Sphingolipid Metabolism in Tumor Cells.

Sphingolipids are a diverse family of complex lipids typically composed of a sphingoid base bound to a fatty acid via amide bond. The metabolism of sphingolipids has long remained out of focus of biochemical studies. Recently, it has been attracting an increasing interest of researchers because of different and often multidirectional effects demonstrated by sphingolipids with a similar chemical structure. Sphingosine, ceramides (N-acylsphingosines), and their phosphorylated derivatives (sphingosine-1-phosphate and ceramide-1-phosphates) act as signaling molecules. Ceramides induce apoptosis and regulate stability of cell membranes and cell response to stress. Ceramides and sphingoid bases slow down anabolic and accelerate catabolic reactions, thus suppressing cell proliferation. On the contrary, their phosphorylated derivatives (ceramide-1-phosphate and sphingosine-1-phosphate) stimulate cell proliferation. Involvement of sphingolipids in the regulation of apoptosis and cell proliferation makes them critically important in tumor progression. Sphingolipid metabolism enzymes and sphingolipid receptors can be potential targets for antitumor therapy. This review describes the main pathways of sphingolipid metabolism in human cells, with special emphasis on the properties of this metabolism in tumor cells.

Biochemical Basis of Selective Accumulation and Targeted Delivery of Photosensitizers to Tumor Tissues.

The method of photodynamic therapy for treatment of malignant neoplasms is based on the selective of accumulation of photosensitizers in the tumor tissue. Insufficient selectivity of photosensitizers in relation to pathologically altered tissues and generalized distribution throughout the body leads to the development of severe toxic effects, including skin phototoxicity. The mechanisms underlying selectivity of photosensitizers for tumor tissue include selective binding to blood proteins and lipoproteins (considering that the number of receptors for those is increased on tumor cell membranes), uptake by macrophages, better solubility at low pH (acidic pH is characteristic of tumor cells), and other mechanisms. At present, increase in the efficiency of photodynamic therapy is largely associated with the additional targeting of photosensitizers to tumor tissues. Targeted delivery strategies are based on the differences in metabolism and gene expression profiles between the tumor and healthy cells. There are differences in expression of receptors, proteases, or transmembrane transporters in these cells. In particular, accelerated metabolism in many types of tumors leads to overexpression of receptors for epidermal growth factor, folic acid, transferrin, and a number of other compounds. This review considers biochemical basis for the selective accumulation of various classes of photosensitizers in tumors (chlorins, phthalocyanines, 5-aminolevulinic acid derivatives, etc.) and discusses various strategies of targeted delivery with emphasis on conjugation of photosensitizers with the receptor ligands overexpressed in tumor cells.