Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer

Dysfunction in the physiological pathways of programmed cell death may prom ote proliferation of malignant tells, and correction of such defects may se lectively induce apoptosis in cancer cells. We measured the levels of ceram ide, a candidate lipid mediator of apoptosis, in human metastatic colorecta l cancer and tested in vitro and in vivo effects of various ceramide analog ues in inducing apoptosis in metastatic colon cancer. Human colon cancer sh owed a >50% decrease in the cellular content of ceramide when compared with normal colon mucosa, Application of ceramide analogues and ceramidase inhi bitors induced rapid cell death through activation of various proapoptotic molecules, such as caspases and release of cytochrome c, Ceramidase inhibit ion increases the ceramide content of tumor cells, resulting in maximum act ivation of the apoptotic cascade. Normal liver cells were completely resist ant to inhibitors of ceramidases, Treatment of nude mice with B13, the most potent ceramidase inhibitor, completely prevented tumor growth using two d ifferent aggressive human colon cancer cell lines metastatic to the liver. Therefore, B13 and related analogues of ceramide and inhibitors of ceramida ses offer a promising therapeutic strategy with selective toxicity toward m alignant but not normal cells. These studies also suggest that the ceramide content in cancer cells might be involved in the pathogenesis of tumor gro wth in vitro and in vivo.