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
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Mentions: Treatment of hepatoma cells in vitro increased the phosphorylation of PKR-like endoplasmic reticulum kinase (PERK) and eIF2α (S51) as judged by western blotting (Fig. 7A). Drug combination treatment reduced the phosphorylation of MEK1 (S218/S222), AKT (T308), and of ERK1/2, and enhanced phosphorylation of JNK1/2. No obvious change was noted in MEK1 S298 phosphorylation. Similar data were obtained when cells were fixed in place and probed by immuno-fluorescence for phosphorylation status by immuno-fluorescence (Fig. 7B–D). The phosphorylation of the autophagy regulatory kinase mTOR was significantly reduced by drug combination treatment, which also was associated to a lesser extent with reduced expression of mTOR protein itself (Fig. 7E) i.e., both total protein and the specific activity of the mTOR protein declined. Expression of activated forms of MEK1 or AKT incompletely suppressed killing by regorafenib and sildenafil treatment (Fig. 7F). Inhibition of JNK1/2 signaling or expression of an activated form of mTOR abolished drug combination toxicity.
Affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.