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lüll Enhancing mda-7/IL-24 therapy in renal carcinoma cells by inhibiting multiple protective signaling pathways using sorafenib and by Ad 5/3 gene delivery Eulitt PJ; Park MA; Hossein H; Cruikshanks N; Yang C; Dmitriev IP; Yacoub A; Curiel DT; Fisher PB; Dent PCancer Biol Ther 2010[Dec]; 10 (12): 1290-305We have determined whether an adenovirus that comprises the tail and shaft domains of a serotype 5 virus and the knob domain of a serotype 3 virus expressing MDA-7/IL-24, Ad.5/3-mda-7, more effectively infects and kills renal carcinoma cells (RCCs) compared to a serotype 5 virus, Ad.5-mda-7. RCCs are a tumor cell type that generally does not express the receptor for the type 5 adenovirus; the coxsackie and adenovirus receptor (CAR). Ad.5/3-mda-7 infected RCCs to a much greater degree than Ad.5-mda-7. MDA-7/IL-24 protein secreted from Ad.5/3-mda-7-infected RCCs induced MDA-7/IL-24 expression and promoted apoptosis in uninfected "bystander" RCCs. MDA-7/IL-24 killed both infected and bystander RCCs via CD95 activation. Knockdown of intracellular MDA-7/IL-24 in uninfected RCCs blocked the lethal effects of conditioned media. Infection of RCC tumors in one flank, with Ad.5/3-mda-7, suppressed growth of infected tumors and reduced the growth rate of uninfected tumors implanted on the opposite flank. The toxicity of the serotype 5/3 recombinant adenovirus to express MDA-7/IL-24 was enhanced by combined molecular or small molecule inhibition of MEK1/2 and PI3K; inhibition of mTOR, PI3K and MEK1/2; or use of the multi-kinase inhibitor sorafenib. In RCCs, combined inhibition of cytoprotective cell signaling pathways enhanced the MDA-7/IL-24-induction of CD95 activation, with greater mitochondrial dysfunction due to loss of MCL-1 and BCL-XL expression, and tumor cell death. Treatment of RCC tumors in vivo with sorafenib also enhanced Ad.5/3-mda-7 toxicity and prolonged animal survival. Future combinations of these approaches hold promise for developing a more effective therapy for kidney cancer.|*Genetic Therapy[MESH]|Adenoviridae/*genetics[MESH]|Animals[MESH]|Apoptosis[MESH]|Benzenesulfonates/immunology/*therapeutic use[MESH]|Blotting, Western[MESH]|Carcinoma, Renal Cell/*therapy[MESH]|Cell Line, Tumor[MESH]|Culture Media, Conditioned[MESH]|Gene Knockdown Techniques[MESH]|Gene Transfer Techniques[MESH]|Humans[MESH]|Interleukins/*genetics[MESH]|Kidney Neoplasms/*therapy[MESH]|Mice[MESH]|Mitochondria/metabolism[MESH]|Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism[MESH]|Niacinamide/analogs & derivatives[MESH]|Phenylurea Compounds[MESH]|Phosphoinositide-3 Kinase Inhibitors[MESH]|Proto-Oncogene Proteins c-bcl-2/genetics/metabolism[MESH]|Pyridines/immunology/*therapeutic use[MESH]|Signal Transduction[MESH]|Sorafenib[MESH]|TOR Serine-Threonine Kinases/antagonists & inhibitors[MESH]|bcl-X Protein/genetics[MESH]|fas Receptor/immunology/metabolism[MESH] |