Killing tumours by ceramide-induced apoptosis: a critique of available drugs.

Over 1000 research papers have described the production of programmed cell death (apoptosis) by interventions that elevate the cell content of ceramide (Cer). Other interventions, which lower cellular Cer, have been found to interfere with apoptosis induced by other agents. Some studies have shown that slowing the formation of proliferation-stimulating sphingolipids also induces apoptosis. These relationships are due to the two different aspects of Cer: Cer itself produces apoptosis, but metabolic conversion of Cer into either sphingosine 1-phosphate or glucosphingolipids leads to cell proliferation. The balance between these two aspects is missing in cancer cells, and yet intervention by stimulating or blocking only one or two of the pathways in Cer metabolism is very likely to fail. This results from two properties of cancer cells: their high mutation rate and the preferential survival of the most malignant cells. Tumours treated with only one or two drugs that elevate Cer can adjust the uncontrolled processes to either maintain or to 'aggravate' the excessive growth, angiogenesis and metastasis characteristics of tumours. These treatments might simply elevate the production of growth factors, receptors and other substances that reduce the effectiveness of Cer. Tumour cells that do not adapt in this way undergo apoptosis, leaving the adapted cells free to grow and, ultimately, to 'subdue' their host. Thus it is important to kill every type of cancer cell present in the tumour rapidly and simultaneously, using as many different agents to control as many pathways as possible. To aid this approach, this article catalogues many of the drugs that act on different aspects of Cer metabolism. The techniques described here may lead to the development of practical chemotherapy for cancer and other diseases of excess proliferation.