Novel Chemical Entities for the Treatment of Human Colorectal Cancer

Abstract

Ceramide plays a key role in human colorectal tumor cell death and proliferation. Current approach for ceramide-based therapy is aimed at the development of ceramide structural mimetics as cytotoxic agents. It has been recently discovered that ceramide plays an essential role in Fas-mediated apoptosis of tumor cells. Fas is a death receptor expressed on the surface of the colorectal cancer cell. FasL is the physiological ligand of Fas and is expressed on the surface of activated T cells. The Fas-FasL pathway participates in the cancer immune surveillance. It has been proved that although Fas is silenced in the majority of tumor cells, low level of Fas is still expressed on tumor cell surface and ceramide effectively increases Fas oligomerization and therefore increases tumor cell sensitivity to FasL-induced cell death. Based on this discovery several structural mimetics of ceramide have been developed as potential enhancers of Fas-mediated apoptosis of human colon cancer cells. These compounds increase human colon carcinoma cell sensitivity to FasL-induced tumor cell death by tumor-specific T cells in vitro.