Hydrolytic pathway protects against ceramide-induced apoptosis in keratinocytes exposed to UVB.

Although ceramides (Cers) are key constituents of the epidermal permeability barrier, they also function as apoptogenic signals for UVB irradiation-induced apoptosis in epidermal keratinocytes. As epidermis is continuously exposed to UV irradiation, we hypothesized that Cer hydrolysis protects keratinocytes from UVB-induced apoptosis by attenuating Cer levels. Both low-dose UVB (L-UVB) (< 35 mJ cm(-2)) and high-dose UVB (H-UVB) (> or = 45 mJ cm(-2)) irradiation inhibited DNA synthesis in cultured human keratinocytes, but apoptosis occurred only after H-UVB.

New antitumor imidazo[2,1-b]thiazole guanylhydrazones and analogues.

The synthesis of new antitumor 6-substituted imidazothiazole guanylhydrazones is described. Moreover, a series of compounds with a different basic chain at the 5 position were prepared. Finally, the replacement of the thiazole ring in the imidazothiazole system was also considered.

Allylic structures in cancer drugs and body metabolites that control cell life and death.

This review presents data supporting the hypothesis that the anticancer activity of ceramide and many antineoplastic drugs is due to a 3-carbon allylic moiety (-C = C-C-) containing oxygen or nitrogen. The polar atom appears as an alcohol, ether, ester, amide, ketone, amine or imino group. Some drugs lack the allylic moiety, but metabolic oxidation or oxygenation in patients introduces the moiety.

Meta-analysis of anticancer drug structures--significance of their polar allylic moieties.

This meta-analysis examines a wide range of small molecule anticancer drugs to search for a structure common to all. Although they encompass a very wide range of structures, nearly all reveal the presence of an allylic O, N, or S atom. In some, the allylic oxygen is a carbonyl group, or an alcohol group, which can be substituted (ester, lactone, glycoside, ether) or replaced by an amino or imino nitrogen Some antineoplastic drugs do not exhibit this moiety but are converted in vivo to allylic derivatives.

Preventing the binding of pathogens to the host by controlling sphingolipid metabolism.

The binding of many pathogens and toxins to human cells can be inhibited by (1) depleting host cells of their surface glycosphingolipids; (2) coating the binding sites on pathogens (adhesins) with glycosphingolipid-like substances (decoys); (3) coating the host's glycosphingolipids with substances that compete with the pathogen for binding. Details of using these methods are described.

Sphingolipids as coenzymes in anion transfer and tumor death.

Many kinds of natural sphingolipids and their analogs stimulate or inhibit a wide assortment of biochemical phenomena and enzymes. The puzzle considered here is: how can these lipids control so many different kinds of processes? In almost every study in which a structural comparison was made, an allylic alcohol moiety [-CH=CH-CH(OH)-] was found to be an essential feature of the sphingolipid. Many of those stimulations lead to cell death, emphasizing the importance of allylic sphingolipid structure in the design of chemotherapeutic agents.

Poly-drug cancer therapy based on ceramide.

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.

Designing anticancer drugs via the achilles heel: ceramide, allylic ketones, and mitochondria.

Published reports are reviewed as the basis of a proposal that an effective antineoplastic drug should contain several features: (a) resemblance to the natural lipid, ceramide; (b) an allylic alcohol and/or allylic ketone moiety; (c) a hydroxyl and/or a nitrogen atom near the allylic group; (d) conjugated double bonds as part of the allylic region. The drug should produce reactive oxygen species in tumor mitochondria, stimulate the generation of ceramide in the tumor, and condense with mitochondrial glutathione. It is pointed out that some antibiotics with these features are also active against cancer cells; perhaps anticancer drugs with these features will prove useful as antibiotics.

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.