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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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Related in: MedlinePlus

Sorafenib and PDE5 inhibitors interact to kill multiple tumor cell types. (A) HEP3B cells were treated with vehicle (DMSO), sorafenib (SOR, 500 nM–2.0 μM) and/or sildenafil (2.0 μM) as indicated. Cells were isolated 24 h after exposure and viability determined by trypan blue exclusion (n = 3, ±SEM) *P 0.05 < greater than vehicle control. (B) Hepatoma cells 24 h after plating were treated with vehicle (DMSO), sorafenib (SOR, 2.0 μM), PDE5 inhibitor (sildenafil, 2 μM); or the drugs in combination. Twenty-four hours after treatment cells were isolated and viability determine by trypan blue (n = 3, ±SEM). *P 0.05 < greater than vehicle control. Upper images were generated using a live/dead assay using a Hermes WiScan instrument. (C) HuH7 cells were treated with vehicle (DMSO), regorafenib (REGO, 300–1,500 nM) and/or sildenafil (2.0 μM) as indicated. Cells were isolated 24 h after exposure and viability determined by trypan blue exclusion (n = 3, ±SEM) *P 0.05 < greater than vehicle control. (D) Hepatoma cells 24 h after plating were treated with vehicle (DMSO), regorafenib (REGO, 0.5 μM), PDE5 inhibitor (sildenafil, 2 μM); or the drugs in combination. Twenty-four hours after treatment cells were isolated and viability determined by trypan blue (n = 3, ±SEM). *P 0.05 < greater than vehicle control. Upper images were generated using a live/dead assay using a Hermes WiScan instrument. (E) Tumor cells 24 h after plating were treated with vehicle (DMSO), regorafenib (REGO, 0.5 μM), sildenafil (2 μM) or the drugs in combination. Twenty-four hours after treatment cells were isolated and viability determined by trypan blue (n = 3, ±SEM). *P 0.05 < greater than vehicle control. (F) Tumor cells were cultured in 100% heat inactivated human serum. Cells were treated with vehicle; sorafenib (5 μM) and sildenafil (2 μM); or with regorafenib (2 μM) and sildenafil (0–0.75 μM). Cells were isolated 24 h after drug exposure and viability determined using a live/dead assay using a Hermes WiScan instrument. Studies were performed in triplicate in 96-well plates with the percentage numbers of live/dead cells being determined in three images per well (n = 3, ±SEM). *P 0.05 < greater than vehicle control.
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Figure 1: Sorafenib and PDE5 inhibitors interact to kill multiple tumor cell types. (A) HEP3B cells were treated with vehicle (DMSO), sorafenib (SOR, 500 nM–2.0 μM) and/or sildenafil (2.0 μM) as indicated. Cells were isolated 24 h after exposure and viability determined by trypan blue exclusion (n = 3, ±SEM) *P 0.05 < greater than vehicle control. (B) Hepatoma cells 24 h after plating were treated with vehicle (DMSO), sorafenib (SOR, 2.0 μM), PDE5 inhibitor (sildenafil, 2 μM); or the drugs in combination. Twenty-four hours after treatment cells were isolated and viability determine by trypan blue (n = 3, ±SEM). *P 0.05 < greater than vehicle control. Upper images were generated using a live/dead assay using a Hermes WiScan instrument. (C) HuH7 cells were treated with vehicle (DMSO), regorafenib (REGO, 300–1,500 nM) and/or sildenafil (2.0 μM) as indicated. Cells were isolated 24 h after exposure and viability determined by trypan blue exclusion (n = 3, ±SEM) *P 0.05 < greater than vehicle control. (D) Hepatoma cells 24 h after plating were treated with vehicle (DMSO), regorafenib (REGO, 0.5 μM), PDE5 inhibitor (sildenafil, 2 μM); or the drugs in combination. Twenty-four hours after treatment cells were isolated and viability determined by trypan blue (n = 3, ±SEM). *P 0.05 < greater than vehicle control. Upper images were generated using a live/dead assay using a Hermes WiScan instrument. (E) Tumor cells 24 h after plating were treated with vehicle (DMSO), regorafenib (REGO, 0.5 μM), sildenafil (2 μM) or the drugs in combination. Twenty-four hours after treatment cells were isolated and viability determined by trypan blue (n = 3, ±SEM). *P 0.05 < greater than vehicle control. (F) Tumor cells were cultured in 100% heat inactivated human serum. Cells were treated with vehicle; sorafenib (5 μM) and sildenafil (2 μM); or with regorafenib (2 μM) and sildenafil (0–0.75 μM). Cells were isolated 24 h after drug exposure and viability determined using a live/dead assay using a Hermes WiScan instrument. Studies were performed in triplicate in 96-well plates with the percentage numbers of live/dead cells being determined in three images per well (n = 3, ±SEM). *P 0.05 < greater than vehicle control.

Mentions: Initial studies examined the dose-response of death receptor CD95 expressing HEP3B tumor cells to increasing concentrations of sorafenib and the PDE5 inhibitor Viagra (sildenafil). Sildenafil enhanced sorafenib toxicity in a dose-dependent fashion (Fig. 1A). Sildenafil interacted with sorafenib to kill hepatoma cells, regardless of whether the tumor cell expressed CD95, i.e., HuH7 are CD95 (Fig. 1B). Regorafenib is a derivative of sorafenib with greater solubility and potency in vitro and in vivo that the parent compound sorafenib. Similar data to that with sorafenib were obtained using regorafenib in combination with sildenafil (Fig. 1C). Sildenafil interacted with regorafenib to kill hepatoma cells, regardless of whether the tumor cell expressed CD95 (Fig. 1D). Similar data were obtained using other PDE5 inhibitors such as Cialis and Levitra (data not shown). Sildenafil and sorafenib also interacted with sildenafil to kill multiple other tumor cell types (Fig. 1E). Of particular note, when tumor cells were cultured in 100% heat inactivated human serum, concentrations of sorafenib/regorafenib at one quarter of their steady state Cmax values were still capable of interacting with sildenafil to rapidly kill tumor cells (Fig. 1F). This data strongly argue that the hypothesis of Houghton and Smith regarding low levels of active-free sorafenib concentrations in patient plasma is very probably incorrect (Smith and Houghton, 2013). In colony formation assays, sildenafil and sorafenib/regorafenib interacted in a synergistic fashion to kill tumor cells, with combination index (CI) values of less than ~0.70 (Table 1).


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)

Sorafenib and PDE5 inhibitors interact to kill multiple tumor cell types. (A) HEP3B cells were treated with vehicle (DMSO), sorafenib (SOR, 500 nM–2.0 μM) and/or sildenafil (2.0 μM) as indicated. Cells were isolated 24 h after exposure and viability determined by trypan blue exclusion (n = 3, ±SEM) *P 0.05 < greater than vehicle control. (B) Hepatoma cells 24 h after plating were treated with vehicle (DMSO), sorafenib (SOR, 2.0 μM), PDE5 inhibitor (sildenafil, 2 μM); or the drugs in combination. Twenty-four hours after treatment cells were isolated and viability determine by trypan blue (n = 3, ±SEM). *P 0.05 < greater than vehicle control. Upper images were generated using a live/dead assay using a Hermes WiScan instrument. (C) HuH7 cells were treated with vehicle (DMSO), regorafenib (REGO, 300–1,500 nM) and/or sildenafil (2.0 μM) as indicated. Cells were isolated 24 h after exposure and viability determined by trypan blue exclusion (n = 3, ±SEM) *P 0.05 < greater than vehicle control. (D) Hepatoma cells 24 h after plating were treated with vehicle (DMSO), regorafenib (REGO, 0.5 μM), PDE5 inhibitor (sildenafil, 2 μM); or the drugs in combination. Twenty-four hours after treatment cells were isolated and viability determined by trypan blue (n = 3, ±SEM). *P 0.05 < greater than vehicle control. Upper images were generated using a live/dead assay using a Hermes WiScan instrument. (E) Tumor cells 24 h after plating were treated with vehicle (DMSO), regorafenib (REGO, 0.5 μM), sildenafil (2 μM) or the drugs in combination. Twenty-four hours after treatment cells were isolated and viability determined by trypan blue (n = 3, ±SEM). *P 0.05 < greater than vehicle control. (F) Tumor cells were cultured in 100% heat inactivated human serum. Cells were treated with vehicle; sorafenib (5 μM) and sildenafil (2 μM); or with regorafenib (2 μM) and sildenafil (0–0.75 μM). Cells were isolated 24 h after drug exposure and viability determined using a live/dead assay using a Hermes WiScan instrument. Studies were performed in triplicate in 96-well plates with the percentage numbers of live/dead cells being determined in three images per well (n = 3, ±SEM). *P 0.05 < greater than vehicle control.
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Figure 1: Sorafenib and PDE5 inhibitors interact to kill multiple tumor cell types. (A) HEP3B cells were treated with vehicle (DMSO), sorafenib (SOR, 500 nM–2.0 μM) and/or sildenafil (2.0 μM) as indicated. Cells were isolated 24 h after exposure and viability determined by trypan blue exclusion (n = 3, ±SEM) *P 0.05 < greater than vehicle control. (B) Hepatoma cells 24 h after plating were treated with vehicle (DMSO), sorafenib (SOR, 2.0 μM), PDE5 inhibitor (sildenafil, 2 μM); or the drugs in combination. Twenty-four hours after treatment cells were isolated and viability determine by trypan blue (n = 3, ±SEM). *P 0.05 < greater than vehicle control. Upper images were generated using a live/dead assay using a Hermes WiScan instrument. (C) HuH7 cells were treated with vehicle (DMSO), regorafenib (REGO, 300–1,500 nM) and/or sildenafil (2.0 μM) as indicated. Cells were isolated 24 h after exposure and viability determined by trypan blue exclusion (n = 3, ±SEM) *P 0.05 < greater than vehicle control. (D) Hepatoma cells 24 h after plating were treated with vehicle (DMSO), regorafenib (REGO, 0.5 μM), PDE5 inhibitor (sildenafil, 2 μM); or the drugs in combination. Twenty-four hours after treatment cells were isolated and viability determined by trypan blue (n = 3, ±SEM). *P 0.05 < greater than vehicle control. Upper images were generated using a live/dead assay using a Hermes WiScan instrument. (E) Tumor cells 24 h after plating were treated with vehicle (DMSO), regorafenib (REGO, 0.5 μM), sildenafil (2 μM) or the drugs in combination. Twenty-four hours after treatment cells were isolated and viability determined by trypan blue (n = 3, ±SEM). *P 0.05 < greater than vehicle control. (F) Tumor cells were cultured in 100% heat inactivated human serum. Cells were treated with vehicle; sorafenib (5 μM) and sildenafil (2 μM); or with regorafenib (2 μM) and sildenafil (0–0.75 μM). Cells were isolated 24 h after drug exposure and viability determined using a live/dead assay using a Hermes WiScan instrument. Studies were performed in triplicate in 96-well plates with the percentage numbers of live/dead cells being determined in three images per well (n = 3, ±SEM). *P 0.05 < greater than vehicle control.
Mentions: Initial studies examined the dose-response of death receptor CD95 expressing HEP3B tumor cells to increasing concentrations of sorafenib and the PDE5 inhibitor Viagra (sildenafil). Sildenafil enhanced sorafenib toxicity in a dose-dependent fashion (Fig. 1A). Sildenafil interacted with sorafenib to kill hepatoma cells, regardless of whether the tumor cell expressed CD95, i.e., HuH7 are CD95 (Fig. 1B). Regorafenib is a derivative of sorafenib with greater solubility and potency in vitro and in vivo that the parent compound sorafenib. Similar data to that with sorafenib were obtained using regorafenib in combination with sildenafil (Fig. 1C). Sildenafil interacted with regorafenib to kill hepatoma cells, regardless of whether the tumor cell expressed CD95 (Fig. 1D). Similar data were obtained using other PDE5 inhibitors such as Cialis and Levitra (data not shown). Sildenafil and sorafenib also interacted with sildenafil to kill multiple other tumor cell types (Fig. 1E). Of particular note, when tumor cells were cultured in 100% heat inactivated human serum, concentrations of sorafenib/regorafenib at one quarter of their steady state Cmax values were still capable of interacting with sildenafil to rapidly kill tumor cells (Fig. 1F). This data strongly argue that the hypothesis of Houghton and Smith regarding low levels of active-free sorafenib concentrations in patient plasma is very probably incorrect (Smith and Houghton, 2013). In colony formation assays, sildenafil and sorafenib/regorafenib interacted in a synergistic fashion to kill tumor cells, with combination index (CI) values of less than ~0.70 (Table 1).

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