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lüll The unhydrolyzable fenretinide analogue 4-hydroxybenzylretinone induces the proapoptotic genes GADD153 (CHOP) and Bcl-2-binding component 3 (PUMA) and apoptosis that is caspase- dependent and independent of the retinoic acid receptor Anding AL; Chapman JS; Barnett DW; Curley RW Jr; Clagett-Dame MCancer Res 2007[Jul]; 67 (13): 6270-7The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) induces apoptosis in a variety of cell lines and has shown promise as an anticancer agent both in vitro and in vivo. The clinical dose of 4-HPR, however, is limited by residual-associated toxicities, indicating a need for a less toxic drug. In this study, we show that 4-hydroxybenzylretinone (4-HBR), the unhydrolyzable analogue of 4-HPR, is effective in producing apoptosis in a variety of 4-HPR-sensitive cell lines, including breast cancer, neuroblastoma, and leukemia cells. We also show through the use of a pan-caspase inhibitor that this 4-HBR-induced apoptosis is dependent, at least in part, on caspase activity. 4-HBR is shown to exhibit binding to the retinoic acid receptors (RAR) at concentrations necessary to induce cell death and induces expression of all-trans-retinoic acid-responsive genes that can be blocked by a RAR pan-antagonist. However, through the use of this RAR pan-antagonist, 4-HBR-induced apoptosis and cell death is shown to be independent of the RAR signaling pathway. To further characterize the mechanism of action of 4-HBR, expression of the endoplasmic reticulum stress-induced genes GADD153 and Bcl-2-binding component 3 was examined. These mRNAs are shown to be rapidly induced in 4-HBR-treated and 4-HPR-treated breast cancer cells, and this up-regulation is also shown to be independent of the RARs. These results suggest that a stress-mediated apoptotic cascade is involved in the mechanism of action of these retinoids.|*Apoptosis[MESH]|Apoptosis Regulatory Proteins/*biosynthesis[MESH]|Caspases/metabolism[MESH]|Cell Line, Tumor[MESH]|Cell Proliferation[MESH]|Fenretinide/*analogs & derivatives[MESH]|HL-60 Cells[MESH]|Humans[MESH]|Hydrolysis[MESH]|Leukemia/metabolism[MESH]|Proto-Oncogene Proteins/*biosynthesis[MESH]|RNA, Messenger/metabolism[MESH]|Receptors, Retinoic Acid/*metabolism[MESH]|Retinoids/metabolism[MESH]|Transcription Factor CHOP/*biosynthesis[MESH]|Vitamin A/*analogs & derivatives/pharmacology[MESH] |