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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

Possible molecular mechanisms by which OSU-03012 (AR-12) and PDE inhibitors could kill tumor cells. The ability of OSU-03012 (AR-12) alone, or enhanced by a PDE5 inhibitor, to reduce GRP78 expression and the function of multiple other chaperones will prevent the correct folding of essential tumor cell proteins resulting in dead tumor cells. The combination of OSU-03012 and a PDE5 inhibitor will also reduce the expression of plasma membrane signaling receptors whose expression is essential for tumor cell growth and invasion. The loss of GRP78 and other chaperones in tumor cells will result in much lower expression levels of key oncogenic kinases, including PI3K-AKT signaling (Liu et al., 2013, 2015; Tsai et al., 2015). Collectively our data strongly argue that it is a strong possibility that our drug combination will abolish the blood–brain barrier and have profound anti-tumor capabilities.
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Figure 9: Possible molecular mechanisms by which OSU-03012 (AR-12) and PDE inhibitors could kill tumor cells. The ability of OSU-03012 (AR-12) alone, or enhanced by a PDE5 inhibitor, to reduce GRP78 expression and the function of multiple other chaperones will prevent the correct folding of essential tumor cell proteins resulting in dead tumor cells. The combination of OSU-03012 and a PDE5 inhibitor will also reduce the expression of plasma membrane signaling receptors whose expression is essential for tumor cell growth and invasion. The loss of GRP78 and other chaperones in tumor cells will result in much lower expression levels of key oncogenic kinases, including PI3K-AKT signaling (Liu et al., 2013, 2015; Tsai et al., 2015). Collectively our data strongly argue that it is a strong possibility that our drug combination will abolish the blood–brain barrier and have profound anti-tumor capabilities.

Mentions: We have previously shown that OSU-03012 as a single agent increases the levels of autophagosomes and autolysosomes and that this effect is significantly enhanced by sildenafil; enhanced autophagy in this system is cytotoxic as judged by the ability of ATG5 or Beclin1 knock down to prevent formation of autophagic vesicles and to prevent tumor cell killing. We also demonstrated that this elevated level of autophagy was suppressed by over-expression of GRP78, and that GRP78 over-expression protected tumor cells. In the present studies, we noted that the drug combination reduced the expression of both MCL-1 and BCL-XL, and as we have previously shown that this down-regulation can lead to increased levels of unbound Beclin1, which stimulate autophagy, the ER stress signaling pathway will likely lead to increased toxic tumor cell autophagy as well as to increased mitochondrial instability. Thus cell death pathways through autophagy and caspase activation will become engaged following OSU + SIL treatment, suggestive that tumor cell resistance mechanisms will be subverted and become ineffective (Fig. 9).


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)

Possible molecular mechanisms by which OSU-03012 (AR-12) and PDE inhibitors could kill tumor cells. The ability of OSU-03012 (AR-12) alone, or enhanced by a PDE5 inhibitor, to reduce GRP78 expression and the function of multiple other chaperones will prevent the correct folding of essential tumor cell proteins resulting in dead tumor cells. The combination of OSU-03012 and a PDE5 inhibitor will also reduce the expression of plasma membrane signaling receptors whose expression is essential for tumor cell growth and invasion. The loss of GRP78 and other chaperones in tumor cells will result in much lower expression levels of key oncogenic kinases, including PI3K-AKT signaling (Liu et al., 2013, 2015; Tsai et al., 2015). Collectively our data strongly argue that it is a strong possibility that our drug combination will abolish the blood–brain barrier and have profound anti-tumor capabilities.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835175&req=5

Figure 9: Possible molecular mechanisms by which OSU-03012 (AR-12) and PDE inhibitors could kill tumor cells. The ability of OSU-03012 (AR-12) alone, or enhanced by a PDE5 inhibitor, to reduce GRP78 expression and the function of multiple other chaperones will prevent the correct folding of essential tumor cell proteins resulting in dead tumor cells. The combination of OSU-03012 and a PDE5 inhibitor will also reduce the expression of plasma membrane signaling receptors whose expression is essential for tumor cell growth and invasion. The loss of GRP78 and other chaperones in tumor cells will result in much lower expression levels of key oncogenic kinases, including PI3K-AKT signaling (Liu et al., 2013, 2015; Tsai et al., 2015). Collectively our data strongly argue that it is a strong possibility that our drug combination will abolish the blood–brain barrier and have profound anti-tumor capabilities.
Mentions: We have previously shown that OSU-03012 as a single agent increases the levels of autophagosomes and autolysosomes and that this effect is significantly enhanced by sildenafil; enhanced autophagy in this system is cytotoxic as judged by the ability of ATG5 or Beclin1 knock down to prevent formation of autophagic vesicles and to prevent tumor cell killing. We also demonstrated that this elevated level of autophagy was suppressed by over-expression of GRP78, and that GRP78 over-expression protected tumor cells. In the present studies, we noted that the drug combination reduced the expression of both MCL-1 and BCL-XL, and as we have previously shown that this down-regulation can lead to increased levels of unbound Beclin1, which stimulate autophagy, the ER stress signaling pathway will likely lead to increased toxic tumor cell autophagy as well as to increased mitochondrial instability. Thus cell death pathways through autophagy and caspase activation will become engaged following OSU + SIL treatment, suggestive that tumor cell resistance mechanisms will be subverted and become ineffective (Fig. 9).

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