Current Medicinal Chemistry (v.18, #34)

It is now accepted that cancer initiation, progression, and invasion occur in a dynamic microenvironment, where many cell types interactwith tumor cells, including stromal cells, the intratumoral vasculature, macrophages and dendritic cells, the various types of lymphocytessuch as NK cells, B and T cells, regulatory T-cells. The complex communications between all these cell populations involve interplaybetween soluble factors, such as cytochines and chemokines, surface receptors and adhesion molecules, and the balance between these eventsdetermines 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 thepathogenesis 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 thedifferent environment-associated parameters, those related to the status/activity of the immune system are particularly relevant. As such, allthe players in the microenvironment represent a challenge to the development of therapeutic agents, requiring re-direction and inclusion ofthese 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 directthe various components of the microenvironment towards an anti-tumor direction. Possible caveats of the different therapeutic approaches arealso considered and discussed.The first review, by Krusch and Salih, addresses the “immunomodulatory” effects of BCR-ABL inhibitors, like imatinib, nilotinib anddasatinib. Multiple effects on different immune effector cell subsets and of these drugs have been reported, the latter being due to theirparticular and diverse potency and spectrum of target kinases. As multiple approaches presently aim to combine BCR-ABL inhibitionwith immunotherapeutic strategies to improve disease control in chronic myeloid leukemia, immunomodulatory effects of the availableBCR-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 alsodiscuss 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 ofthe proteasome inhibitor (PI) bortezomib and of some immunomodulatory drugs (IMiDs) on the interactions of myeloma cells, cells of theimmune 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 andmechanisms. Moreover, the hypoxic microenvironment inside the bone marrow might significantly contribute to the induction andmaintenance of a pro-angiogenic profile, given the well-known as hypoxia is involved in promoting angiogenesis in all its forms. In thisarticle, an overview of the literature is presented focusing on the mechanisms implicated in the “angiogenic switch”, which corresponds to thetransition from the avascular to the vascular phase of the disease. The anti-angiogenic effects of PI and IMiDs, which substantially contributeto their anti-MM activity, is also discussed, summarizing possible caveats and perspectives about anti-angiogenic strategies that could beaddressed 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 lymphocytefunction, promoting survival of normal and malignant B cells, is described. In this study, the effects of cholesterol synthesis inhibitors, suchas statins, on the interaction between BMSC and T lymphocytes or on natural killer cell-mediated functions is analyzed and compared withother drugs known to act on BMSC, including thalidomide or lenalidomide. Besides lowering the plasma lipid levels, statins indeed showstrong anti-inflammatory and immunomodulatory effects. On the other hand, these drugs can affect growth and survival of solid tumour andleukaemic cells, thus they have been proposed in the treatment of multiple myeloma, in association with drugs, as thalidomide, known to acton the cancer microenvironment.....

Effects of BCR-ABL Inhibitors on Anti-Tumor Immunity by M. Krusch, H.R. Salih (5174-5184).
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 uponcytogenetic 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/progenitorcells, which provokes a relapse of disease after cessation of therapy. Evidence from patients treated with allogenic stem celltransplantation or IFN-.. points to an important role of anti-tumor immunity for durable control of CML disease. Data from multiple invitro and ex vivo studies indicate that BCR-ABL inhibitors may also influence anti-tumor immunity. Varying effects on differentimmune effector cell subsets and of the different compounds have been reported, the latter being due to their particular and diversepotency and spectrum of target kinases. As multiple approaches presently aim to combine BCR-ABL inhibition with immunotherapeuticstrategies to improve disease control in CML, immunomodulatory effects of the available BCR-ABL inhibitors may be of direct clinicalrelevance. Here we review the available data regarding the effects of imatinib, nilotinib, and dasatinib on dendritic cells, T cells andnatural 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 dramaticallyimproved, 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 onlyMM cells, but also their microenvironment. Indeed, the disease develops as a result of genetic abnormalities and of reciprocal interactionsbetween MM cells and the permissive BM microenvironment, which delivers growth- and pro-survival signals and confers resistance todrugs.As for solid tumors, bone marrow (BM) angiogenesis is emerging as a critical component of MM development and progression, andhence as an attractive therapeutic target for the disease. The patho-physiology of MM associated angiogenesis is complex and involves aplethora of soluble factors, cellular players and mechanisms. Moreover, the hypoxic microenvironment inside the BM might significantlycontribute to the induction and maintenance of a pro-angiogenic profile, given the well-known role of hypoxia in promoting angiogenesisin all its forms.Here we present an overview of the literature focusing on the mechanisms implicated in the “angiogenic switch”, which corresponds tothe transition from the avascular to the vascular phase of the disease. We also review evidence on the anti-angiogenic effects of PI andIMiDs, which substantially contribute to their anti-MM activity. Finally, we summarize possible caveats and perspectives about antiangiogenicstrategies 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, caneffectively be used not only in the treatment of hypercholesterolemia, but also in other human disorders; indeed, statinshave strong anti-inflammatory and immunomodulatory effects, so that they can influence the onset and outcome ofinflammation and autoimmunity. On the other hand, it has been shown that statins can affect growth and survival of solidtumour and leukemic cells, thus they have been proposed in the treatment of neoplasias as multiple myeloma, inassociation 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 endothelialcells, macrophages and dendritic cells, the various types of lymphocytes such as NK cells, B and T cells. The interplay between all thesecell 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, thesurvival, 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 nowproposed as targets of new therapies. Herein, we analyze the effects that statins can exert on cancer cells, stromal cells and human naturalkiller cells, to discuss whether they can be proposed as anti-cancer drugs.

Gamma delta (γ 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 cellsindependent of antigen processing or presentation by classical MHC molecules, and 2) embody the anti-tumour effector functions of bothNK cells and cytotoxic T cells. It was serendipitously discovered that aminobisphosphonates (ABP), a class of drugs used as adjuvantcancer therapy for the treatment of malignant osteolytic bone disease, have the unexpected side-effect of potently activating the antitumoureffector functions of human peripheral γ δ T cells. Such beneficial therapeutic synergisms are rare, and no time has been wasted todetermine how to best harness the anti-cancer potential of γ δ T cells and ABP. Despite promising experimental results, the full clinicalpotential of this immunotherapeutic strategy has been hampered by the subversive strategies employed by cancer cells to obstructactivation of anti-tumour immune responses. These include the promotion of regulatory T cells (Tregs) that maintain tumour toleranceand the corruption of dendritic cell (DC) function and maturation. Toll-like receptor (TLR) agonists have a long history of breaking freeof tumour-induced immune-suppression by resetting DC function and abrogating Treg induced tolerance. This review presents data tosupport the notion that TLR signalling may perfectly complement the anti-tumour synergy of ABP and activated γ δ T cells, and thiscombined 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 manydifferent mechanisms, including accumulation of regulatory T cells (Treg). Adaptive Treg (Tr1) generated in the tumormicroenvironment express CD39 and CD73 ectonucleotidases, produce adenosine and are COX2+PGE2+. Adenosine and PGE2produced by Tr1 or tumor cells bind to their respective receptors on the surface of T effector cells (Teff) and cooperate in up-regulatingcytosolic 3’5’-cAMP levels utilizing adenylyl cyclase isoform 7 (AC-7). In Teff, increased cAMP mediates suppression of anti-tumorfunctions. Treg, in contrast to Teff, seem to require high cAMP levels for mediating suppression. This differential requirement of Tregand 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 cAMPsynthesis in Teff all represent novel therapeutic strategies that used in combination with conventional therapies could restore anti-tumorfunctions of Teff . At the same time, these inhibitors could disarm Tr1 cells by depriving them of the factors promoting their generationand activity or by down-regulating 3’5’-cAMP levels. Thus, the pharmacologic control of Treg-Teff interactions offers a novel strategyfor 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 mangroveassociatedmicrobes with a focus on bioactivity, highlighting the unique chemical diversity of these metabolic products.

Determinants of Increased Cardiovascular Disease in Obesity and Metabolic Syndrome by N. Vazzana, F. Santilli, S. Sestili, C. Cuccurullo, G. Davi (5267-5280).
Obesity is associated with an increased mortality and morbidity for cardiovascular disease (CVD) and adipose tissue isrecognised as an important player in obesity-mediated CVD. The diagnosis of the metabolic syndrome (MS) appears to identifysubstantial additional cardiovascular risk above and beyond the individual risk factors, even though the pathophysiology underlying thisevidence is still unravelled.The inflammatory response related to fat accumulation may influence cardiovascular risk through its involvement not only in bodyweight 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 ininflammation and its ability to disrupt insulin-signaling. The cross-talk between impaired insulin-signaling and inflammatory pathwaysenhances 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 inthis setting.Despite the availability of multiple interventions to counteract these metabolic changes, including appropriate diet, regular exercise, antiobesitydrugs and bariatric surgery, relative failure to control the incidence of MS and its complications reflects both the multifactorialnature of these diseases as well as the scarce compliance of patients to established strategies. Evaluation of the impact of thesetherapeutic strategies on the pathobiology of atherothrombosis, as discussed in this review, will translate into an optimized approach forcardiovascular prevention.

Serotonin and its Receptors in the Human CNS with New Findings - A Mini Review by A.S.M. Hung, T.Y.M. Tsui, J.C.Y. Lam, M.S.M. Wai, W.M. Chan, D.T. Yew (5281-5288).
Serotonin (5-hydroxytryptamine, 5-HT) is well known to be closely associated with emotional disorders, such as depressionand schizophrenia. The seven main members of 5-HT receptor family including the different subtypes are involved in the functionalpathways in the brain and their balance in activity helps to maintain the normal mental stability. As any detrimental changes in the 5-HTsystem is believed to alter emotion in human, different drugs including serotonin reuptake inhibitors (SSRIs) are nowadays commonlyused as anti- depressives. In this review, 5-HT1A and 5-HT2A receptors and serotonergic positive cells in the human were highlighted inparticular. It is hoped that this review will give a map of these major 5-HT receptors and serotonergic neurons in the human CNS tofacilitate further deciphering of their functions.

Flavonoids as Acetylcholinesterase Inhibitors by I. Uriarte-Pueyo, M.I. Calvo (5289-5302).
Flavonoids are new promising potential natural compounds for treating Alzheimer's disease (AD). Actually most promisingdrugs for symptomatic treatment of AD are acetylcholinesterase inhibitors (AChEI). Flavonoids with AChE inhibitory activity and due totheir well known antioxidant activity could be new multipotent drugs for AD treatment. This work focuses on natural and syntheticflavonoids inhibitors of the enzyme acetylcholinesterase (AChE). Over, all this review refers to 128 flavonoids, which are classified inchemical structure, and summarizes 64 references.

Nanostructures for Drug Delivery to the Brain by L. Martin-Banderas, M.A. Holgado, J.L. Venero, J. Alvarez-Fuentes, M. Fernandez-Arevalo (5303-5321).
This review aims to summarize present approaches employed in delivering drugs to the central nervous system. Changes inblood-brain barrier (BBB) function have been reported in several neurological disorders. A brief description of the blood brain barrierand the main pathologies related to this barrier disfunction are described. Treatments for these disorders are based on several availablestrategies for delivering drugs into the brain, through circumvention of the BBB, as disruption of the BBB, prodrugs, molecular Trojanhorses, among others. Particular attention will be placed on nanocarriers and more specifically on polymeric nanoparticles, which arepresented as the most promising strategy for CNS delivery, helping drugs to be targeted more efficiently to the brain. This also allowsattacking previously untreatable disorders such as brain tumors and other neurodegenerative diseases. New strategies and technologiescommercialized by different pharmaceutical companies are also included.