Current Medicinal Chemistry - Volume 14, Issue 10, 2007

Apoptosis or programmed cell death is a cellular mechanism used to regulate cell number and eliminate damaged or mutated cells. Many chemotherapeutic agents and ionizing radiation induce not only apoptotic signaling pathways, but also survival responses such as DNA damage responses and cell cycle arrest, which allow for DNA repair. These survival responses determine the toxicity as well as the efficacy of the cancer treatment. Two main DNA damage responses include the activation of the anti-apoptotic transcription factor NF-κB and the activation of cell cycle checkpoint kinases. Strategies of combining chemotherapeutics with (a) inhibitors of NF-κB or (b) inhibitors of checkpoint kinases, may therefore enhance the efficacy of current cancer therapies. This review will be focused on recent progress made in combining traditional chemotherapeutic drugs with small molecule inhibitors of NF-κB and the checkpoint kinases, Chk1 and Chk2.

Developmental immunotoxicity (DIT) is increasingly recognized as a significant risk factor contributing to later life immune dysfunction as well chronic disease. In fact, recent increases in the incidence of asthma, allergic disease, autoimmunity and childhood infections maybe linked to problematic early life environmental exposures. The immune system of the non-adult is particularly susceptible to environmental influences whether from prenatal exposure to environmental toxins, maternallyadministered drugs, infections or from postnatal exposure to toxicants, infectious agents and allergens. Additionally, adultexposure models of immunotoxicity have been largely ineffective in predicting DIT risk. DIT-induced immune dysfunction can take many forms depending upon the environmental factor(s) involved and the precise developmental timing of exposure. If one examines the spectrum of published studies, a predominant phenotype has emerged that includes: Th balance skewing toward Th2, suppression of Th1 function, regulatory T cell function alteration, T cell repertoire abnormalities, problematic regulation of inflammatory cell function leading to hyperinflammatory responses and perturbation of cytokine networks. Early-life immune insult can also result in damage to the neurological and cardiovascular systems as well as endocrine and reproductive organs. Most therapeutic approaches to date have addressed the disease outcomes of DIT (e.g. asthma, allergy, autoimmunity, infections, and cancer) rather than focusing on the underlying immune dysfunction that creates the increased disease risk. While identification and prevention of problematic early life exposures is the best protection against DIT, this is not always possible. Therefore, identification of potential therapeutic approaches to reverse the immune dysfunction in the juvenile or adult is needed. In this review, we consider potential phytotherapeutic candidates among herbal- and fungal-derived medicinals for possible postnatal correction of the most predominant DIT-induced immune problems.

ERp57/GRp58 is a thiol-protein disulphide oxidoreductase and has been studied in many clinically relevant systems, both as a chaperone protein and as a membrane receptor for the steroid hormone, 1,25(OH)2D3. Our laboratory investigates phenomena associated with rapid, membrane-initiated signaling by steroid hormones synthesized from vitamin D (cholecalciferol). We have recently reported that the cell surface receptor for the metabolite 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], which we have termed the 1,25D3-MARRS (Membrane Associated, Rapid Response Steroid binding) receptor, is in fact identical to ERp57/GRp58. Here we review the dynamic role ERp57/GRp58/1,25D3-MARRS receptor plays in a variety of cellular processes. Starting with its structure at the DNA and protein levels, we review the available literature about its role as a chaperone protein, in immune function through the assembly of MHC class I molecules, DNA binding, and its function as the 1,25D3-MARRS receptor. Finally, we present the role it may play in relation to important disease states. While ERp57/GR58/1,25D3-MARRS receptor is a pivotal protein in many cell functions, it has yet to be determined whether-and to what extent-these phenomena are regulated by the vitamin D endocrine system. However, 1,25(OH)2D3 is involved in differentiation of certain cancer cells and in muscle function, and ERp57/1,25D3-MARRS protein has been reported to be involved in such processes. Thus, medicinal chemistry aimed at the 1,25D3-MARRS receptor in lymphocytes, cancer cells, bone, intestinal epithelia, and kidney may add to the current therapeutic regimens for various disease states.

Adipokines are proteins produced by white adipose tissue, which is an active secretory organ. Regulation of immune and inflammatory responses is among the multiple physiological processes involving adipokines. Leptin, adiponectin and resistin are the most extensively studied adipokines. Leptin may promote inflammation by inducing Th1 phenotype development, whereas adiponectin may combat inflammation by reducing the production of pro-inflammatory cytokines. Resistin belongs to a family of proteins found in foci of inflammation, where they contribute to the inflammatory response. All three adipokines have been detected in synovial fluid from joints affected with the inflammatory disease rheumatoid arthritis (RA) or the degenerative disease osteoarthritis (OA). Recent evidence points to involvement of leptin in RA and OA and indicates that adiponectin and/or resistin mediate inflammation in arthritis. Thus, fat tissue is an active organ whose products contribute to inflammatory and degenerative processes underlying common joint diseases.

In the post-genome era, RNA has emerged as a valid molecular target involved in many biochemical pathways such as cellular protein interactions. This includes transcription and translation, HIV-Rev and HIV-tat proteins binding to HIV RNA that encode HIV genetic information. The binding of natural and synthetic aminoglycosides to RNA or RNA-protein complexes has been a central focus of small molecules-RNA recognition events, since they bind selectively to a variety of RNA targets. The understanding of the contribution of shape-based and charge motifs involved in aminoglycosides-RNA complexes gives remarkable information of the translational miscoding process, thereby opening new insights for drug discovery. This review comprises relevant information about aminoglycosides antibiotics, including chemical structure, molecular mechanism, structureactivity relationships, recent advances in aminoglycoside mimetics over the last four years, resistance mechanisms and structuretoxicity relationships.

Antagonists of the beta-adrenergic receptor (β-AR antagonists) are a heterogeneous class of drugs. Selected members of this class are highly recommended in congestive heart failure (HF) and after acute myocardial infarction. Hydrosolubility, half life and prevalent route of excretion define the pharmacokinetic profile of individual drugs, whereas the respective degree of affinity for β1-AR and β2-AR, the level of coexistent agonist properties and several β-AR independent properties (e. g. antioxidant, direct vasodilating effect) contribute to shape the pharmacodynamic profile. Genetically determined differences in the response to β-AR antagonists and, probably, age-related changes in the neuroautonomic system are further source of variability in the effect of β-AR antagonists on bronchial tone. Patients with chronic obstructive pulmonary disease (COPD) are theoretically at risk of worsening respiratory flows and symptoms caused by β-AR antagonists prescribed for concurrent HF or myocardial infarction. Most of these patients, however, do not experience side effects, maybe because the improved haemodynamic due to β-AR antagonists therapy may in turn improve the respiratory function. Occasional patients can develop untoward respiratory effects of β-AR antagonists, and this risk is higher for those with severe COPD or active asthma. We provide some simple common sense rules for selecting patients with COPD or asthma that are suitable for β-AR antagonists therapy while minimizing the risk of adverse respiratory effects.

The discovery of stem cells (SC) has shed new light on the understanding of mechanisms responsible for ischemic and degenerative disorders, and opened a new field for regenerative medicine. Furthermore, dysregulation of SC self-renewal and their transformation seem to be involved also in the development of cancer, suggesting that pharmacological treatment devoted to regulate SC genomic and phenotypic functions might represent a potential new strategy even for the treatment of neoplastic disorders. SC display a promiscuous set of transcription factors and an open chromatin structure which are required to maintain their multipotentiality, while they are progressively quenched during differentiation into specific multiple lineages. The mechanisms that govern stem cell fate decisions are under tight control but remain potentially alterable. Recent studies have shown that several currently used drugs such as colony stimulating factors, statins, angiotensin-II receptor antagonists/ACEinhibitors, Erythropoietin, nitric oxide donors, estrogens and glitazones, have modulatory activity on SC functions. These drugs mostly enhance SC survival and mobilization. Furthermore, a series of new pharmacological agents such as the chemokine receptor antagonist AMD3100, glycogen synthase kinase-3 (GSK-3) inhibitors and histone deacetylase inhibitors (HDACi), that modulate the growth, differentiation and mobilization of SC, have been recently discovered and are currently under evaluation in both in vivo experimental models and preliminary clinical trials. Thus, modulation of SC properties through pharmacological treatment represents a new field of investigation which may lead to the development of novel strategies for the treatment not only of ischemic and degenerative disorders, but also of cancer.

Epidemiologic and experimental research on the potential carcinogenic effects of extremely low frequency electromagnetic fields (ELF-EMF) has been performed for a long time. Epidemiologic studies regarding ELF-EMF-exposure have focused primarily on leukaemia development due to residential sources in children and adults, and from occupational exposure in adults, but also on other kinds of cancer. Genotoxic investigations of EMF have shown contradictory results, a biological mechanism is still lacking that can explain the link between cancer development and ELF-EMF-exposure. Recent laboratory research has attempted to show general biological effects, and such that could be related to cancer development and/or promotion. Metabolic processes which generate oxidants and antioxidants can be influenced by environmental factors, such as ELF-EMF. Increased ELF-EMF exposure can modify the activity of the organism by reactive oxygen species leading to oxidative stress. It is well established that free radicals can interact with DNA resulting in single strand breaks. DNA damage could become a site of mutation, a key step to carcinogenesis. Furthermore, different cell types react differently to the same stimulus, because of their cell type specific redox status. The modulation of cellular redox balance by the enhancement of oxidative intermediates, or the inhibition or reduction of antioxidants, is discussed in this review. An additional aspect of free radicals is their function to influence other illnesses such as Parkinson's and Alzheimer's diseases. On the other hand, modulation of antioxidants by ELF-EMF can lower the intracellular defence activity promoting the development of DNA damage. It has also been demonstrated that low levels of reactive oxygen species trigger intracellular signals that involve the transcription of genes and leading to responses including cell proliferation and apoptosis. In this review, a general overview is given about oxidative stress, as well as experimental studies are reviewed as they are related to changes in oxidant and antioxidant content after ELFEMF exposure inducing different biological effects. Finally, we conclude from our review that modulations on the oxidant and antioxidant level through ELF-EMF exposure can play a causal role in cancer development.

Leishmaniasis is a parasitic disease caused by hemoflagellate, Leishmania spp. The parasite is transmitted by the bite of an infected female phlebotomine sandfly. The disease is prevalent throughout the world and in at least 88 countries. Nearly 25 compounds are reported to have anti-leishmanial effects but not all are in use. The pentavalent antimony compounds have remained mainstay for nearly 75 years. Pentavalent antimony is a prodrug that is reduced by glutathione to active trivalent species catalyzed by thiol-dependent-reductase. However, emergence of resistance led to the use of other compounds -amphotericin B, pentamidine, paromomycin, allopurinol etc. Amphotericin B, an antifungal macrolide polyene is characterized by the hydrophilic polyhydroxyl and hydrophobic polyene faces on it long axis. Presently, it is the only drug with highest cure rate. It acts on membrane sterols resulting in parasite cell lysis. Its lipid formulations have been developed to minimize side effects. Other anti-fungals like ketoconazole, fluconazole and terbinafine are found less effective. Recently, anticancer alkylphosphocholines have been found most effective oral compounds. These act as membrane synthetic ether-lipid analogues, and consist of alkyl chains in the lipid portions. Most promising of these are miltefosine (hexadecylphosphocholine), edelfosine (ET-18-OCH3) and ilmofosine (BM 41.440). However, the recent focus has been on identifying newer therapeutic targets in the parasite such as DNA topoisomerases. The present review describes the current understanding of different drugs against leishmaniasis, their chemistry, mode of action and the mechanism of resistance in the parasite. Future perspectives in the area of new anti-leishmanial drug targets are also enumerated. However, due to the vastness of the topic main emphasis is given on visceral leishmaniasis.