Lenalidomide (
Revlimid) is approved for the treatment of transfusion-dependent patients with
anemia due to low- or intermediate-1-risk
Myelodysplastic Syndromes (MDS) associated with a del 5q
cytogenetic abnormality with or without additional
cytogenetic abnormalities, and in combination with
dexamethasone for the treatment of
multiple myeloma patients who have received at least one prior
therapy. Previous reports suggest that
lenalidomide is anti-angiogenic and this property appears to be related to efficacy in patients with MDS. We have investigated the effect of
lenalidomide on the formation of microvessels in a novel in vitro angiogenesis assay utilizing human umbilical arterial rings and in a capillary-like cord formation assay using cultured primary endothelial cells. We found that
lenalidomide consistently inhibits both sprout formation by arterial rings and cord formation by endothelial cells in a dose-dependent manner. We also found an inhibitory effect of
lenalidomide on the associations between
cadherin 5,
beta-catenin and CD31, adherens junction
proteins whose interaction is critical for endothelial cell cord formation. Furthermore,
lenalidomide inhibited
VEGF-induced PI3K-Akt pathway signaling, which is known to regulate adherens junction formation. We also found a strong inhibitory effect of
lenalidomide on
hypoxia-induced endothelial cell formation of cords and HIF-1 alpha expression, the main mediator of
hypoxia-mediated effects and a key driver of angiogenesis and
metastasis. Anti-metastatic activity of
lenalidomide in vivo was confirmed in the B16-F10 mouse
melanoma model by a >40% reduction in
melanoma lung colony counts versus untreated mice. Our results suggest that inhibitory effects on microvessel formation, in particular adherens junction formation and inhibition of
hypoxia-induced processes support a potential anti-angiogenic and anti-metastatic mechanism for this clinically active drug.