Nexavar/Stivarga and viagra interact to kill tumor cells.
Bottom Line: PDE5 and PDGFRα/β were over-expressed in liver tumors compared to normal liver tissue.Knock down of PDE5 or of PDGFRα/β recapitulated the effects of the individual drugs.The drug combination also reduced mTOR protein expression.
Affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.Show MeSH
Related in: MedlinePlus
Mentions: We next attempted to define whether biomarkers of regorafenib and sildenafil i.e., physiologic effects, could be observed in tumor cells. Sildenafil treatment increased phosphorylation of VASP-1 (S239), which is a known cGMP dependent kinase (PKG) site (Fig. 3A–E). Identical data were obtained when cells were treated with dibutyrl-cGMP (data not shown). Prior studies using sorafenib had shown that the drug could cause a modest endoplasmic reticulum stress response, with increased phosphorylation of eIF2α (S51) (Park et al., 2008). Regorafenib treatment increased eIF2α (S51) phosphorylation (Fig. 3A–E). Studies in future figures make use of the drug FTY720 (Gilenya, Fingolimod) which is a histone deacetylase inhibitor; an inhibitor of sphingosine-1-phosphate production and also down-regulates expression of sphingosine-1-phosphate receptors, e.g., EDG-1. Treatment of tumor cells for 6 h with FTY720 abolished expression of EDG-1 (Fig. 3F). Of additional note, combined treatment of cells with regorafenib and sildenafil also abolished EDG-1 expression within 6 h. Expression of a dominant negative eIF2α (S51A) protein abolished the ability of (regorafenib + sildenafil) treatment to reduce EDG-1 expression within 6 h (Fig. 3G). Inhibition of the PERK-eIF2α-ATF4-CHOP pathway protected cells from combination treatment lethality (Fig. 3H).
Affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.