title: GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease.
abstract: The chaperone GRP78/Dna K is conserved throughout evolution down to prokaryotes. The GRP78 inhibitor OSU-03012 (AR-12) interacted with sildenafil (Viagra) or tadalafil (Cialis) to rapidly reduce GRP78 levels in eukaryotes and as a single agent reduce Dna K levels in prokaryotes. Similar data with the drug combination were obtained for: HSP70, HSP90, GRP94, GRP58, HSP27, HSP40 and HSP60. OSU-03012/sildenafil treatment killed brain cancer stem cells and decreased the expression of: NPC1 and TIM1; LAMP1; and NTCP1, receptors for Ebola/Marburg/Hepatitis A, Lassa fever, and Hepatitis B viruses, respectively. Pre-treatment with OSU-03012/sildenafil reduced expression of the coxsakie and adenovirus receptor in parallel with it also reducing the ability of a serotype 5 adenovirus or coxsakie virus B4 to infect and to reproduce. Similar data were obtained using Chikungunya, Mumps, Measles, Rubella, RSV, CMV, and Influenza viruses. OSU-03012 as a single agent at clinically relevant concentrations killed laboratory generated antibiotic resistant E. coli and clinical isolate multi-drug resistant N. gonorrhoeae and MRSE which was in bacteria associated with reduced Dna K and Rec A expression. The PDE5 inhibitors sildenafil or tadalafil enhanced OSU-03012 killing in N. gonorrhoeae and MRSE and low marginally toxic doses of OSU-03012 could restore bacterial sensitivity in N. gonorrhoeae to multiple antibiotics. Thus, Dna K and bacterial phosphodiesterases are novel antibiotic targets, and inhibition of GRP78 is of therapeutic utility for cancer and also for bacterial and viral infections.
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Laurence
authors.initials: L
authors.lastname: Booth
authors.forename: Jane L
authors.initials: JL
authors.lastname: Roberts
authors.forename: Devin R
authors.initials: DR
authors.lastname: Cash
authors.forename: Seyedmehrad
authors.initials: S
authors.lastname: Tavallai
authors.forename: Sophonie
authors.initials: S
authors.lastname: Jean
authors.forename: Abigail
authors.initials: A
authors.lastname: Fidanza
authors.forename: Tanya
authors.initials: T
authors.lastname: Cruz-Luna
authors.forename: Paul
authors.initials: P
authors.lastname: Siembiba
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Cycon
authors.forename: Cynthia N
authors.initials: CN
authors.lastname: Cornelissen
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000818:Animals; D001419:Bacteria / Q000187:drug effects; D002243:Carbolines / Q000008:administration & dosage / Q000494:pharmacology; D016923:Cell Death; D045744:Cell Line, Tumor; D024901:Drug Resistance, Multiple, Bacterial; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D000068581:Tadalafil; D014780:Viruses / Q000187:drug effects
chemical_list: D002243:Carbolines; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; C500894:OSU 03012; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D011720:Pyrazoles; D013449:Sulfonamides; D000068581:Tadalafil; D000068677:Sildenafil Citrate