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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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Molecular manipulation of regorafenib and sildenafil targets recapitulates the effects of drug combination treatment. (A) Tissue microarrays of normal and tumor tissue matched from the same patients were stained for expression of PDE5 followed by H&E. The panels show five matched normal liver and hepatocellular tumor sections, each from the same patient (five patients). (B) Further normal liver and liver tumor sections stained to determine the expression of PDE5. (C) HuH7 cells were transfected with a control scrambled siRNA (siSCR) or three different siRNA molecules to knock down expression of PDE5 (siPDE5 #1, #2, #3). Thirty-six hours after transfection were treated with vehicle (DMSO) or regorafenib (REG, 0.5 μM) or with sorafenib (SOR, 2.0 μM). Twenty-four hours after treatment cells were isolated and viability determine by trypan blue (n = 3, ±SEM). *P < 0.05 greater than corresponding value in siSCR cells. (D) Tissue microarrays were stained for expression of PDGFRα/β followed by H&E. The parts show six matched normal liver and hepatocellular tumor sections, each from the same patient (six patients). (E) HEP3B cells were transfected with a control scrambled siRNA (siSCR) or siRNA molecules to knock down expression of PDGFRα and PDGFRβ. Thirty-six hours after transfection were treated with vehicle (DMSO) or sildenafil (SIL, 1.0–2.0 μM). Twenty-four hours after treatment cells were isolated and viability determine by trypan blue (n = 3, ±SEM). *P < 0.05 greater than corresponding value in siSCR cells.
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Figure 2: Molecular manipulation of regorafenib and sildenafil targets recapitulates the effects of drug combination treatment. (A) Tissue microarrays of normal and tumor tissue matched from the same patients were stained for expression of PDE5 followed by H&E. The panels show five matched normal liver and hepatocellular tumor sections, each from the same patient (five patients). (B) Further normal liver and liver tumor sections stained to determine the expression of PDE5. (C) HuH7 cells were transfected with a control scrambled siRNA (siSCR) or three different siRNA molecules to knock down expression of PDE5 (siPDE5 #1, #2, #3). Thirty-six hours after transfection were treated with vehicle (DMSO) or regorafenib (REG, 0.5 μM) or with sorafenib (SOR, 2.0 μM). Twenty-four hours after treatment cells were isolated and viability determine by trypan blue (n = 3, ±SEM). *P < 0.05 greater than corresponding value in siSCR cells. (D) Tissue microarrays were stained for expression of PDGFRα/β followed by H&E. The parts show six matched normal liver and hepatocellular tumor sections, each from the same patient (six patients). (E) HEP3B cells were transfected with a control scrambled siRNA (siSCR) or siRNA molecules to knock down expression of PDGFRα and PDGFRβ. Thirty-six hours after transfection were treated with vehicle (DMSO) or sildenafil (SIL, 1.0–2.0 μM). Twenty-four hours after treatment cells were isolated and viability determine by trypan blue (n = 3, ±SEM). *P < 0.05 greater than corresponding value in siSCR cells.

Mentions: We next determined the relative expression of PDE5 and PDGFRα/β in normal liver and in hepatoma, as well as on- and off-target effects of our drugs in promoting drug combination killing. PDE5 was over-expressed in hepatocellular carcinoma tissues but not in normal liver from the same patient (Fig. 2A; similar data were obtained in multiple other samples, Fig. 2B). Knock down of PDE5 expression enhanced regorafenib toxicity in CD95 HuH7 cells (Fig. 2C). In prior studies, we have shown that PDGFRα/β play an important role in the biology of sorafenib in terms of its toxic combination with other therapeutic agents such as histone deacetylase inhibitors (Martin et al., 2009; Park et al., 2010; Cruickshanks et al., 2013). PDGFRα/β was over-expressed in hepatocellular carcinoma tissues but not in normal liver tissue from the same patient (Fig. 2D). Knock down of PDGFRα/β expression enhanced the toxicity sildenafil in tumor cells (Fig. 2E).


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)

Molecular manipulation of regorafenib and sildenafil targets recapitulates the effects of drug combination treatment. (A) Tissue microarrays of normal and tumor tissue matched from the same patients were stained for expression of PDE5 followed by H&E. The panels show five matched normal liver and hepatocellular tumor sections, each from the same patient (five patients). (B) Further normal liver and liver tumor sections stained to determine the expression of PDE5. (C) HuH7 cells were transfected with a control scrambled siRNA (siSCR) or three different siRNA molecules to knock down expression of PDE5 (siPDE5 #1, #2, #3). Thirty-six hours after transfection were treated with vehicle (DMSO) or regorafenib (REG, 0.5 μM) or with sorafenib (SOR, 2.0 μM). Twenty-four hours after treatment cells were isolated and viability determine by trypan blue (n = 3, ±SEM). *P < 0.05 greater than corresponding value in siSCR cells. (D) Tissue microarrays were stained for expression of PDGFRα/β followed by H&E. The parts show six matched normal liver and hepatocellular tumor sections, each from the same patient (six patients). (E) HEP3B cells were transfected with a control scrambled siRNA (siSCR) or siRNA molecules to knock down expression of PDGFRα and PDGFRβ. Thirty-six hours after transfection were treated with vehicle (DMSO) or sildenafil (SIL, 1.0–2.0 μM). Twenty-four hours after treatment cells were isolated and viability determine by trypan blue (n = 3, ±SEM). *P < 0.05 greater than corresponding value in siSCR cells.
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Figure 2: Molecular manipulation of regorafenib and sildenafil targets recapitulates the effects of drug combination treatment. (A) Tissue microarrays of normal and tumor tissue matched from the same patients were stained for expression of PDE5 followed by H&E. The panels show five matched normal liver and hepatocellular tumor sections, each from the same patient (five patients). (B) Further normal liver and liver tumor sections stained to determine the expression of PDE5. (C) HuH7 cells were transfected with a control scrambled siRNA (siSCR) or three different siRNA molecules to knock down expression of PDE5 (siPDE5 #1, #2, #3). Thirty-six hours after transfection were treated with vehicle (DMSO) or regorafenib (REG, 0.5 μM) or with sorafenib (SOR, 2.0 μM). Twenty-four hours after treatment cells were isolated and viability determine by trypan blue (n = 3, ±SEM). *P < 0.05 greater than corresponding value in siSCR cells. (D) Tissue microarrays were stained for expression of PDGFRα/β followed by H&E. The parts show six matched normal liver and hepatocellular tumor sections, each from the same patient (six patients). (E) HEP3B cells were transfected with a control scrambled siRNA (siSCR) or siRNA molecules to knock down expression of PDGFRα and PDGFRβ. Thirty-six hours after transfection were treated with vehicle (DMSO) or sildenafil (SIL, 1.0–2.0 μM). Twenty-four hours after treatment cells were isolated and viability determine by trypan blue (n = 3, ±SEM). *P < 0.05 greater than corresponding value in siSCR cells.
Mentions: We next determined the relative expression of PDE5 and PDGFRα/β in normal liver and in hepatoma, as well as on- and off-target effects of our drugs in promoting drug combination killing. PDE5 was over-expressed in hepatocellular carcinoma tissues but not in normal liver from the same patient (Fig. 2A; similar data were obtained in multiple other samples, Fig. 2B). Knock down of PDE5 expression enhanced regorafenib toxicity in CD95 HuH7 cells (Fig. 2C). In prior studies, we have shown that PDGFRα/β play an important role in the biology of sorafenib in terms of its toxic combination with other therapeutic agents such as histone deacetylase inhibitors (Martin et al., 2009; Park et al., 2010; Cruickshanks et al., 2013). PDGFRα/β was over-expressed in hepatocellular carcinoma tissues but not in normal liver tissue from the same patient (Fig. 2D). Knock down of PDGFRα/β expression enhanced the toxicity sildenafil in tumor cells (Fig. 2E).

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