Methylnaltrexone potentiates the anti-angiogenic effects of mTOR inhibitors

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

Research output: Contribution to journalArticle

27 Scopus citations

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 ∼100 nM. Adding 10 nM MNTX to EC shifted the IC50 of temsirolimus inhibition of VEGF-induced proliferation and migration from ∼10 nM to ∼1 nM and from ∼50 to ∼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.

Original languageEnglish (US)
Article number5
JournalJournal of Angiogenesis Research
Volume2
Issue number1
DOIs
StatePublished - 2010

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Developmental Biology

Fingerprint Dive into the research topics of 'Methylnaltrexone potentiates the anti-angiogenic effects of mTOR inhibitors'. Together they form a unique fingerprint.

  • Cite this

    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