OSU-03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood-Brain Barrier: Implications for Anti-Cancer Therapies.
Bottom Line: Sildenafil (Viagra) interacted in a greater than additive fashion with OSU-03012 to kill stem-like GBM cells.In multiplex assays on plasma and human tumor tissue from an OSU-03012/sildenafil treated mouse, we noted a profound reduction in uPA signaling and identified FGF and JAK1/2 as response biomarkers for potentially suppressing the killing response.Inhibition of FGFR signaling and to a lesser extent JAK1/2 signaling profoundly enhanced OSU-03012/sildenafil lethality.
Affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.Show MeSH
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Mentions: As treatment of cells with CEL + SIL or with OSU + SIL weakly reduced expression of c-MET compared to other growth factor receptors, we determined whether a clinically relevant inhibitor of c-MET (crizotinib) could enhance the lethality of CEL + SIL or with OSU + SIL. In a cell type dependent fashion, that did not correlate with basal expression or down-regulation of c-MET protein, crizotinib enhanced CEL + SIL or OSU + SIL lethality (Fig. 3A). The lethality of CEL + SIL was potently enhanced in all GBM cells by the multi-kinase inhibitor sorafenib (Fig. 3B,C). Unlike [OSU + SIL] treatment in Fig. 2, the JAK1/2 inhibitor ruxolitinib did not significantly enhance CEL + SIL toxicity and the IGF1R inhibitor OSI-906 only enhanced CEL + SIL toxicity in GBM6 and GBM14 cells. In GBM cells that expressed ERBB1 and ERBB1 vIII, the ERBB1/2 inhibitor lapatinib strongly enhanced CEL + SIL lethality. In a previous manuscript, we demonstrated that the histone deacetylase inhibitor and blocker of sphingosine-1-phosphate receptor signaling, FTY720 (multiple sclerosis drug: Gilenya), enhanced CEL + SIL lethality. The more potent HDAC inhibitors AR-42, vorinostat enhanced CEL + SIL lethality in GBM cells with AR-42 being most potent on a molar basis (Fig. 3D). Similar cell killing data were obtained in multiple GI tumor cell types (Fig. 3E). The lethality of the OSU + SIL drug combination was also enhanced by HDAC inhibitors (Fig. 3F,G). The multiple sclerosis drug FT720 as well as another multiple sclerosis drug (monomethyl fumarate [MMF]) enhanced OSU + SIL lethality (Fig. 3H).
Affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.