Therefore, a therapeutic agent that can sensitize tumor cell Fas resistance may represent an effective enhancer of CTL based cancer immunotherapy against metastatic colon and breast cancers. Our data suggest that LCL85 is potentially such sellekchem an agent. Although LCL85 does not effectively sensitize Colon 26 Inhibitors,Modulators,Libraries cells to FasL induced apoptosis, LCL85 is effective in suppress ing Colon 26 cell metastatic potential in vivo, suggesting that other host factors, such as IFN and TNF se creted Inhibitors,Modulators,Libraries by T cells, might also act to sensitize the tumor cells to apoptosis in vivo, which requires further study. Background Fas is a member of the TNF death receptor superfamily. Despite other non apoptotic cellular responses emanating from its signaling, the major and best known function of Fas is apoptosis.

Fas is expressed on tumor cell surface, and its physiological ligand, FasL, is expressed on activated T cells and NK cells. Compelling experimental data from both human cancer patients and mouse tumor models indicate that the Fas mediated apoptosis pathway plays a key role in suppression of cancer development and in host cancer immunosurveillance. Furthermore, human Inhibitors,Modulators,Libraries cancer genomics data indicate that Fas is not significantly focally amplified across a dataset of 3131 tumors, but is signifi cantly Inhibitors,Modulators,Libraries focally deleted across the entire dataset of these 3131 tumors, including human colorectal cancer. These data thus strongly suggest that Fas functions as a tumor suppressor. To avoid apoptosis, tumor cells tend to down regulate Fas expression or alter the expression of key mediators of the Fas mediated apoptosis signaling pathway to advance the disease.

This is well supported by the pheno menon that resistance to apoptosis, including Fas mediated Inhibitors,Modulators,Libraries apoptosis, is a hallmark in human cancers, particularly in metastatic human colorectal cancer and breast cancer. Therefore, therapeutic intervention of tumor cell resistance to Fas mediated apoptosis potentially represents an effective approach to render tumor cell sensitivity to FasL cytotoxic T lymphocytes of the host immunosurveillance system or to CTL based adoptive cancer immunotherapy to suppress tumor pro gression. During the last decade, sphingolipids have emerged as bioeffectors that mediate various cellular processes, including proliferation and apoptosis of cancer cells.

Sphingolipid deregulation, namely the balance between ceramide and sphingosine 1 phosphate, has been implied as a key factor in tumor pathogenesis and apoptosis resistance. Although it has been de monstrated that de novo generated http://www.selleckchem.com/products/Pazopanib-Hydrochloride.html ceramides may confer certain types of tumor cells with resistance to apoptosis, ceramide, the central molecule of the sphingolipid metabolism pathway, generally promotes apoptosis. The role of ceramide in Fas mediated apoptosis has also been well documented.