GRP78/dna K is a target for nexavar/stivarga/votrient in the treatment of human malignancies, viral infections and bacterial diseases
Autor(es): Roberts Jane L, Tavallai Mehrad, Nourbakhsh Aida, Fidanza Abigail, Cruz-Luna Tanya, Smith Elizabeth, Siembida Paul, Plamondon Pascale, Cycon Kelly A, Doern Christopher D, Booth Laurence, Dent Paul
Resumo: Prior tumor cell studies have shown that the drugs sorafenib (Nexavar) - regorafenib (Stivarga) reduce expression of the chaperone GRP78. Sorafenib/regorafenib - the multi-kinase inhibitor pazopanib (Votrient) interacted with sildenafil (Viagra) to further rapidly reduce GRP78 levels in eukaryotes - as single agents to reduce Dna K levels in prokaryotes. Similar data were obtained in tumor cells in vitro - in drug-treated mice for: HSP70, mitochondrial HSP70, HSP60, HSP56, HSP40, HSP10, - cyclophilin A. Prolonged 'rafenib/sildenafil treatment killed tumor cells - also rapidly decreased the expression of: the drug efflux pumps ABCB1 - ABCG2; - NPC1 - NTCP, receptors for Ebola/Hepatitis A - B viruses, respectively. Pre-treatment with the 'Rafenib/sildenafil combination reduced expression of the Coxsackie - Adenovirus receptor in parallel with it also reducing the ability of a serotype 5 Adenovirus or Coxsackie virus B4 to infect - to reproduce. Sorafenib/pazopanib - sildenafil was much more potent than sorafenib/pazopanib as single agents at preventing Adenovirus, Mumps, Chikungunya, Dengue, Rabies, West Nile, Yellow Fever, - Enterovirus 71 infection - reproduction. 'Rafenib drugs/pazopanib as single agents killed laboratory generated antibiotic resistant E. coli which was associated with reduced Dna K - Rec A expression. Marginally toxic doses of 'Rafenib drugs/pazopanib restored antibiotic sensitivity in pan-antibiotic resistant bacteria including multiple strains of blakpc Klebsiella pneumoniae. Thus, Dna K is an antibiotic target for sorafenib, - inhibition of GRP78/Dna K has therapeutic utility for cancer - for bacterial - viral infections.
Imprenta: Journal of Cellular Physiology, v. 230, n. 10, p. 2552-2578, 2015
Identificador do objeto digital: 10.1002/jcp.25014
Descritores: Chikungunya virus - Biochemistry ; Chikungunya virus - Biosynthesis ; Chikungunya virus - Cell ; Chikungunya virus - Cytopathology ; Chikungunya virus - DNA ; Chikungunya virus - Proteins ; Chikungunya virus - Viral infections ; Chikungunya Virus - Virus ; Chikungunya virus - Molecular screening ; Chikungunya virus - Chikungunya fever ; Chikungunya virus - Dengue
Data de publicação: 2015
