Current Medicinal Chemistry - Volume 16, Issue 24, 2009

Tamoxifen is a widely known anti-estrogen which has been employed in adjuvant treatment of early-stage, estrogen- sensitive breast cancer for over 20 years. Less well known are the effects of tamoxifen on immune function, which we discuss here. We review the growing body of evidence which demonstrates immunomodulatory effects of tamoxifen, including in vitro and in vivo studies as well as observations made in breast cancer patients treated with tamoxifen. Taken together these studies suggest that tamoxifen is capable of inducing a shift from cellular (T-helper 1) to humoral (T-helper 2) immunity. Interestingly, the immunomodulatory effects of tamoxifen appear to be independent of the estrogen-receptor and may be mediated through the multidrug resistance gene product, Permeability-glycoprotein, for which a role in immunity has recently emerged. We furthermore discuss the clinical implications of the immunomodulatory effects of tamoxifen which are twofold. First, tamoxifen may be useful in the treatment of immune-mediated disorders, particularly of those arising from aberrant T-helper 1 cell activity, including allograft rejection, Crohn's disease, and Th1-mediated autoimmune conditions such as diabetes mellitus, scleroderma, and multiple sclerosis. Second, given that cellular T-helper 1 immunity is targeted against cancer cells, the tamoxifen-induced shift away from cellular immunity represents a significant step in fostering a cancerogenic environment. This may limit the anti-cancer effects of tamoxifen and thus explain why tamoxifen is inferior compared to other anti-estrogens in preventing disease recurrence in early-stage breast tumors.

With the rapid rise of tumor resistance, combinatorial anticancer therapies have gained favor over singlemolecule inhibition to maximize the suppression of oncogenic pathways. In this regard, HSP90 inhibitors have rapidly emerged as a class of promising drugs that can target multiple oncogenic pathways simultaneously. HSP90 is a highly conserved protein chaperone involved in essential cellular functions such as protein folding and cell signaling in both stressed and unstressed cells. In the last decade, a large number of oncogenic client proteins have been identified to associate with HSP90 and contribute to malignant transformation. Development of HSP90 inhibitors, derived from the natural compound geldanamycin that mimics the ATP binding site of HSP90, was designed to target HSP90 and allow degradation of these client proteins. Preclinical and clinical data with HSP90 inhibitors in various cancer models are promising, and evidences also hint at the potential for tumor-selective cytotoxicity as well as enhanced sensitization to chemo- and radiotherapy. This review will discuss the effects of HSP90 inhibition in cancer, the known mechanistic basis for the oncogenic toxicity and selectivity, as well as the current progress on single or combinatorial therapies with HSP90 inhibitors.

Among the various human cytochrome P450s (CYP450s) that catalyze the biotransformation of xenobiotics, CYP450 2D6 (CYP2D6) is one of the most important based on the number and wide variety of its drug substrates. CYP2D6 shows a high degree of interindividual variability, which is primarily due to the extensive genetic polymorphism that influences its expression and function. A number of drugs have been clinically implicated in major drug-drug interactions (DDI) via CYP2D6 inhibition. In order to avoid or minimize issues related to CYP2D6-mediated DDIs, pharmaceutical companies routinely screen for potential CYP2D6 liability of lead candidates in the early stage of the drug discovery process. This review summarizes the medicinal chemistry tactics employed to mitigate inhibitory activity at CYP2D6, identified through an extensive literature survey covering the 1998-2008 period.

The natural product hymenialdisine was first isolated in 1980 from the marine sponges of the genera Hymeniacidon, Acanthella, Axinella and Pseudaxinyssa. The structure was elucidated on the basis of X-ray crystallography demonstrating a structurally interesting pyrrole-azepin-8-one ring system bonded to a glycocyamidine ring. Great interest has been taken in synthesizing this type of scaffold due to its potent activity in competitive kinase inhibition. In addition, several patents have claimed pharmacological use of these compounds for prevention and treatment of different diseases. The challenging syntheses of hymenialdisine and its analogues are described in this review as well as their evaluation as kinase inhibitors.

A decrease in the number of functioning pancreatic β-cells and insufficient insulin biosynthesis and/or secretion are the hallmarks of diabetes. Therefore, the identification of alternative sources to induce insulin-producing surrogate β-cells is of great importance. For the induction of insulin-producing cells from various cells and/or tissues, it is useful to mimic and reproduce expression alterations of various pancreatic transcription factors observed during normal pancreas development and to induce key pancreatic transcription factors which have the potency to induce insulin and other β-cell-related genes. MafA, PDX-1 and NeuroD directly bind to the insulin gene promoter and function as very important transcription factors in pancreatic β-cell differentiation and mature β-cell function. The combination of MafA, PDX-1 and NeuroD markedly induces insulin biosynthesis in various non-β-cells and thereby is a useful tool to efficiently induce insulin- producing surrogate β-cells.

Tumor necrosis factor-alpha (TNF-α) is a central regulator of inflammation, and TNF-α antagonists may be effective in treating inflammatory disorders in which TNF-α plays an important pathogenetic role. Recombinant or modified proteins are an emerging class of therapeutic agents. To date, several recombinant or modified proteins which acts as TNF antagonists have been disclosed. In particular, antibodies that bind to and neutralise TNF have been sought as a means to inhibit TNF activity. Inhibition of TNF has proven to be an effective therapy for patients with rheumatoid arthritis and other forms of inflammatory disease including psoriasis, psoriatic arthritis, and ankylosing spondylitis, inflammatory bowel disease. Additionally, the efficacy of preventing septic shock and AIDS has been questioned as a result of recent research. The currently available therapies include a soluble p75 TNF receptor:Fc construct, etanercept, a chimeric monoclonal antibody, infliximab, and a fully human monoclonal antibody, adalimumab. Certolizumab pegol is a novel TNF inhibitor which is an antigen-binding domain of a humanized TNF antibody coupled to polyethylene glycol (PEG) to increase halflife, and thus is Fc-domain-free. In this review, we discuss briefly the present understanding of TNF-α-mediated biology and the current therapies in clinical use, and focus on some of the new therapeutic approaches with small-molecule inhibitors. Moreover, we examine recent reports providing important insights into the understanding of efficacy of thalidomide and its analogs, as TNF-α activity inhibitories, especially in therapies of several inflammatory diseases within the nervous system.

The present paper summarizes the possible roles of frequent and unfavourable genetic variants in cerebrovascular disorders, such as stroke and leukoaraiosis. It also approaches the topic theoretically from functional and mathematical points of view, which can help make the accumulating data on genetic variants more understandable. The interplay of an unfavourable genetic polymorphism and environmental clinical factors can result in a cerebrovascular disease or a state of vascular dementia. These constantly changing functional interactions need a highly specialised approach. There is, therefore, a great need to summarise the results on genetic polymorphisms concisely, and to discuss their special but shared features, which make their evaluation difficult with the methods used for the well-known Mendelian factors. The development of a correct approach to genetic polymorphisms may have a great impact on the understanding and prevention of cerebrovascular diseases.

This review aims to present different aspects related to cruzipain, one of the most important proteins of the etiological agent of Chagas disease that has been extensively studied in the last two decades, including all the particularities of the molecule as well as to highlight its participation in multiple relevant functions of the parasite to favour the cell invasion phenomena, to facilitate host tissues proteolytic degradation and to trigger the evasion mechanism from host immune response. Cruzipain has been related with parasite metabolism and identified as both an important candidate for vaccine development and for trypanocidal drug design. We have reported for the first time that this enzyme is a sulfated glycoprotein. Indeed, the sulfated oligosaccharides are main targets for immune responses and are involved in tissue damage in mice immunized in absence of infection contributing to get deeper into the knowledge of the molecule composition and helping to elucidate its role in the infection and/or pathogenesis of the disease. A whole view including all the aspects related to the major cysteine proteinase of Trypanosoma cruzi studied so far including recent advances as proteinase, antigen and glycoprotein will be discussed.