Resveratrol inhibits tumor cell adhesion to endothelial cells by blocking ICAM-1 expression.

Resveratrol, a grape polyphenol, is thought to have anti-inflammatory, cardioprotective, and cancer preventive properties. However, the mechanisms by which resveratrol might produce these effects are not clearly defined. A study was performed on whether resveratrol could prevent tumor cells from adhering to endothelial cells, which is an essential step during tumor metastasis. Phorbol 12- myristate 13-acetate (PMA) induced human fibrosarcoma HT1080 cells to adhere to endothelial ECV304 cells. Resveratrol inhibited PMA-induced HT1080 cells adhesion in a dose-dependent manner. To further study the mechanisms of this resveratrol-mediated blockade of tumor cell adhesion, the expression of the cell adhesion molecules intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin were examined. PMA induced ICAM-1 expression in HT1080 cells. In contrast, the expression of VCAM-1 and E-selectin were not altered by PMA treatment. The increase in tumor cell adhesion to endothelial cells following PMA treatment was partially inhibited by ICAM-1 siRNA or neutralizing antibodies. Resveratrol reduced the PMA-induced ICAM-1 expression in HT1080 cells as determined by RT-PCR, flow cytometry and ELISA. As the induction of ICAM-1 requires activation of the transcription factor NF-κB, the effects of resveratrol on the activation of this factor in HT1080 cells was also investigated. Resveratrol inhibited the PMA-induced NF-κB activation and NF-κB-dependent luciferase activity. These results suggest that resveratrol may exert an anti- metastatic effect by inhibiting NF-κB activation and ICAM-1 expression, leading to suppression of tumor cell adhesion to endothelial cells. Cancer metastasis is a multi-step process beginning with the invasion of malignant cells from the primary tumor into the vascular or lymphatic circulation. Loss of cell adhesive molecules induces the disassembly of free cancer cells from the primary tumor masses, disseminating them to distant sites via blood vessels and lymphatics, and eventually elicits the transition from benign tumors to metastatic tumors (1, 2). The circulating tumor cells interact with the endothelial cells of blood vessels, and this is considered a preliminary event during tumor metastasis (3). The adhesive interactions between tumor cells and the capillary wall do not result from random adhesion of cancer cells but rather is a selection process favoring certain tumor cells with specific properties (4). As with leukocytes, attachment of cancer cells to the vascular endothelium seems to be initiated by the interaction between sialyl Lewis X, a surface carbohydrate expressed on several cell types including many tumor cells (5). Various adhesive molecules, including intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin have been identified as being responsible for the endothelial adhesion of cancer cells. ICAM-1 and VCAM-1 are 95 and 110 kDa proteins, respectively, and both belong to the immunoglobulin superfamily. Besides endothelial cells, ICAM-1 is also expressed by monocytes, B and T cells, keratinocytes, chondrocytes, and epithelial cells. VCAM-1 is expressed in endothelial cells, monocytes, dendritic cells, myoblast, and bone marrow fibroblasts. The 115 kDa protein E-selectin is known to be expressed exclusively on endothelial cells (6). Some of these adhesive molecules are constitutively expressed while others are induced by many different environmental signals and distributed in a tissue-specific manner as well. Clinical studies show elevated serum levels of soluble ICAM-1 and VCAM-1 in patients with cancer and these levels correlate with tumor progression (7). Resveratrol (3,5,40-trihydroxystilbene), which was first isolated from the roots of white hellebore (Veratrum glandiflorum O. Loes), has been shown to inhibit or retard the growth of various cancer cells in culture and implanted tumors in vivo (8).