Current Medicinal Chemistry - Volume 18, Issue 34, 2011

It is now accepted that cancer initiation, progression, and invasion occur in a dynamic microenvironment, where many cell types interact with tumor cells, including stromal cells, the intratumoral vasculature, macrophages and dendritic cells, the various types of lymphocytes such as NK cells, B and T cells, regulatory T-cells. The complex communications between all these cell populations involve interplay between soluble factors, such as cytochines and chemokines, surface receptors and adhesion molecules, and the balance between these events determines whether there is a tumour cell growth promotion or inhibition. As for haematological malignancies, accumulating evidence indicates that the cellular microenvironment plays an important role in the pathogenesis of multiple myeloma (MM), chronic lymphocytic and myeloid leukemias and follicular lymphomas. Accordingly, the survival, drug-resistance and proliferation of leukemic cells have been shown to be largely dependent on a supportive microenvironment. Among the different environment-associated parameters, those related to the status/activity of the immune system are particularly relevant. As such, all the players in the microenvironment represent a challenge to the development of therapeutic agents, requiring re-direction and inclusion of these non-neoplastic supportive cells into future treatment strategies. In this special issue, different aspects of this problem are presented focusing on possible therapeutic combined approaches aimed to direct the various components of the microenvironment towards an anti-tumor direction. Possible caveats of the different therapeutic approaches are also considered and discussed. The first review, by Krusch and Salih, addresses the “immunomodulatory” effects of BCR-ABL inhibitors, like imatinib, nilotinib and dasatinib. Multiple effects on different immune effector cell subsets and of these drugs have been reported, the latter being due to their particular and diverse potency and spectrum of target kinases. As multiple approaches presently aim to combine BCR-ABL inhibition with immunotherapeutic strategies to improve disease control in chronic myeloid leukemia, immunomodulatory effects of the available BCR-ABL inhibitors may be of direct clinical relevance. The authors review the available data regarding the effects of imatinib, nilotinib, and dasatinib on dendritic cells, T cells and natural killer cells as central effector cells of anti-tumor immunity. They also discuss the possible contribution of dasatinib to the elimination of chronic myeloid leukemia stem cells by enhancing anti-tumor immunity. The contribution by Ferrero and Ferrarini takes into consideration the microenvironment of multiple myeloma, discussing the effects of the proteasome inhibitor (PI) bortezomib and of some immunomodulatory drugs (IMiDs) on the interactions of myeloma cells, cells of the immune system and endothelial cells. Comparison with drugs acting on endothelium, and the potential additional impact on myeloma therapy, is also presented. Indeed, the patho-physiology of MM associated angiogenesis involves a plethora of soluble factors, cellular players and mechanisms. Moreover, the hypoxic microenvironment inside the bone marrow might significantly contribute to the induction and maintenance of a pro-angiogenic profile, given the well-known as hypoxia is involved in promoting angiogenesis in all its forms. In this article, an overview of the literature is presented focusing on the mechanisms implicated in the “angiogenic switch”, which corresponds to the transition from the avascular to the vascular phase of the disease. The anti-angiogenic effects of PI and IMiDs, which substantially contribute to their anti-MM activity, is also discussed, summarizing possible caveats and perspectives about anti-angiogenic strategies that could be addressed to improve the efficacy of treatments for MM patients. In the review by Alessandro Poggi and myself, the role of bone marrow mesenchymal stromal cells (BMSC) in modulating T lymphocyte function, promoting survival of normal and malignant B cells, is described. In this study, the effects of cholesterol synthesis inhibitors, such as statins, on the interaction between BMSC and T lymphocytes or on natural killer cell-mediated functions is analyzed and compared with other drugs known to act on BMSC, including thalidomide or lenalidomide. Besides lowering the plasma lipid levels, statins indeed show strong anti-inflammatory and immunomodulatory effects. On the other hand, these drugs can affect growth and survival of solid tumour and leukaemic cells, thus they have been proposed in the treatment of multiple myeloma, in association with drugs, as thalidomide, known to act on the cancer microenvironment.....

In chronic myeloid leukemia (CML), BCR-ABL-mediated oncogenic signaling can be successfully targeted with the BCRABL- inhibitors imatinib, nilotinib, and dasatinib leading to complete cytogenetic (Philadelphia chromosome not detectable upon cytogenetic testing of bone marrow) and even complete molecular (BCR-ABL not detectable by PCR in peripheral blood) responses. However, CML apparently can not be cured by BCR-ABL inhibitors alone, likely due to treatment-resistance of CML stem/progenitor cells, which provokes a relapse of disease after cessation of therapy. Evidence from patients treated with allogenic stem cell transplantation or IFN-α points to an important role of anti-tumor immunity for durable control of CML disease. Data from multiple in vitro and ex vivo studies indicate that BCR-ABL inhibitors may also influence anti-tumor immunity. Varying effects on different immune effector cell subsets and of the different compounds have been reported, the latter being due to their particular and diverse potency and spectrum of target kinases. As multiple approaches presently aim to combine BCR-ABL inhibition with immunotherapeutic strategies to improve disease control in CML, immunomodulatory effects of the available BCR-ABL inhibitors may be of direct clinical relevance. Here we review the available data regarding the effects of imatinib, nilotinib, and dasatinib on dendritic cells, T cells and natural killer cells as important cellular components of anti-tumor immunity.

Survival of patients affected by Multiple Myeloma (MM), a B-cell tumor of malignant plasma cells, has dramatically improved, owing to the recent introduction of the proteasome inhibitor (PI) Bortezomib and of the immunomodulatory drugs (IMiDs). This major advance originates from accumulating knowledge on MM biology, leading to the development of drugs targeting not only MM cells, but also their microenvironment. Indeed, the disease develops as a result of genetic abnormalities and of reciprocal interactions between MM cells and the permissive BM microenvironment, which delivers growth- and pro-survival signals and confers resistance to drugs. As for solid tumors, bone marrow (BM) angiogenesis is emerging as a critical component of MM development and progression, and hence as an attractive therapeutic target for the disease. The patho-physiology of MM associated angiogenesis is complex and involves a plethora of soluble factors, cellular players and mechanisms. Moreover, the hypoxic microenvironment inside the BM might significantly contribute to the induction and maintenance of a pro-angiogenic profile, given the well-known role of hypoxia in promoting angiogenesis in all its forms. Here we present an overview of the literature focusing on the mechanisms implicated in the “angiogenic switch”, which corresponds to the transition from the avascular to the vascular phase of the disease. We also review evidence on the anti-angiogenic effects of PI and IMiDs, which substantially contribute to their anti-MM activity. Finally, we summarize possible caveats and perspectives about antiangiogenic strategies that could be addressed to improve the efficacy of treatments for MM patients.

There is increasing evidence that statins, inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A reductase, can effectively be used not only in the treatment of hypercholesterolemia, but also in other human disorders; indeed, statins have strong anti-inflammatory and immunomodulatory effects, so that they can influence the onset and outcome of inflammation and autoimmunity. On the other hand, it has been shown that statins can affect growth and survival of solid tumour and leukemic cells, thus they have been proposed in the treatment of neoplasias as multiple myeloma, in association with drugs, as thalidomide, known to act on the cancer microenvironment. In the current view, tumor microenvironment include many cell types that interact with tumor cells: among them, stromal and endothelial cells, macrophages and dendritic cells, the various types of lymphocytes such as NK cells, B and T cells. The interplay between all these cell populations, and the balance between these, determines whether there is a tumour cell growth promotion or inhibition. In haematological malignancies, such as multiple myeloma, chronic lymphocytic and myeloid leukemias and follicular lymphomas, the survival, drug-resistance and proliferation of leukemic cells have been shown to be largely dependent on a supportive microenvironment, so that some cellular components of it, mainly mesenchymal stromal cells, cancer associated fibroblasts and macrophages, are now proposed as targets of new therapies. Herein, we analyze the effects that statins can exert on cancer cells, stromal cells and human natural killer cells, to discuss whether they can be proposed as anti-cancer drugs.

Gamma delta (&ggr:δ) T cells are intrinsically important for preventing the development and progression of hematologic cancers. These innate T cells are particularly suited for the application of cancer therapy due to the fact they: 1) recognize transformed cells independent of antigen processing or presentation by classical MHC molecules, and 2) embody the anti-tumour effector functions of both NK cells and cytotoxic T cells. It was serendipitously discovered that aminobisphosphonates (ABP), a class of drugs used as adjuvant cancer therapy for the treatment of malignant osteolytic bone disease, have the unexpected side-effect of potently activating the antitumour effector functions of human peripheral &ggr:δ T cells. Such beneficial therapeutic synergisms are rare, and no time has been wasted to determine how to best harness the anti-cancer potential of &ggr:δ T cells and ABP. Despite promising experimental results, the full clinical potential of this immunotherapeutic strategy has been hampered by the subversive strategies employed by cancer cells to obstruct activation of anti-tumour immune responses. These include the promotion of regulatory T cells (Tregs) that maintain tumour tolerance and the corruption of dendritic cell (DC) function and maturation. Toll-like receptor (TLR) agonists have a long history of breaking free of tumour-induced immune-suppression by resetting DC function and abrogating Treg induced tolerance. This review presents data to support the notion that TLR signalling may perfectly complement the anti-tumour synergy of ABP and activated &ggr:δ T cells, and this combined innate artillery could provide the necessary ammunition to topple malignancy's stronghold on the immune system.

Tumor-induced dysfunction of immune cells is a common problem in cancer. Tumors induce immune suppression by many different mechanisms, including accumulation of regulatory T cells (Treg). Adaptive Treg (Tr1) generated in the tumor microenvironment express CD39 and CD73 ectonucleotidases, produce adenosine and are COX2+PGE2+. Adenosine and PGE2 produced by Tr1 or tumor cells bind to their respective receptors on the surface of T effector cells (Teff) and cooperate in up-regulating cytosolic 3'5'-cAMP levels utilizing adenylyl cyclase isoform 7 (AC-7). In Teff, increased cAMP mediates suppression of anti-tumor functions. Treg, in contrast to Teff, seem to require high cAMP levels for mediating suppression. This differential requirement of Treg and Teff for cAMP offers an opportunity for pharmacologic interventions using selected inhibitors of the adenosine/PGE2 pathways. Blocking of adenosine/PGE2 production by Tr1 or blocking binding of these factors to their receptors on T cells or inhibition of cAMP synthesis in Teff all represent novel therapeutic strategies that used in combination with conventional therapies could restore anti-tumor functions of Teff . At the same time, these inhibitors could disarm Tr1 cells by depriving them of the factors promoting their generation and activity or by down-regulating 3'5'-cAMP levels. Thus, the pharmacologic control of Treg-Teff interactions offers a novel strategy for restoration of anti-tumor Teff functions and silencing of Treg. Used in conjunction with anti-cancer drugs or with immune therapies, this strategy has a potential to improve therapeutic effects by preventing or reversing tumor-induced immune suppression.

This review summarizes the sources and characteristics of various natural products that can be extracted from mangroveassociated microbes with a focus on bioactivity, highlighting the unique chemical diversity of these metabolic products.

Obesity is associated with an increased mortality and morbidity for cardiovascular disease (CVD) and adipose tissue is recognised as an important player in obesity-mediated CVD. The diagnosis of the metabolic syndrome (MS) appears to identify substantial additional cardiovascular risk above and beyond the individual risk factors, even though the pathophysiology underlying this evidence is still unravelled. The inflammatory response related to fat accumulation may influence cardiovascular risk through its involvement not only in body weight homeostasis, but also in coagulation, fibrinolysis, endothelial dysfunction, insulin resistance (IR) and atherosclerosis. Moreover, there is evidence that oxidative stress may be a mechanistic link between several components of MS and CVD, through its role in inflammation and its ability to disrupt insulin-signaling. The cross-talk between impaired insulin-signaling and inflammatory pathways enhances both metabolic IR and endothelial dysfunction, which synergize to predispose to CVD. Persistent platelet hyperreactivity/activation emerges as the final pathway driven by intertwined interactions among IR, adipokine release, inflammation, dyslipidemia and oxidative stress and provides a pathophysiological explanation for the excess risk of atherothrombosis in this setting. Despite the availability of multiple interventions to counteract these metabolic changes, including appropriate diet, regular exercise, antiobesity drugs and bariatric surgery, relative failure to control the incidence of MS and its complications reflects both the multifactorial nature of these diseases as well as the scarce compliance of patients to established strategies. Evaluation of the impact of these therapeutic strategies on the pathobiology of atherothrombosis, as discussed in this review, will translate into an optimized approach for cardiovascular prevention.

Serotonin (5-hydroxytryptamine, 5-HT) is well known to be closely associated with emotional disorders, such as depression and schizophrenia. The seven main members of 5-HT receptor family including the different subtypes are involved in the functional pathways in the brain and their balance in activity helps to maintain the normal mental stability. As any detrimental changes in the 5-HT system is believed to alter emotion in human, different drugs including serotonin reuptake inhibitors (SSRIs) are nowadays commonly used as anti- depressives. In this review, 5-HT1A and 5-HT2A receptors and serotonergic positive cells in the human were highlighted in particular. It is hoped that this review will give a map of these major 5-HT receptors and serotonergic neurons in the human CNS to facilitate further deciphering of their functions.

Flavonoids are new promising potential natural compounds for treating Alzheimer's disease (AD). Actually most promising drugs for symptomatic treatment of AD are acetylcholinesterase inhibitors (AChEI). Flavonoids with AChE inhibitory activity and due to their well known antioxidant activity could be new multipotent drugs for AD treatment. This work focuses on natural and synthetic flavonoids inhibitors of the enzyme acetylcholinesterase (AChE). Over, all this review refers to 128 flavonoids, which are classified in chemical structure, and summarizes 64 references.

This review aims to summarize present approaches employed in delivering drugs to the central nervous system. Changes in blood-brain barrier (BBB) function have been reported in several neurological disorders. A brief description of the blood brain barrier and the main pathologies related to this barrier disfunction are described. Treatments for these disorders are based on several available strategies for delivering drugs into the brain, through circumvention of the BBB, as disruption of the BBB, prodrugs, molecular Trojan horses, among others. Particular attention will be placed on nanocarriers and more specifically on polymeric nanoparticles, which are presented as the most promising strategy for CNS delivery, helping drugs to be targeted more efficiently to the brain. This also allows attacking previously untreatable disorders such as brain tumors and other neurodegenerative diseases. New strategies and technologies commercialized by different pharmaceutical companies are also included.