GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease
Autor(es): Booth Laurence, Roberts Jane L, Cash Devin R, Tavallai Seyedmehrad, Jean Sophonie, Fidanza Abigail, Cruz-Luna Tanya, Siembiba Paul, Cycon Kelly A, Cornelissen Cynthia N, Dent Paul
Resumo: 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 - 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 - HSP60. OSU-03012/sildenafil treatment killed brain cancer stem cells - decreased the expression of: NPC1 - TIM1; LAMP1; - NTCP1, receptors for Ebola/Marburg/Hepatitis A, Lassa fever, - Hepatitis B viruses, respectively. Pre-treatment with OSU-03012/sildenafil reduced expression of the coxsakie - adenovirus receptor in parallel with it also reducing the ability of a serotype 5 adenovirus or coxsakie virus B4 to infect - to reproduce. Similar data were obtained using Chikungunya, Mumps, Measles, Rubella, RSV, CMV, - Influenza viruses. OSU-03012 as a single agent at clinically relevant concentrations killed laboratory generated antibiotic resistant E. coli - clinical isolate multi-drug resistant N. gonorrhoeae - MRSE which was in bacteria associated with reduced Dna K - Rec A expression. The PDE5 inhibitors sildenafil or tadalafil enhanced OSU-03012 killing in N. gonorrhoeae - MRSE - low marginally toxic doses of OSU-03012 could restore bacterial sensitivity in N. gonorrhoeae to multiple antibiotics. Thus, Dna K - bacterial phosphodiesterases are novel antibiotic targets, - inhibition of GRP78 is of therapeutic utility for cancer - also for bacterial - viral infections.
Imprenta: Journal of Cellular Physiology, v. 230, n. 7, p. 1661-1676, 2015
Identificador do objeto digital: 10.1002/jcp.24919
Descritores: Chikungunya virus - Biochemistry ; Chikungunya virus - Biosynthesis ; Chikungunya virus - Cell ; Chikungunya virus - DNA ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Proteins ; Chikungunya virus - Viral infections ; Chikungunya Virus - Virus ; Chikungunya virus - Chikungunya fever
Data de publicação: 2015
