aldose reductase prevents colon cancer metastasis. Carcinogenesis

D ow nloaded from Colon cancer is the third most common cause of cancer and is the second leading cause of cancer deaths in the USA. Although inhibition of aldose reductase (AR) is known to prevent human colon cancer cell growth in nude mice xenografts, the role of AR in the regulation of cancer metastasis is not known. We now demonstrate the mechanisms by which AR regulates colon cancer metastasis in vitro and in vivo. Inhibition of AR prevented the EGF or FGF-induced migration and invasion of human colon cancer (HT-29; KM20) cells by>70%, and also inhibited (>80%) the adhesion of the cancer cells to endothelial cells. Treatment of endothelial cells with AR inhibitors significantly (~85%) down-regulated the EGF or FGF-induced expression of ICAM-1, VCAM-1 and VE-cadherin. Further, liver metastasis of green fluorescent protein-labeled KM20 cells injected into the spleen of athymic nude mice was significantly (>65%) prevented by AR inhibitor, fidarestat or AR-siRNA delivered systemically into the mice. Simila