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: PDE5 inhibitors are known to enhance the levels of reactive oxygen and reactive nitrogen species in cells (e.g., Das et al., 2010; Musicki et al., 2014). Treatment of tumor cells with sildenafil and regorafenib rapidly increased the levels of ROS and RNS (Fig. 4A). Inhibition of nitric oxide synthase enzymes using L-NG-Nitroarginine Methyl Ester (L-NAME) inhibited cell killing by sildenafil and sorafenib, as did quenching of ROS production by incubation with N-acetyl cysteine (NAC) or by expression of thioredoxin (TRX) (Fig. 4B). Knock down of inducible nitric oxide synthase (iNOS) or endothelial nitric oxide synthase (eNOS) expression suppressed killing by the drug combination (Fig. 4C). Of note, knock down of iNOS abolished the drug combination interaction but did not alter sorafenib toxicity as a single agent, whereas knock down of eNOS modestly but significantly reduced sorafenib toxicity. Sorafenib and sildenafil were still capable of interacting to kill in cells lacking eNOS expression. The combination of sildenafil and sorafenib surprisingly increased iNOS expression (Fig. 4D).
Affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.