Current Molecular Pharmacology - Volume 3, Issue 2, 2010

Sphingolipid metabolites are critical to the regulation of a number of fundamental biological processes including cancer. Whereas ceramide and sphingosine mediate and trigger apoptosis or cell growth arrest, sphingosine 1- phosphate promotes proliferation, cell survival and angiogenesis. The delicate equilibrium between the intracellular levels of each of these sphingolipids is controlled by the enzymes that either produce or degrade these metabolites. Sphingosine kinase-1 is a crucial regulator of this two-pan balance, because it produces the pro-survival and pro-angiogenic sphingosine 1-phosphate and decreases the amount of both ceramide and sphingosine, the pro-apoptotic sphingolipids. Moreover, its gene is oncogenic, its mRNA is overproduced in several solid tumors, its overexpression protects cells from apoptosis, and its activity is down-regulated by anti-cancer treatments. Therefore, the sphingosine kinase-1/sphingosine 1-phosphate signaling pathway appears to be a target of interest for therapeutic manipulation.

Lipid peroxidation leads to the formation of a number of aldehydes by-products, including acrolein. The most abundant aldehydes are 4-hydroxy-nonenal (4-HNE) and malondialdehyde (MDA) while acrolein is the most reactive. In Alzheimer's brain, acrolein was found to be elevated in hippocampus and temporal cortex where oxidative stress is high. In late onset Alzheimer's disease (AD), a 2-fold increase in levels of acrolein/guanosine adducts in nDNA was isolated from the hippocampus of AD as compared to age-matched control. These adducts are biologically relevant in that they may promote DNA-DNA and DNA-protein cross-linking while 4-HNE/guanosine adducts in nDNA were not elevated in AD. In AD, the activity of the glutathione-S-transferase, the main enzyme responsible for the detoxification of acrolein is significantly decreased in hippocampus. On neuronal primary culture from hippocampus, acrolein caused cell death and its toxicity is higher than 4-hydroxynonenal. Acrolein could modulate tau phosphorylation through different pathways. Acrolein has been shown to inhibit the mitochondrial activity. Due to its high reactivity, acrolein is not only a marker of lipid peroxidation but also an initiator of oxidative stress by adducting cellular nucleophilic groups found on proteins, lipids, and nucleic acid. As a strong electrophile molecule, acrolein can react about 110-150 times faster with the thiol group of cysteine than with 4-hydroxynonenal and decrease the level of the antioxidant glutathione. Taken together, these reactions suggest that acrolein could play a role in the pathophysiology of AD. In this review, we will summarize some mechanisms implicated in the toxicity of this by-product of lipid peroxidation in brain and their implication in AD.

The PI3K pathway constitutes an important pathway for regulating the signaling of multiple essential biological processes for which deregulation might contribute to cancer. As such, the PI3K pathway is one of the most frequently altered pathways in human tumors, providing constitutive pathway activation. The evidence indicates that the PI3K pathway is a potential target for cancer chemotherapy. Indeed, many companies and academic laboratories have initiated a variety of approaches to inhibit the pathway at different points. These proteins are kinases, which are very “druggable” targets a priori and, according to the “addiction hypothesis,” cancer cells with this pathway activated will be more dependent upon this pathway for their survival. In this work, we will focus on PI3K protein as a major target for therapeutic intervention. We thoroughly review the clinical achievements and major concerns raised by the pharmacological intervention of PI3Ks.

Nelfinavir (Viracept®) was originally designed as a specific HIV protease inhibitor and, since its introduction in 1997, has served as an effective, reliable, and well-tolerated HIV drug. Although nelfinavir is being increasingly displaced by second generation HIV protease inhibitors that allow better combination treatments, it has again become a focus of interest due to an interesting paradoxical effect: nelfinavir inhibits experimentally-induced tissue degeneration or cell damage by preventing loss of the mitochondrial membrane potential, and even protects mitochondria in cancer cells but, conversely, it selectively induces a mitochondria-independent cell death mechanism in cancer cells by the so-called endoplasmic reticulum/unfolded protein stress response, allowing nelfinavir to act on otherwise chemo-resistant cancer cells. Furthermore, anti-microbial effects of nelfinavir have been described, including an efficacy against malaria, tuberculosis, and SARS, mostly by cross-reacting with microbial aspartic proteases. Several cancer-related clinical studies on nelfinavir as a single agent or in combination therapies have been launched and are expected to add to the usefulness of this versatile drug for cancer treatment strategies or other purposes.