Том 11, № 4 (2011)

Cationic Mn(III) N-alkylpyridyl (MnTalkyl-2(or 3)-PyP5+) and N, N-dialkylimidazolylporphyrins (MnTDalkyl-2-ImP5+) have been regarded as the most powerful SOD mimics/peroxynitrite scavengers – i. e. antioxidants. The ethyl-, MnTE-2-PyP5+ (AEOL10113), and hexylpyridyl-, MnTnHex-2-PyP5+ and diethylimidazolylporphyrin, MnTDE-2-ImP5+ (AEOL10150) have been mostly studied in vitro and in vivo. Given the in vivo abundance of cellular reductants, MnPs can couple with them in removing superoxide. Thus, they could be readily reduced from MnIIIP to MnIIP with ascorbate and glutathione, and in a subsequent step reduce either O2 .- (while acting as superoxide reductase) or oxygen (while exerting pro-oxidative action). Moreover, MnPs can catalyze ascorbate oxidation and in turn hydrogen peroxide production. The in vivo type of MnP action (anti- or pro-oxidative) will depend upon the cellular levels of reactive species, endogenous antioxidants, availability of oxygen, ratio of O2 .-- to peroxide-removing systems, redox ability of MnPs and their cellular localization/bioavailibility. To exemplify the switch from an anti- to pro-oxidative action we have explored a very simple and straightforward system – the superoxide-specific aerobic growth of SOD-deficient E. coli. In such a system, cationic MnPs, ortho and meta MnTE-2-(or 3)-PyP5+ act as powerful SOD mimics. Yet, in the presence of exogenous ascorbate, the SOD mimics catalyze the H2O2 production, causing oxidative damage to both wild and SOD-deficient strains and inhibiting their growth. Catalase added to the medium reversed the effect indicating that H2O2 is a major damaging/signaling species involved in cell growth suppression. The experiments with oxyR- and soxRS-deficient E. coli were conducted to show that E. coli responds to increased oxidative stress exerted by MnP/ascorbate system by induction of oxyR regulon and thus upregulation of antioxidative defenses such as catalases and peroxidases. As anticipated, when catalase was added into medium to remove H2O2, E. coli did not respond with upregulation of its own antioxidant systems.

Nitroxides are low molecular weight (150-400 Da) superoxide dismutase mimics that exhibit antioxidant, radical scavenging, and radioprotective activity. Additionally, the paramagnetic nature of nitroxides makes them viable as both spin probes for electron paramagnetic resonance imaging as well as contrast agents for magnetic resonance imaging. These imaging techniques enable in vivo monitoring of nitroxide metabolism. In biological systems, nitroxide metabolism occurs predominantly via reduction of the nitroxide to a hydroxylamine. The rate of nitroxide reduction can increase or decrease due to oxidative stress, suggesting that nitroxides can provide an imaging-based assay of tissue redox status. The current review briefly summarizes the potential clinical applications of nitroxides, and focuses on the biochemical and tumor microenvironmental factors that affect the rate of nitroxide reduction. The potential therapeutic applications and bio-reduction mechanisms are discussed in the context of their relevance to oncology.

The nitrone compound PBN, α-phenyl-tert-butylnitrone, and closely related nitrones have anti-cancer activity in several experimental cancer models. The three experimental models most extensively studied include A) the rat choline deficiency liver cancer model, B) the rat C6 glioma model and C) the mouse APCMin/+ colon cancer model. The two PBN-nitrones mostly studied are PBN and a PBN derivative 2,4-disulfophenyl-tert-butylnitrone, referred as OKN-007. OKN-007 is a proprietary compound that has had extensive commercial development (designated as NXY-059) for another indication, acute ischemic stroke, and after extensive clinical studies was shown to lack efficacy for this indication but was shown to be very safe for human use. This compound administered orally in the rat glioma model has potent activity in treating fully formed gliomas. In this report observations made on the PBN-nitrones in experimental cancer models will be summarized. In addition the experimental results will be discussed in the general framework of the properties of the compounds with a view to try to understand the mechanistic basis of how the PBN-nitrones act as anti-cancer agents. Possible mechanisms related to the suppression of NO production, S-nitrosylation of critical proteins and inhibition of NF-κB activation are discussed.

Sphingolipids are major constituents of the cells with emerging roles in the regulation of cellular processes. Deregulation of sphingolipid metabolism is reflected as various pathophysiological conditions including metabolic disorders and several forms of cancer. Ceramides, ceramide-1-phosphate (C1P), glucosyl ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P) are among the bioactive sphingolipid species that have important roles in the regulation of cell death, survival and chemotherapeutic resistance. Some of those species are known to accumulate in the cells upon chemotherapy while some others are known to exhibit an opposite pattern. Even though the length of fatty acid chain has a deterministic effect, in general, upregulation of ceramides and sphingosine is known to induce apoptosis. However, S1P, C1P and GluCer are proliferative for cells and they are involved in the development of chemoresistance. Therefore, sphingolipid metabolism appears as a good target for the development of novel therapeutics or supportive interventions to increase the effectiveness of the chemotherapeutic drugs currently in hand. Some approaches involve manipulation of the synthesis pathways yielding the increased production of apoptotic sphingolipids while the proliferative ones are suppressed. Some others are trying to take advantage of cytotoxic sphingolipids like short chain ceramide analogs by directly delivering them to the malignant cells as a distinct chemotherapeutic intervention. Numerous studies in the literature show the feasibility of those approaches especially in acute and chronic leukemias. This review compiles the current knowledge about sphingolipids and their roles in chemotherapeutic response with the particular attention to leukemias.