The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions.
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.
Lu
Ling
L
Department of Immunotherapeutics, Celgene Corporation, 86 Morris Avenue, Summit, NJ 07901, USA.
Payvandi
Faribourz
F
Wu
Lei
L
Zhang
Ling-Hua
LH
Hariri
Robert J
RJ
Man
Hon-Wah
HW
Chen
Roger S
RS
Muller
George W
GW
Hughes
Christopher C W
CC
Stirling
David I
DI
Schafer
Peter H
PH
Bartlett
J Blake
JB
D022005:Adherens Junctions / Q000187:drug effects; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D066298:In Vitro Techniques; D000077269:Lenalidomide; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008833:Microcirculation / Q000187:drug effects; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D014469:Umbilical Arteries / Q000187:drug effects / Q000254:growth & development; D051176:beta Catenin / Q000378:metabolism; D000099152:Cadherin 5; D000099162:Endothelial PAS Domain-Containing Protein 1
D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D015820:Cadherins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000077269:Lenalidomide; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D051057:Proto-Oncogene Proteins c-akt; D013792:Thalidomide; D051176:beta Catenin; D000099152:Cadherin 5; D000099162:Endothelial PAS Domain-Containing Protein 1; C495270:CTNNB1 protein, human; C497442:HIF1A protein, human; C467566:pomalidomide; C494918:AKT1 protein, human