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Nexavar/Stivarga and viagra interact to kill tumor cells.

Tavallai M, Hamed HA, Roberts JL, Cruickshanks N, Chuckalovcak J, Poklepovic A, Booth L, Dent P - J. Cell. Physiol. (2015)

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.

View Article: PubMed Central - PubMed

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

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Regorafenib/sildenafil treatment alter multiple cell signaling processes in drug treated tumors at cessation of drug treatment. Parts (A–E) HuH7 and HT29 tumors, treated as described in Figures 9 and 10, were isolated 7 days after the start of drug exposure or were isolated at the time of sacrifice, when tumor volume was >1,500 mm3 (n.b. tumor mass for REGO + SIL treated tumors was only ~500 mm3). Tumors were freeze-thawed and lysed according to established procedures/manufacturer instructions. Tumors were subjected to multiplex assays to determine the levels of plasma cytokines/growth factors and the phosphorylation/expression of multiple membrane and intracellular signal transduction proteins (n = 8, ±SEM). #P < 0.05 lower value than vehicle control treated tumors; ~P < 0.05 greater value than in vehicle control treated tumors. (F) HuH7 cells were treated with vehicle control; regorafenib (0.5 μM) and sildenafil (2 μM); BGJ398 (1 μM); Lapatinib (1 μM); MK2206 (1 μM) or in the combinations indicated in the part. Cells were examined 12 h after treatment using a live/dead assay in a Hermes WiScan instrument. Red/yellow cells = dead; green cells = alive (n = 3, ±SEM). *P < 0.05 greater than corresponding value in (regorafenib + sildenafil) treatment alone.
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Figure 11: Regorafenib/sildenafil treatment alter multiple cell signaling processes in drug treated tumors at cessation of drug treatment. Parts (A–E) HuH7 and HT29 tumors, treated as described in Figures 9 and 10, were isolated 7 days after the start of drug exposure or were isolated at the time of sacrifice, when tumor volume was >1,500 mm3 (n.b. tumor mass for REGO + SIL treated tumors was only ~500 mm3). Tumors were freeze-thawed and lysed according to established procedures/manufacturer instructions. Tumors were subjected to multiplex assays to determine the levels of plasma cytokines/growth factors and the phosphorylation/expression of multiple membrane and intracellular signal transduction proteins (n = 8, ±SEM). #P < 0.05 lower value than vehicle control treated tumors; ~P < 0.05 greater value than in vehicle control treated tumors. (F) HuH7 cells were treated with vehicle control; regorafenib (0.5 μM) and sildenafil (2 μM); BGJ398 (1 μM); Lapatinib (1 μM); MK2206 (1 μM) or in the combinations indicated in the part. Cells were examined 12 h after treatment using a live/dead assay in a Hermes WiScan instrument. Red/yellow cells = dead; green cells = alive (n = 3, ±SEM). *P < 0.05 greater than corresponding value in (regorafenib + sildenafil) treatment alone.

Mentions: We then examined the activities of multiple signal transduction pathways/proteins in tumors 7 days after the start of treatment. Treatment of HuH7 and HT29 tumors with (regorafenib + sildenafil) reduced plasma levels of FGF and GM-CSF and increased the levels of PDGFbb (Figs. 10A and 11A). Regorafenib and sildenafil treatment also reduced the expression of multiple tumor growth factors in the blood of animals carrying HuH7 tumors (Fig. 11B). In both HuH7 and HT29 tumors, we observed drug combination exposure caused activation of AKT though total S6 phosphorylation was reduced in both tumor types (Fig. 11C). These findings were associated with reduced PDGFRβ phosphorylation and decreased NFκB activity (Fig. 11D and E). As observed for HT29 tumors, obvious biomarkers for third drug combinations include AKT inhibitors, FGFR inhibitors, and ERBB1/2 inhibitors. Inhibition of AKT or ERBB1/2 signaling enhanced (regorafenib + sildenafil) killing (Fig. 11F).


Nexavar/Stivarga and viagra interact to kill tumor cells.

Tavallai M, Hamed HA, Roberts JL, Cruickshanks N, Chuckalovcak J, Poklepovic A, Booth L, Dent P - J. Cell. Physiol. (2015)

Regorafenib/sildenafil treatment alter multiple cell signaling processes in drug treated tumors at cessation of drug treatment. Parts (A–E) HuH7 and HT29 tumors, treated as described in Figures 9 and 10, were isolated 7 days after the start of drug exposure or were isolated at the time of sacrifice, when tumor volume was >1,500 mm3 (n.b. tumor mass for REGO + SIL treated tumors was only ~500 mm3). Tumors were freeze-thawed and lysed according to established procedures/manufacturer instructions. Tumors were subjected to multiplex assays to determine the levels of plasma cytokines/growth factors and the phosphorylation/expression of multiple membrane and intracellular signal transduction proteins (n = 8, ±SEM). #P < 0.05 lower value than vehicle control treated tumors; ~P < 0.05 greater value than in vehicle control treated tumors. (F) HuH7 cells were treated with vehicle control; regorafenib (0.5 μM) and sildenafil (2 μM); BGJ398 (1 μM); Lapatinib (1 μM); MK2206 (1 μM) or in the combinations indicated in the part. Cells were examined 12 h after treatment using a live/dead assay in a Hermes WiScan instrument. Red/yellow cells = dead; green cells = alive (n = 3, ±SEM). *P < 0.05 greater than corresponding value in (regorafenib + sildenafil) treatment alone.
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Figure 11: Regorafenib/sildenafil treatment alter multiple cell signaling processes in drug treated tumors at cessation of drug treatment. Parts (A–E) HuH7 and HT29 tumors, treated as described in Figures 9 and 10, were isolated 7 days after the start of drug exposure or were isolated at the time of sacrifice, when tumor volume was >1,500 mm3 (n.b. tumor mass for REGO + SIL treated tumors was only ~500 mm3). Tumors were freeze-thawed and lysed according to established procedures/manufacturer instructions. Tumors were subjected to multiplex assays to determine the levels of plasma cytokines/growth factors and the phosphorylation/expression of multiple membrane and intracellular signal transduction proteins (n = 8, ±SEM). #P < 0.05 lower value than vehicle control treated tumors; ~P < 0.05 greater value than in vehicle control treated tumors. (F) HuH7 cells were treated with vehicle control; regorafenib (0.5 μM) and sildenafil (2 μM); BGJ398 (1 μM); Lapatinib (1 μM); MK2206 (1 μM) or in the combinations indicated in the part. Cells were examined 12 h after treatment using a live/dead assay in a Hermes WiScan instrument. Red/yellow cells = dead; green cells = alive (n = 3, ±SEM). *P < 0.05 greater than corresponding value in (regorafenib + sildenafil) treatment alone.
Mentions: We then examined the activities of multiple signal transduction pathways/proteins in tumors 7 days after the start of treatment. Treatment of HuH7 and HT29 tumors with (regorafenib + sildenafil) reduced plasma levels of FGF and GM-CSF and increased the levels of PDGFbb (Figs. 10A and 11A). Regorafenib and sildenafil treatment also reduced the expression of multiple tumor growth factors in the blood of animals carrying HuH7 tumors (Fig. 11B). In both HuH7 and HT29 tumors, we observed drug combination exposure caused activation of AKT though total S6 phosphorylation was reduced in both tumor types (Fig. 11C). These findings were associated with reduced PDGFRβ phosphorylation and decreased NFκB activity (Fig. 11D and E). As observed for HT29 tumors, obvious biomarkers for third drug combinations include AKT inhibitors, FGFR inhibitors, and ERBB1/2 inhibitors. Inhibition of AKT or ERBB1/2 signaling enhanced (regorafenib + sildenafil) killing (Fig. 11F).

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.

View Article: PubMed Central - PubMed

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

Show MeSH
Related in: MedlinePlus