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Singleton PA, Mambetsariev N, Lennon FE, et al. Methylnaltrexone potentiates the anti-angiogenic effects of mTOR inhibitors. J Angiogenes Res. 2010;2(1):5doi: 10.1186/2040-2384-2-5.
Singleton, P. A., Mambetsariev, N., Lennon, F. E., Mathew, B., Siegler, J. H., Moreno-Vinasco, L., Salgia, R., Moss, J., & Garcia, J. G. (2010). Methylnaltrexone potentiates the anti-angiogenic effects of mTOR inhibitors. Journal of angiogenesis research, 2(1), 5. https://doi.org/10.1186/2040-2384-2-5
Singleton, Patrick A, et al. "Methylnaltrexone potentiates the anti-angiogenic effects of mTOR inhibitors." Journal of angiogenesis research vol. 2,1 (2010): 5. doi: https://doi.org/10.1186/2040-2384-2-5
Singleton PA, Mambetsariev N, Lennon FE, Mathew B, Siegler JH, Moreno-Vinasco L, Salgia R, Moss J, Garcia JG. Methylnaltrexone potentiates the anti-angiogenic effects of mTOR inhibitors. J Angiogenes Res. 2010 Feb 19;2(1):5. doi: 10.1186/2040-2384-2-5. PMID: 20298531; PMCID: PMC2831839.
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J Angiogenes Res. 2010 Feb 19;2(1):5. doi: 10.1186/2040-2384-2-5.

Methylnaltrexone potentiates the anti-angiogenic effects of mTOR inhibitors.

Journal of angiogenesis research

Patrick A Singleton, Nurbek Mambetsariev, Frances E Lennon, Biji Mathew, Jessica H Siegler, Liliana Moreno-Vinasco, Ravi Salgia, Jonathan Moss, Joe Gn Garcia

Affiliations

  1. Department of Medicine, University of Chicago, 5841 S Maryland Avenue, W604, Chicago, IL 60637, USA. [email protected]

PMID: 20298531 PMCID: PMC2831839 DOI: 10.1186/2040-2384-2-5

Abstract

BACKGROUND: Recent cancer therapies include drugs that target both tumor growth and angiogenesis including mammalian target of rapamycin (mTOR) inhibitors. Since mTOR inhibitor therapy is associated with significant side effects, we examined potential agents that can reduce the therapeutic dose.

METHODS: Methylnaltrexone (MNTX), a peripheral mu opioid receptor (MOR) antagonist, in combination with the mTOR inhibitors temsirolimus and/or rapamycin, was evaluated for inhibition of VEGF-induced human pulmonary microvascular endothelial cell (EC) proliferation and migration as well as in vivo angiogenesis (mouse Matrigel plug assay).

RESULTS: MNTX inhibited VEGF-induced EC proliferation and migration with an IC50 of approximately 100 nM. Adding 10 nM MNTX to EC shifted the IC50 of temsirolimus inhibition of VEGF-induced proliferation and migration from approximately 10 nM to approximately 1 nM and from approximately 50 to approximately 10 nM respectively. We observed similar effects with rapamycin. On a mechanistic level, we observed that MNTX increased EC plasma membrane-associated tyrosine phosphate activity. Inhibition of tyrosine phosphatase activity (3,4-dephostatin) blocked the synergy between MNTX and temsirolimus and increased VEGF-induced tyrosine phosphorylation of Src with enhanced PI3 kinase and mTOR Complex 2-dependent phosphorylation of Akt and subsequent activation of mTOR Complex 1 (rapamycin and temsirolimus target), while silencing Src, Akt or mTOR complex 2 components blocked VEGF-induced angiogenic events.

CONCLUSIONS: Our data indicate that MNTX exerts a synergistic effect with rapamycin and temsirolimus on inhibition of VEGF-induced human EC proliferation and migration and in vivo angiogenesis. Therefore, addition of MNTX could potentially lower the dose of mTOR inhibitors which could improve therapeutic index.

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