Metastatic spread is the major cause of cancer death. Current treatments for metastatic diseases are palliative but not curative. We have previously reported that the retinoid X receptor (RXR)-selective ligand bexarotene was efficacious as a chemopreventive and chemotherapeutic agent in a rat carcinogen-induced mammary carcinoma model. We further demonstrated that bexarotene prevented and overcame multidrug resistance in several preclinical human tumor models. To explore the role of bexarotene in cancer treatment further, we studied the influence of bexarotene on angiogenesis and metastasis in solid tumors. Human breast cancer cells and non-small-cell lung cancer cells were subjected to Matrigel invasion assay in the presence of bexarotene. Compared to cells treated with vehicle control, the invasiveness of tumor cells was greatly reduced by bexarotene in both cell lines. Furthermore, bexarotene inhibited angiogenesis by directly inhibiting human umbilical vein endothelial cell growth and indirectly inhibiting tumor cell-mediated migration of human umbilical vein endothelial cells through Matrigel matrix. Analysis of the tumor conditioned medium indicated that bexarotene decreased the secretion of angiogenic factors and matrix metalloproteinases while increased the tissue inhibitor of matrix metalloproteinases. In the experimental metastasis xenograft model, treatment with bexarotene decreased the incidence of lung metastasis and lung tumor nodule formation. Our results suggest a role of bexarotene in inhibition of angiogenesis and metastasis in solid tumors.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]