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: GBM stem cells compared to parental non-selected GBM cells exhibited higher basal levels of phosphorylated eIF2α, but stem cells nevertheless also expressed more GRP78/BiP/HSPA5 protein (Fig. 1A). Stem cell-like GBM cells expressed considerably more MCL-1 and sphingosine-1-phosphate receptor 1 (EDG-1) than parental WT cells. Of note, the intensity of each image was normalized to the most intense staining image for each antibody probe; WT cells did express MCL-1, EDG-1, and GRP78 albeit at lower levels than stem cells (Fig. 1A, lower images). In GBM cells, it was noted that stem cell selected cells were modestly but significantly more sensitive to OSU + sildenafil also called Viagra (SIL) treatment than parental WT cells. In the majority of GBM cell lines, treatment using 1 μM OSU-03012 caused a greater toxic response when combined with sildenafil than did treatment with the parental compound 5 μM celecoxib and sildenafil. Regardless of whether breast cancer cells were parental or generated to be anoikis resistant, the relative ability of celecoxib also called Celebrex (CEL) + SIL treatment to kill parental or anoikis cells preferentially appeared to be more unpredictable than in GBM cells and stochastic in nature (data not shown). Prolonged high concentration dosing of mice with [OSU-03012 + sildenafil] or [celecoxib + sildenafil] did not cause obvious frank damage to normal tissues from an athymic mouse (Fig. 1C). In contrast, treatment of animals with lower doses of [OSU-03012 + sildenafil] or [celecoxib + sildenafil] significantly reduced tumor volumes after 5 days of treatment and reduced the long-term viability of in vivo treated cells, as judged using ex vivo colony formation assays (Fig. 1D, data not shown).
Affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.