Abstract 424: Invasion and metastasis of human colon cancer cells is prevented by aldose reductase inhibition

Abstract

Abstract Worldwide colorectal cancer (CRC) is the third most common cause of cancer and is the second leading cause of cancer deaths in the USA. Although therapeutic options for patients with CRC have increased substantially, including earlier diagnosis, improved surgery as well as chemo- and radiation therapies, ∼61% of patients have metastatic disease and of these, 90% die within 5 years of diagnosis. Hence better therapeutic interventions to manage the metastatic process in CRC patients are mandatory. We have recently shown that inhibition of aldose reductase (AR), an enzyme that catalyzes reduction of lipid aldehydes and their glutathione conjugates, prevents human colon cancer cell growth in culture as well as in nude mice xenografts by inhibiting the NF-kB-dependent activation of inflammatory and carcinogenic markers. We have now investigated the effect of AR inhibition in metastatic spread of human CRC cells in nude mice and the molecular mechanisms by which AR inhibition prevents colon cancer cell invasion, migration, adhesion and metastasis. Our results indicate that AR inhibition prevents growth factors-induced migration and invasion of HT-29 CRC cells in a dose-dependent manner. AR inhibition also significantly inhibited adhesion of CRC cells to endothelial cells and inhibited the expression of ICAM-1, VCAM-1 and VE-cadherin. Further, we injected KM20 cells, transfected with a plasmid containing green fluorescent protein (GFP), into the spleen of athymic nude mice to establish liver metastases. The mice were treated with AR inhibitor or siRNA for 30 days. Our results indicate that AR inhibition or ablation prevents in vivo invasion and metastasis of CRC cells by reducing levels of AR, MMP2, cyclin D1, and CD34 and suppresses the activation of NF-kB. Since AR inhibitor fidarestat aggressively prevents human tumor growth and metastasis in nude mice and cellular models, and has already undergone phase-iii clinical studies for diabetic neuropathy, it is an excellent candidate for clinical application in preventing colon cancer tumorigenesis and metastasis. Funding Support: NIH/NCI CA129383 (SKS). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 424.