Dysfunction in the physiological pathways of programmed cell death may promote proliferation of malignant cells, and correction of such defects may selectively induce apoptosis in
cancer cells. We measured the levels of
ceramide, a candidate
lipid mediator of apoptosis, in human metastatic
colorectal cancer and tested in vitro and in vivo effects of various
ceramide analogues in inducing apoptosis in metastatic
colon cancer. Human
colon cancer showed a > 50% decrease in the cellular content of
ceramide when compared with normal colon mucosa. Application of
ceramide analogues and
ceramidase inhibitors induced rapid cell death through activation of various proapoptotic molecules, such as
caspases and release of
cytochrome c.
Ceramidase inhibition increases the
ceramide content of
tumor cells, resulting in maximum activation of the apoptotic cascade. Normal liver cells were completely resistant to inhibitors of
ceramidases. Treatment of nude mice with B13, the most potent
ceramidase inhibitor, completely prevented
tumor growth using two different aggressive human
colon cancer cell lines metastatic to the liver. Therefore, B13 and related analogues of
ceramide and inhibitors of
ceramidases offer a promising therapeutic strategy with selective toxicity toward malignant but not normal cells. These studies also suggest that the
ceramide content in
cancer cells might be involved in the pathogenesis of
tumor growth in vitro and in vivo.