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OSU-03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood-Brain Barrier: Implications for Anti-Cancer Therapies.

Booth L, Roberts JL, Tavallai M, Nourbakhsh A, Chuckalovcak J, Carter J, Poklepovic A, Dent P - J. Cell. Physiol. (2015)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.

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Related in: MedlinePlus

Third drug combinations with [OSU-03012 + sildenafil] and with [celecoxib + sildenafil] to further enhance tumor cell killing. A: GBM5/6/12/14 cells in 96-well plates were treated with vehicle; celecoxib (5 μM) + sildenafil (2 μM); or OSU-03012 (1 μM) + sildenafil, with or without the drug crizotinib (1 μM) and after 12 h of treatment were subjected to live/dead assays where the percentage cell death is noted below each image (n = 3 ± SEM). *P <0.05 greater than death value in two drug treated cells. B,C: GBM5/6/12/14 cells in 96-well plates were treated with vehicle; celecoxib (5 μM) + sildenafil (2 μM), with or without the drugs: sorafenib (0.5, 2.0 μM); ruxolitinib (0.5 μM); OSI-994 (1 μM); lapatinib (1 μM), as indicated. After 12 h of treatment cells were subjected to live/dead assays where the percentage cell death is noted below each image (n = 3 ± SEM). *P <0.05 greater than death value in two drug treated cells. D–F: GBM5/6/12/14 cells or [Huh7, HEPG2 liver], [HT29, HCT116 colon], [PANC1, Mia Paca2 pancreatic] cells in 96-well plates were treated with vehicle; celecoxib (5 μM) + sildenafil (2 μM) or OSU-03012 (1 μM) + sildenafil with or without the drugs: AR-42 (250 nM); vorinostat (500 nM); valproate (0.1 mM), as indicated. After 12 h of treatment, cells were subjected to live/dead assays where the percentage cell death is noted below each image (n = 3 ± SEM). *P <0.05 greater than death value in two drug treated cells. G,H: GBM cells were treated with vehicle; celecoxib (5 μM) + sildenafil (2 μM) or OSU-03012 (1 μM) + sildenafil with or without FTY720 (50 nM) with or without MMF (5 μM). After 12 h of treatment, cells were subjected to live/dead assays.
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Figure 3: Third drug combinations with [OSU-03012 + sildenafil] and with [celecoxib + sildenafil] to further enhance tumor cell killing. A: GBM5/6/12/14 cells in 96-well plates were treated with vehicle; celecoxib (5 μM) + sildenafil (2 μM); or OSU-03012 (1 μM) + sildenafil, with or without the drug crizotinib (1 μM) and after 12 h of treatment were subjected to live/dead assays where the percentage cell death is noted below each image (n = 3 ± SEM). *P <0.05 greater than death value in two drug treated cells. B,C: GBM5/6/12/14 cells in 96-well plates were treated with vehicle; celecoxib (5 μM) + sildenafil (2 μM), with or without the drugs: sorafenib (0.5, 2.0 μM); ruxolitinib (0.5 μM); OSI-994 (1 μM); lapatinib (1 μM), as indicated. After 12 h of treatment cells were subjected to live/dead assays where the percentage cell death is noted below each image (n = 3 ± SEM). *P <0.05 greater than death value in two drug treated cells. D–F: GBM5/6/12/14 cells or [Huh7, HEPG2 liver], [HT29, HCT116 colon], [PANC1, Mia Paca2 pancreatic] cells in 96-well plates were treated with vehicle; celecoxib (5 μM) + sildenafil (2 μM) or OSU-03012 (1 μM) + sildenafil with or without the drugs: AR-42 (250 nM); vorinostat (500 nM); valproate (0.1 mM), as indicated. After 12 h of treatment, cells were subjected to live/dead assays where the percentage cell death is noted below each image (n = 3 ± SEM). *P <0.05 greater than death value in two drug treated cells. G,H: GBM cells were treated with vehicle; celecoxib (5 μM) + sildenafil (2 μM) or OSU-03012 (1 μM) + sildenafil with or without FTY720 (50 nM) with or without MMF (5 μM). After 12 h of treatment, cells were subjected to live/dead assays.

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).


OSU-03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood-Brain Barrier: Implications for Anti-Cancer Therapies.

Booth L, Roberts JL, Tavallai M, Nourbakhsh A, Chuckalovcak J, Carter J, Poklepovic A, Dent P - J. Cell. Physiol. (2015)

Third drug combinations with [OSU-03012 + sildenafil] and with [celecoxib + sildenafil] to further enhance tumor cell killing. A: GBM5/6/12/14 cells in 96-well plates were treated with vehicle; celecoxib (5 μM) + sildenafil (2 μM); or OSU-03012 (1 μM) + sildenafil, with or without the drug crizotinib (1 μM) and after 12 h of treatment were subjected to live/dead assays where the percentage cell death is noted below each image (n = 3 ± SEM). *P <0.05 greater than death value in two drug treated cells. B,C: GBM5/6/12/14 cells in 96-well plates were treated with vehicle; celecoxib (5 μM) + sildenafil (2 μM), with or without the drugs: sorafenib (0.5, 2.0 μM); ruxolitinib (0.5 μM); OSI-994 (1 μM); lapatinib (1 μM), as indicated. After 12 h of treatment cells were subjected to live/dead assays where the percentage cell death is noted below each image (n = 3 ± SEM). *P <0.05 greater than death value in two drug treated cells. D–F: GBM5/6/12/14 cells or [Huh7, HEPG2 liver], [HT29, HCT116 colon], [PANC1, Mia Paca2 pancreatic] cells in 96-well plates were treated with vehicle; celecoxib (5 μM) + sildenafil (2 μM) or OSU-03012 (1 μM) + sildenafil with or without the drugs: AR-42 (250 nM); vorinostat (500 nM); valproate (0.1 mM), as indicated. After 12 h of treatment, cells were subjected to live/dead assays where the percentage cell death is noted below each image (n = 3 ± SEM). *P <0.05 greater than death value in two drug treated cells. G,H: GBM cells were treated with vehicle; celecoxib (5 μM) + sildenafil (2 μM) or OSU-03012 (1 μM) + sildenafil with or without FTY720 (50 nM) with or without MMF (5 μM). After 12 h of treatment, cells were subjected to live/dead assays.
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Figure 3: Third drug combinations with [OSU-03012 + sildenafil] and with [celecoxib + sildenafil] to further enhance tumor cell killing. A: GBM5/6/12/14 cells in 96-well plates were treated with vehicle; celecoxib (5 μM) + sildenafil (2 μM); or OSU-03012 (1 μM) + sildenafil, with or without the drug crizotinib (1 μM) and after 12 h of treatment were subjected to live/dead assays where the percentage cell death is noted below each image (n = 3 ± SEM). *P <0.05 greater than death value in two drug treated cells. B,C: GBM5/6/12/14 cells in 96-well plates were treated with vehicle; celecoxib (5 μM) + sildenafil (2 μM), with or without the drugs: sorafenib (0.5, 2.0 μM); ruxolitinib (0.5 μM); OSI-994 (1 μM); lapatinib (1 μM), as indicated. After 12 h of treatment cells were subjected to live/dead assays where the percentage cell death is noted below each image (n = 3 ± SEM). *P <0.05 greater than death value in two drug treated cells. D–F: GBM5/6/12/14 cells or [Huh7, HEPG2 liver], [HT29, HCT116 colon], [PANC1, Mia Paca2 pancreatic] cells in 96-well plates were treated with vehicle; celecoxib (5 μM) + sildenafil (2 μM) or OSU-03012 (1 μM) + sildenafil with or without the drugs: AR-42 (250 nM); vorinostat (500 nM); valproate (0.1 mM), as indicated. After 12 h of treatment, cells were subjected to live/dead assays where the percentage cell death is noted below each image (n = 3 ± SEM). *P <0.05 greater than death value in two drug treated cells. G,H: GBM cells were treated with vehicle; celecoxib (5 μM) + sildenafil (2 μM) or OSU-03012 (1 μM) + sildenafil with or without FTY720 (50 nM) with or without MMF (5 μM). After 12 h of treatment, cells were subjected to live/dead assays.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.

Show MeSH
Related in: MedlinePlus