R428 is a potent and selective inhibitor of Axl (IC50 = 14 nM) with antiproliferative activity (Holland et al.). Axl is a receptor tyrosine kinase that is involved in cell survival, proliferation, adhesion, and migration (Chen et al.). R428 exhibits over 100-fold selectivity for Axl over insulin receptor, epidermal growth factor receptor, human epidermal growth factor receptor 2, and platelet-derived growth factor receptor β (Holland et al.).
DIFFERENTIATION
· Inhibits preadipocyte differentiation into mature adipocytes (Lijnen et al.).
· Induces beta cell maturation from human induced pluripotent stem cells (Kushner et al.; Yabe et al.).
CANCER RESEARCH
· Inhibits Axl expression and breast cancer cell metastasis (Holland et al.).
· Blocks lysosomal acidification and induces apoptosis in cancer cells (Chen et al.).
DIFFERENTIATION
· Inhibits preadipocyte differentiation into mature adipocytes (Lijnen et al.).
· Induces beta cell maturation from human induced pluripotent stem cells (Kushner et al.; Yabe et al.).
CANCER RESEARCH
· Inhibits Axl expression and breast cancer cell metastasis (Holland et al.).
· Blocks lysosomal acidification and induces apoptosis in cancer cells (Chen et al.).
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Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
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Resources and Publications
Educational Materials (2)
Publications (5)
Induction of functional islet-like cells from human iPS cells by suspension culture. Regenerative therapy 2019 jun
Abstract
Introduction To complement islet transplantation for type1 diabetic patients, cell-based therapy using pluripotent stem cells such as ES cells and iPS cells is promising. Many papers have already reported the induction of pancreatic $\beta$ cells from these cell types, but a suspension culture system has not usually been employed. The aim of this study is to establish a suspension culture method for inducing functional islet-like cells from human iPS cells. Methods We used 30 ml spinner type culture vessels for human iPS cells throughout the differentiation process. Differentiated cells were analyzed by immunostaining and C-peptide secretion. Cell transplantation experiments were performed with STZ-induced diabetic NOD/SCID mice. Blood human C-peptide and glucagon levels were measured serially in mice, and grafts were analyzed histologically. Results We obtained spherical pancreatic beta-like cells from human iPS cells and detected verifiable amounts of C-peptide secretion in vitro. We demonstrated reversal of hyperglycemia in diabetic model mice after transplantation of these cells, maintaining non-fasting blood glucose levels along with the human glycemic set point. We confirmed the secretion of human insulin and glucagon dependent on the blood glucose level in vivo. Immunohistological analysis revealed that grafted cells became $\alpha$, $\beta$ and $\delta$ cells in vivo. Conclusions These results suggest that differentiated cells derived from human iPS cells grown in suspension culture mature and function like pancreatic islets in vivo.
Axl inhibitor R428 induces apoptosis of cancer cells by blocking lysosomal acidification and recycling independent of Axl inhibition. American journal of cancer research 2018
Abstract
R428 (BGB324) is an anti-cancer drug candidate under clinical investigation. It inhibits the receptor tyrosine kinase Axl and induces apoptosis of many types of cancer cells, but the relationship between the two has not been well established. We investigated the molecular mechanisms of the R428-induced apoptosis and found that R428 induced extensive cytoplasmic vacuolization and caspase activation, independent of its inhibitory effects on Axl. Further analyses revealed that R428 blocked lysosomal acidification and recycling, accumulated autophagosomes and lysosomes, and induced cell apoptosis. Inhibition of autophagy by autophagy inhibitors or autophagic gene-knockout alleviated the R428-induced vacuoles formation and cell apoptosis. Our study uncovered a novel function and mechanism of R428 in addition to its ability to inhibit Axl. These data will help to better direct the application of R428 as an anti-cancer reagent. It also adds new knowledge to understand the regulation of autophagy and apoptosis.
Stem cells to insulin secreting cells: two steps forward and now a time to pause? Cell stem cell 2014 nov
Abstract
Two groups recently reported the in vitro differentiation of human embryonic stem cells into insulin-secreting cells, achieving an elusive goal for regenerative medicine. Herein we provide a perspective regarding these developments, compare phenotypes of the insulin-containing cells to human $\beta$ cells, and discuss implications for type 1 diabetes research and clinical care.
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