title: GRP78/Dna K Is a Target for Nexavar/Stivarga/Votrient in the Treatment of Human Malignancies, Viral Infections and Bacterial Diseases.
abstract: Prior tumor cell studies have shown that the drugs sorafenib (Nexavar) and regorafenib (Stivarga) reduce expression of the chaperone GRP78. Sorafenib/regorafenib and the multi-kinase inhibitor pazopanib (Votrient) interacted with sildenafil (Viagra) to further rapidly reduce GRP78 levels in eukaryotes and as single agents to reduce Dna K levels in prokaryotes. Similar data were obtained in tumor cells in vitro and in drug-treated mice for: HSP70, mitochondrial HSP70, HSP60, HSP56, HSP40, HSP10, and cyclophilin A. Prolonged 'rafenib/sildenafil treatment killed tumor cells and also rapidly decreased the expression of: the drug efflux pumps ABCB1 and ABCG2; and NPC1 and NTCP, receptors for Ebola/Hepatitis A and B viruses, respectively. Pre-treatment with the 'Rafenib/sildenafil combination reduced expression of the Coxsackie and Adenovirus receptor in parallel with it also reducing the ability of a serotype 5 Adenovirus or Coxsackie virus B4 to infect and to reproduce. Sorafenib/pazopanib and sildenafil was much more potent than sorafenib/pazopanib as single agents at preventing Adenovirus, Mumps, Chikungunya, Dengue, Rabies, West Nile, Yellow Fever, and Enterovirus 71 infection and reproduction. 'Rafenib drugs/pazopanib as single agents killed laboratory generated antibiotic resistant E. coli which was associated with reduced Dna K and 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, and inhibition of GRP78/Dna K has therapeutic utility for cancer and for bacterial and viral infections.
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.
authors: Jane L
authors: JL
authors: Roberts
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.
authors: Mehrad
authors: M
authors: Tavallai
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.
authors: Aida
authors: A
authors: Nourbakhsh
authors: ZeptoMetrix, 872 Main Street, Buffalo, New York.
authors: Abigail
authors: A
authors: Fidanza
authors: ZeptoMetrix, 872 Main Street, Buffalo, New York.
authors: Tanya
authors: T
authors: Cruz-Luna
authors: ZeptoMetrix, 872 Main Street, Buffalo, New York.
authors: Elizabeth
authors: E
authors: Smith
authors: ZeptoMetrix, 872 Main Street, Buffalo, New York.
authors: Paul
authors: P
authors: Siembida
authors: ZeptoMetrix, 872 Main Street, Buffalo, New York.
authors: Pascale
authors: P
authors: Plamondon
authors: ZeptoMetrix, 872 Main Street, Buffalo, New York.
authors: Kelly A
authors: KA
authors: Cycon
authors: Department of Pathology, Virginia Commonwealth University, Richmond, Virginia.
authors: Christopher D
authors: CD
authors: Doern
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.
authors: Laurence
authors: L
authors: Booth
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.
authors: Paul
authors: P
authors: Dent
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000188:drug therapy; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D004926:Escherichia coli / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007191:Indazoles; D009369:Neoplasms / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011116:Polynucleotide 5'-Hydroxyl-Kinase / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D000077157:Sorafenib; D013449:Sulfonamides / Q000494:pharmacology*; D014777:Virus Diseases / Q000188:drug therapy
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D007191:Indazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; C559147:regorafenib; D009536:Niacinamide; C516667:pazopanib; D000077157:Sorafenib; D011116:Polynucleotide 5'-Hydroxyl-Kinase