GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease

• Published in: Journal of cellular physiology 2015-07, Vol.230 (7), p.1661-1676
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Adenovirus; Animals; Antibiotics; Bacteria - drug effects; Carbolines - administration & dosage; Carbolines - pharmacology; Cell Death; Cell Line, Tumor; Cytomegalovirus; Deoxyribonucleic acid; DNA; Drug resistance; Drug Resistance, Multiple, Bacterial; E coli; Ebola virus; Escherichia coli; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Hepatitis; Hepatitis A virus; Hepatitis B virus; Humans; Infections; Marburg virus; Mice; Mice, Nude; Neoplasms, Experimental - drug therapy; Original s; Phosphodiesterase 5 Inhibitors - administration & dosage; Phosphodiesterase 5 Inhibitors - pharmacology; Piperazines - administration & dosage; Piperazines - pharmacology; Purines - administration & dosage; Purines - pharmacology; Pyrazoles - administration & dosage; Pyrazoles - pharmacology; Sildenafil Citrate; Stem cells; Sulfonamides - administration & dosage; Sulfonamides - pharmacology; Tadalafil; Vector-borne diseases; Viruses - drug effects
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.24919

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. J. Cell. Physiol. 230: 1661–1676, 2015. © 2014 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.