Poly-drug cancer therapy based on ceramide.

Abstract

Thousands of research studies have reported that many kinds of cancer cells and tumors can be killed by treatments that increase the concentration of a simple cellular sphingolipid, ceramide (Cer). While there are many ways to elevate tumor Cer levels, this approach is complicated by the central, complex role of Cer in cell homeostasis: Cer is readily metabolized to form other sphingolipids that increase the tumor's growth rate, metastasis, and resistance to the patient's immune system. This review points out the need to prevent this metabolic conversion while simultaneously stimulating the enzymes that increase the formation of Cer. I describe here many of the enzymes that need stimulation or inhibition, and drugs or metabolites or dietary components that modify each of the enzymes. The review also points to the importance of the allylic alcohol group in Cer and in many cancer drugs, suggesting that the hydroxyl group participates in phosphate transfer to and from proteins by forming a temporary phosphate ester. The allylic hydroxyl may also reduce the ketone moieties in mitochondrial ubiquinone, with formation of reactive oxygen species and apoptogenic breakdown. The level of Cer in tumors can be increased by: (1) direct administration of Cer or a Cer analogue, and (2) stimulation of Cer synthesis from its elementary precursors, or from (3) sphingomyelin by hydrolysis, or from (4) the glucosphingolipids by hydrolysis, or (5) by acylation of sphingosine. In addition, Cer concentration can be raised by slowing its conversion to (6) sphingomyelin, (7) glucosylCer, (8) Cer phosphate, and (9) sphingosine + fatty acid by hydrolysis. Therapeutic radiation stimulates the de novo synthesis of Cer in tumors. Conversion of sphingosine (from Cer) to sphingosine phosphate probably also ought to be blocked.