We examined the interaction between the non-coxib OSU-03012 with phosphodiesterase 5 (PDE5) inhibitors to determine the role of the chaperone GRP78/BiP/HSPA5 in the response of cells. Sildenafil (Viagra) interacted in a greater than additive fashion with OSU-03012 to kill tumor cells including stem-like and anoikis resistant cells. Treatment of cells with OSU-03012/sildenafil: abolished the expression of growth factor receptors and plasma membrane drug efflux pumps; and caused a more rapid degradation of GRP78 and of other important chaperone proteins e.g. HSP27, HSP40, HSP60, HSP70 and HSP90. Decreased expression of receptors and pumps was dependent upon enhanced PERK-eIF2 signaling and blocked by GRP78 over-expression. The combination of OSU-03012/sildenafil synergized with sorafenib to kill tumor cells. GRP78 is also a protein required for human virus reproduction. Pre-treatment of mammalian cells with OSU-03012/sildenafil reduced expression of the coxsakie and adenovirus receptor in parallel with also reducing the ability of a serotype 5 adenovirus or coxsakie virus B4 to infect and to reproduce. Similar data were obtained using Cytomegalovirus and Influenza viruses. OSU-03012/sildenafil decreased the expression of: NPC1 and TIM1; LAMP1; and NTCP1, receptors for Ebola / Hepatitis A, Lassa fever, and Hepatitis B viruses, respectively. Bacteria express a GRP78 homologue and phosphodiesterases, and treatment of multi-antibiotic resistant E. coli and N. gonorrhoeae with OSU-03012/PDE5 inhibitor combinations was bactericidal and restored antibiotic sensitivity. Thus modulation of GRP78 function may be of therapeutic use in multiple human pathologies.

Citation Format: Laurence A. Booth, Jane L. Roberts, Paul Dent. GRP78 / BiP / HSPA5 expression and those of other chaperone proteins is rapidly degraded by OSU-03012 and Viagra exposure: Implications for anti-cancer and anti-pathogen therapies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1741. doi:10.1158/1538-7445.AM2015-1741

©2015 American Association for Cancer Research.
2015