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: Expression of ERBB1, ERBB2, and of ERBB3 and ERBB4 in BT474 breast cancer cells was reduced by OSU + SIL treatment (Fig. 2A). Treatment of GBM cells with CEL + SIL and with OSU + SIL rapidly reduced total expression of ERBB1 (GBM12) and ERBB1 vIII (GBM6) within 6 h, whereas expression of c-MET was reduced to a much lesser extent and in a cell-dependent fashion (Fig. 2B). Drug combination exposures rapidly reduced expression of S1PR1 (EDG1) and S1PR5 (EDG5) as they did in a cell type dependent fashion for the IL6R and the IL8R (Fig. 2C,D). Expression of the IGF1R and of TNFαR1 were also reduced by the drug combination (Fig. 2E). Drug combination treatment also reduced the total expression of multiple plasma membrane associated drug efflux pumps; pumps that are generally over-expressed in recurrent patient tumors and are partly responsible for chemotherapy resistance as well as for a functional blood–brain barrier (Fig. 2F). Identical data were obtained in vivo examining normal brain and liver tissues (Fig. 2G,H). Similar data showing knock down of ABCB1 and ABCG2 expression were also obtained in stem cell selected variants of GBM5/6/12/14 (data not shown). In previous studies, we have shown that expression of the death receptor CD95 (FAS) does not alter after particular these drug exposures and in fact becomes plasma membrane localized and clustered, observations indicative of CD95 activation (Booth et al., 2014a,b).
Affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.