title: Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro.
abstract: The thalidomide analogue and immunomodulatory drug (IMiD) lenalidomide (CC-5013, REVLIMID) is emerging as a useful treatment for a number of cancers and has recently entered phase III trials for multiple myeloma. It has been suggested that the anti-tumor effect of lenalidomide is related to its anti-angiogenic potency. In this regard, we have previously shown that lenalidomide inhibits angiogenesis in both rat and human in vitro models but does not affect endothelial cell proliferation. We now show that oral administration of lenalidomide attenuates growth factor-induced angiogenesis in vivo; the rat mesenteric window assay was utilized to show that lenalidomide significantly inhibits vascularization in a dose-dependent manner. We also found that lenalidomide significantly inhibits growth factor-induced endothelial cell migration. This correlates with the inhibitory effect of lenalidomide on growth factor-induced Akt phosphorylation, thereby providing a potential mechanism for its anti-migratory and subsequent anti-angiogenic effects. These data further support the use of lenalidomide as an orally administered drug for the effective treatment of angiogenesis-dependent conditions, including cancer, and suggest a potential mechanism of action.
authors.affiliation: Department of Cellular and Molecular Medicine, St. George's Hospital Medical School, London, UK.
authors.forename: Keith
authors.initials: K
authors.lastname: Dredge
authors.forename: Rebecca
authors.initials: R
authors.lastname: Horsfall
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
authors.forename: Ling-Hua
authors.initials: LH
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.forename: Yang
authors.initials: Y
authors.lastname: Tang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Shirley
authors.forename: George
authors.initials: G
authors.lastname: Muller
authors.forename: Peter
authors.initials: P
authors.lastname: Schafer
authors.forename: David
authors.initials: D
authors.lastname: Stirling
authors.forename: Angus G
authors.initials: AG
authors.lastname: Dalgleish
authors.forename: J Blake
authors.initials: JB
authors.lastname: Bartlett
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D002465:Cell Movement / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D000077269:Lenalidomide; D008297:Male; D008643:Mesentery / Q000098:blood supply / Q000166:cytology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D013792:Thalidomide / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D020533:Angiogenesis Inhibitors; D011518:Proto-Oncogene Proteins; D013792:Thalidomide; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077269:Lenalidomide