibitor, cyclin dependent kinase inhibitor and insulin-like growth factor receptor inhibitor were analyzed. It is pointed out that molecular targeted therapy is a targeted blocker to interfere with the signal transduction pathway, which is regulated by the specific molecule and is closely related to the occurrence of tumor, so as to inhibit tumor growth and metastasis.

Growth Factors and Cytokines

Abstract: Growth factors and cytokines. The initial discussion is on the prospects for the cytokine TRAIL and ovarian cancer. Ensuing topics are: TRAIL and its mechanism, the tumor necrosis superfamily, platelet-derived growth factor, epidermal growth factor, transforming growth factor, fibroblast growth factor, neurotrophins and nerve growth factor, colony stimulating factor, erythropoietin, interferon, insulin-like growth factors, and overview. The chapter ends with a summary, a list of references, review multiple-choice questions and a case-based problem.

Method for preparing platelet-derived growth factor receptor inhibitor AG1296

Abstract: The invention discloses a method for preparing a platelet-derived growth factor receptor inhibitor AG1296. The inhibitor is synthesized by taking 3-(3,4-dimethoxyphenylamino)-3-phenyl-acrylate as a raw material. According to the method disclosed by the invention, the synthesizing cost of the AG1296 can be greatly reduced, and the method has wide popularization and application prospects.