To avoid apoptosis, selleck chemicals Tubacin 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 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 ceramides may confer certain types of tumor cells with resistance to apoptosis, ceramide, the central molecule of the sphingolipid Inhibitors,Modulators,Libraries metabolism pathway, generally promotes apoptosis. The role of ceramide in Fas mediated apoptosis has also been well documented. Ceramide enables Fas receptor to cluster to increase Fas mediated apoptosis, and modulate Fas receptor activation. Ceramide has also been shown to regulate apoptosis through modulating key molecules of the Fas mediated apoptosis pathways.
Elevation of acid ceramidase, the enzyme that converts ceramide to sphingosine and subsequently sphingosine Inhibitors,Modulators,Libraries 1 phosphate, Inhibitors,Modulators,Libraries has been frequently observed in apoptosis resistant cancer cells, including metastatic colon carcinoma cells. These observations thus suggest that targeting ceramide metabolism to increase ceramide accumulation might be an effective approach to overcome cancer cell resistance to Fas mediated apoptosis. In this study, we demonstrated that aromatic ceramide analog LCL85 ef fectively overcomes metastatic Inhibitors,Modulators,Libraries human colon and breast cancer cell resistance to Fas mediated apoptosis at least partially through inducing proteasomal degradation of cIAP1 and xIAP in vitro. More significantly, we demon strated that LCL85 effectively suppresses colon and breast cancer metastasis in vivo.
Our data determined that LCL85 is potentially an effective apoptosis sensitizer that warrants further Inhibitors,Modulators,Libraries development as an adjunct agent to increase the efficacy of FasL CTL based cancer immunotherapy. Methods Mice BALB c mice were obtained from National Cancer Institute. All studies are approved by the Georgia Regents University Institutional Animal Care and Use Committee. Cell lines All human cell lines established from primary and meta static colon and breast cancer tissues, and mouse breast cancer cell line 4 T1 selleck chemicals were obtained from American Type Culture Collection.