| Lenalidomide is an immunomodulatory drug, inhibiting TNF-α secretion with an IC50 of 13 nM.[1] As a thalidomide analogues, lenalidomide possesses pleiotropic anti-myeloma properties including immune-modulation, anti-angiogenic, anti-inflammatory and anti-proliferative effects. Lenalidomide (1 µM lenalidomide on PC3 cells and LNCaP cells, 0.01 µM lenalidomide on DU145 cells) decreases about 50% of the IC50 of docetaxel and also decreases invasion in human prostate carcinoma (PC) cells lines PC3, DU145, and LNCaP cells and anchorage independent growth in PC3 cells. Lenalidomide/docetaxel-treated cells (1 µM lenalidomide on PC3 cells and 0.01 µM lenalidomide on DU145 cells) is increased 2.2- and 1.3-fold changes in apoptosis and 1.2- and 1.3-fold changes in overall cell death over single agent docetaxel in PC3 and DU145 cells, respectively. Furthermore, 1 µM lenalidomide enhances docetaxel-mediated p53 phosphorylation (by 170%), BAD phosphorylation (by 23%), and p38 phosphorylation (by 71%) in the docetaxel resistant PC3 cell line.[2] Lenalidomide (1µM) treatment blocks chronic lymphocytic leukemia (CLL) cell??nduced T-cell actin synapse dysfunction, mimicked Ab blockade experiments, and down-regulated expression of CLL inhibitory ligands (CD200, CD270, CD274, and CD276) and their receptors on T cells. Lenalidomide (1µM) treatment (ie, pretreatment of CLL cells or direct addition of the drug to primary coculture) prevents tumor-induced immune suppression and down-regulates immunosuppressive ligand (CD200, CD270, CD274, and CD276) expression in FL, DLBCL, Hodgkin lymphoma, MM, SCC, and OC cells. Furthermore, lenalidomide treatment inhibits induction of T-cell Rho-GTPase signaling (RhoA, Rac1, and Cdc42) defects in healthy donor T cells.[3] Low doses of lenalidomide (1, 5, 10 and 40 nM) treated primary human bone marrow CD34+ cells consistently promote erythropoiesis in vitro, and signi?cantly increase the ratio of erythroid to granulocyte-monocyte colony-forming units.[4] In the animal model, PC3 challenged mice are treated with lenalidomide (50 mg/kg, daily) and docetaxel, median survival increases from 48 to 59 days and the rate of tumor growth is significantly reduced.[2] Oral treatment of lenalidomide significantly inhibits the induction of angiogenesis by bFGF in a dose-dependent manner in each of the four variables measured. Lenalidomide decreases the percentage of vascularized area from 5.16% in the control group to 2.58 and 1.69 in the 50 and 250 mg/kg group, respectively. Lenalidomide reduces the numbers of branch points from 24.88 in the control group to 15.2 and 4.09 in the 50 and 250 mg/kg group, respectively. Lenalidomide inhibits the microvascular length from 2.42 in controls to 1.95 and 0.76 in rats treated with 50 mg/kg and 250 mg/kg, respectively. Lenalidomide reduces the calculated total MVL from 21.07 in the control group to 8.11 and 1.90 in the 50 mg/kg and 250 mg/kg drug-treated groups, respectively.[5] |
