Current Medicinal Chemistry (v.18, #15)
Editorial [Hot Topic: IDO1, Cancer and Cancer-Associated Inflammation (Guest Editor: Sergio Rutella)] by Sergio Rutella (2204-2204).
Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme expressed by professional antigen presenting cells such asdendritic cells (DC) or by a variety of cell types at sites of inflammation. IDO1 has been implicated in the development of immune toleranceto tumors. It is likely that IDO1 is not the only immune regulatory molecule but it is part of a more complex network of interactions andregulatory pathways that are operational in the DC compartment and possibly in other cell types.The biochemical properties of IDO1 are addressed in the first article, from Dr. Lancellotti and co-workers, which extensively covers thestructural and functional properties of the enzyme, with a view to the development of novel inhibitor molecules. They also provide a thoroughdiscussion of the “ideal” inhibitor of IDO1, based on our current knowledge of the structural elements responsible for the optimal interactionwith the catalytic site of IDO1. Dr. Fallarino and Dr. Grohmann discuss the contribution of IDO1 to the generation of regulatory T cells (Treg), a T-cell subset withremarkable plasticity that has attracted much attention over the last years. They also address the relative contribution of tryptophan starvationand kynurenine production to the amplification of Treg cells and, even more intriguingly, they focus on the inter-relations and interconversionsbetween Treg cells and Th17, a recently described T-cell subset with pro-inflammatory actions. These data open a fascinatingscenario and point to IDO1 as a molecular mechanism controlling the adaptability of Treg cells and ultimately dictating the balance betweenimmunity and tolerance. Articles in this Issue also impart essential information on IDO1 expression and regulation in the antigen-presenting cell compartment. Dr.Heitger and Dr. Trabanelli provide us with an overview of the mechanisms that control IDO1 transcription and expression in human DC. TheAuthors also discuss the implications of the pharmacological manipulation of IDO1 activity in pertinent clinical scenarios such as cancer,hematopoietic stem cell transplantation and autoimmunity. Dr. Munn reviews the current evidence interconnecting the IDO pathway with Treg biology. As clearly stated in this paper, IDO is likelyto represent a crucial regulatory checkpoint that controls the differentiation of naive T cells into Treg cells, the activation of mature, preexistingTreg cells and the inflammation-induced conversion of Treg cells into pro-inflammatory T helper-like cells, a phenomenon termed“reprogramming”. These are important advances in our understanding of Treg-mediated suppression in cancer, also in view of the successfulapplication of IDO-inhibitor drugs to the clinic. Moving to the role of IDO1 in infectious diseases, Dr. Boasso provides a close analysis of the down-stream effects of IDO over-activationon the immune alterations that characterize HIV disease. This review examines the mechanisms of IDO1 induction during HIV infection anddiscusses how IDO1 contributes to HIV immunopathogenesis through the inhibition of T-cell responses, the alteration of the Th1/Th2balance, and the generation of Treg cells at sites of active viral replication. This knowledge opens exciting therapeutic perspectives aimed atinhibiting the IDO pathway in HIV-infected patients. Dr. Prendergast and co-workers present a discussion on IDO1 as a regulator of cancer-associated inflammation rather than simply asuppressor of immune function. IDO1 can also be viewed as a candidate molecule to define cancer-associated inflammation as it isdistinguished from chronic inflammatory states that are not associated with cancer. The Authors offer a new perspective whereby IDO1activity defines a state that can support, or in some cases antagonize, disease development and progression. On a related point, Dr. Cesario and co-workers discuss the inter-connections between IDO1 and cyclooxygenase (COX)-2, an enzymeinvolved in the biosynthesis of prostanoids. COX-2-derived prostaglandins contribute to inflammation and induce IDO1 as well as Tregactivity, potentially driving cancer-associated immune suppression. Selective COX-2 inhibitors reduce IDO1 protein levels and augment theefficacy of anti-tumor DC-based vaccines, thus pointing to this class of drugs as potential modulators of IDO1 function in vivo.In conclusion, this Issue introduces the most recent findings and advances on IDO1 expression and regulation in diverse clinical settings,including chronic inflammation, HIV infection and cancer. Importantly, IDO inhibitor drugs have now entered the clinical arena and arebeing offered to patients with advanced cancer. This will hopefully become a viable therapeutic option also for patients with HIV infectionand with certain inflammatory and autoimmune conditions.
Biochemical Properties of Indoleamine 2,3-dioxygenase: From Structure to Optimized Design of Inhibitors by S. Lancellotti, L. Novarese, R. De Cristofaro (2205-2214).
The enzyme indoleamine 2,3-dioxygenase (IDO, EC 22.214.171.124) belongs to the family of heme-containing oxidoreductasesand catalyzes the first and rate-limiting step in the kynurenine pathway, the major pathway of tryptophan metabolism. IDO is folded intoone large and one small distinct ..-helical domains, with the heme prosthetic ring positioned between them. The enzyme, through theoxidative properties of the Fe3+ atom present at the centre of the heme ring, catalyses the oxidative cleavage of the pyrrole ring of L-Trpto generate N-formyl-kynurenine. The active IDO conformer exists only in the presence of reducing cofactors (such as cytochrome b5),requiring the single electron reduction of ferric-to-ferrous iron (Fe3+..Fe2+), which facilitates binding of L-Trp and O2 to the enzymeactive site. IDO, through production of kynurenine and other downstream metabolites, can regulate immune responses, suppressingeffector T-cell function and favouring the differentiation of regulatory T cells. Local expression of the enzyme during inflammation isanother self-protection mechanism, which limits antigen-specific immune responses, especially in some organs, as the central nervoussystem. The detailed knowledge of the structural and functional properties of IDO, was a fundamental step to design and develop newmolecules for the pharmacological inhibition of IDO activity in several clinical settings.
Using an Ancient Tool for Igniting and Propagating Immune Tolerance: IDO as an Inducer and Amplifier of Regulatory T Cell Functions by F. Fallarino, U. Grohmann (2215-2221).
Although most CD4+CD25+ regulatory T (Treg) cells develop in the thymus (i.e., natural Treg or nTreg), accumulating evidencesuggests that they can also develop in the periphery (adaptive/induced Treg or iTreg). Both types of cells are functionally associated withthe expression of Foxp3, a transcription factor that is constitutively expressed in nTreg cells and inducible during iTreg cell generation fromCD4+CD25- T lymphocytes. Multiple factors are involved in the generation and function of Treg cells, but a major role seems to be playedby indoleamine 2,3-dioxygenase (IDO). IDO can both deplete tryptophan in local tissue microenvironments and generateimmunoregulatory catabolites, known as kynurenines. Tryptophan starvation and presence of kynurenines can induce the conversion ofnaive CD4+CD25- T cells into highly suppressive CD4+CD25+Foxp3+ Treg cells. In turn, Treg cells induce IDO in dendritic cells (DCs) andconvert inflammatory into regulatory DCs, which can further expand the Treg cell compartment by tryptophan catabolism. Evidencesuggests that the modulation of IDO activity favors the interconversion between Treg cells and T helper type 17 (TH17) inflammatorycells. Thus, in the periphery, tolerogenic immune responses mediated by Treg cells can be induced and amplified by IDO, a tryptophancatabolizing enzyme that also contributes to the plasticity of the Treg cell lineage.
Regulation of Expression and Function of IDO in Human Dendritic Cells by A. Heitger (2222-2233).
In the human immune system, IDO expression and activity (IDO competence), are preferentially found in the antigenpresentingcell population, of which dendritic cells (DCs) represent an essential part. As will be comprehensively reviewed, IDOcompetence in human DCs, in general, is induced by molecules such as interferon-.., which otherwise initiate immunity. IDO activitytherefore, can be interpreted as a negative feedback pathway that limits uncontrolled immune responses. Because of its potentimmunosuppressive effects (down-regulation of T cell responses or the expansion of T cell regulatory activity), IDO competence inhuman DCs is tightly regulated, at the transcriptional, translational and post-translational levels. I will critically discuss the experimentalprerequisites and limits of attributing IDO competence to a mechanism of immunosuppression and examine, whether IDO competenceitself can be viewed as mediating immunosuppression, or as representing one component among other immunosuppressive factors,involved in tolerogenic function of DCs. Finally, the newly emerging concepts of manipulating IDO competence as a therapy for eitheraugmenting immune responses, such as in cancer, or down-regulating immune responses, such as in transplantation, will be summarized.
Induction of Regulatory T Cells by Dendritic Cells through Indoleamine 2,3-dioxygenase: A Potent Mechanism of Acquired Peripheral Tolerance by S. Trabanelli, D. Ocadlikova, C. Evangelisti, S. Parisi, A. Curti (2234-2239).
Indoleamine 2,3-dioxygenase (IDO) is an intracellular heme-containing enzyme that catalyzes the initial rate-limiting step intryptophan degradation along the kynurenine pathway. Recent works have demonstrated a crucial role for IDO in the induction ofimmune tolerance during infections, pregnancy, transplantation, autoimmunity, and neoplasias. IDO is widely expressed in human tissuesand cell subsets, including dendritic cells, where it modulates their function by increasing tolerogenic capacities. The aim of the presentpaper is to highlight the most recent data about IDO expression in dendritic cells and its role as a potent inducer of T regulatory cells.
Indoleamine 2,3-dioxygenase, Tregs and Cancer by D.H. Munn (2240-2246).
The IDO pathway is implicated in a number of settings which lead to acquired peripheral tolerance. One such setting may bethe functional tolerance displayed by tumor-bearing hosts toward tumor-associated antigens. Foxp3+ Tregs are now recognized as a majorcontributor to tumor-induced immune suppression and functional tolerance. Emerging evidence links the IDO pathway with Treg biologyat several points. The first is the ability of IDO-expressing DCs to drive the differentiation of naive CD4+ T cells toward a Foxp3+(inducible Treg) phenotype. The second link is the ability of IDO-expressing DCs to directly activate mature, pre-existing Tregs formarkedly enhanced suppression of target cells. And the third link is the ability of IDO to prevent the inflammation-induced conversion(“reprogramming”) of Tregs into pro-inflammatory T-helper-like cells in vivo. Taken together, these findings suggest that IDO mayrepresent an important regulatory checkpoint influencing Treg activity: both by stabilizing and augmenting the suppressive phenotype,and by preventing Treg reprogramming into non-suppressive helper-like cells.
Wounding the Immune System with its Own Blade: HIV-Induced Tryptophan Catabolism and Pathogenesis by A. Boasso (2247-2256).
Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme which plays a key role in maintaining the physiologicimmune balance between the efficient responses to insulting pathogens and the control of harmful autoimmune reactions. During HIVinfection, multiple mechanisms involving both viral and cellular components, contribute to enhance IDO expression and activity in anuncontrolled manner. The downstream effects of IDO overactivation collectively contribute to the immune alterations which characterizeHIV disease. This review explores the cellular and molecular pathways which result in IDO upregulation during HIV infection andconsiders the consequences of IDO hyperactivity on the immune system, their relevance in the context of HIV immunopathogenesis andthe potential for specific therapeutic intervention.
Indoleamine 2,3-dioxygenase as a Modifier of Pathogenic Inflammation in Cancer and other Inflammation-Associated Diseases by G.C. Prendergast, M.Y. Chang, L. Mandik-Nayak, R. Metz, A.J. Muller (2257-2262).
Chronic inflammation underlies the basis for development and progression of cancers and a variety of other disorders, butwhat specifically defines its pathogenic nature remains largely undefined. Recent genetic and pharmacological studies in the mousesuggest that the immune modulatory enzyme indoleamine 2,3-dioxygenase (IDO), identified as an important mediator of immune escapein cancer, can also contribute to the development of pathology in the context of chronic inflammatory models of arthritis and allergicairway disease. IDO-deficient mice do not display spontaneous disorders of classical inflammation and small molecule inhibitors of IDOdo not elicit generalized inflammatory reactions. Rather, in the context of a classical model of skin cancer that is promoted by chronicinflammation, or in models of inflammation-associated arthritis and allergic airway disease, IDO impairment can alleviate diseaseseverity. Here we offer a survey of preclinical literature suggesting that IDO functions as a modifier of inflammatory states rather thansimply as a suppressor of immune function. We propose that IDO induction in a chronically inflamed tissue may shape the inflammatorystate to support, or in some cases retard, pathogenesis and disease severity.
The Interplay between Indoleamine 2,3-Dioxygenase 1 (IDO1) and Cyclooxygenase (COX)-2 In Chronic Inflammation and Cancer by A. Cesario, B. Rocca, S. Rutella (2263-2271).
The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) degrades the essential amino acid tryptophan into kynurenine and otherdownstream metabolites that suppress effector T-cell function and favor the differentiation of regulatory T cells. IDO1 is traditionallyviewed as a general suppressor of T-cell activation and mediator of immune escape in cancer. Recently, evidence has emerged to supporta greater functional complexity of IDO1 as modifier of pathogenic inflammation. For instance, IDO1 activity may sustain autoantibodyproduction by B cells, and elicit the development of cancer in the context of chronic inflammation.Cyclooxygenase (COX)-2 metabolizes the first enzymatic step in the conversion of arachidonic acid into prostanoids. In particular,prostaglandin (PG)E2 generated at sites of inflammation and/or immune response is mainly COX-2-derived and has pro-inflammatoryand immune regulatory activities. Pharmacological blockade of COX-2 in animal models of cancer translates into down-regulation ofIDO1 expression at tumor sites and decreased levels of kynurenine in the circulation, underpinning the view that IDO1 might bedownstream of COX-2. This article reviews preclinical studies focusing on IDO1 and COX-2 as inter-related molecular targets for therapeutic intervention inchronic inflammation and cancer. COX-2 inhibition might, in principle, be pursued in cancer-associated inflammation characterized byIDO1 hyper-activity, with the foreseeable aim at altering the immune response within the tumor microenvironment.
Contribution of Catecholamine Reactive Intermediates and Oxidative Stress to the Pathologic Features of Heart Diseases by V.M. Costa, F. Carvalho, M.L. Bastos, R.A. Carvalho, M. Carvalho, F. Remiao (2272-2314).
Pathologic heart conditions, particularly heart failure (HF) and ischemia-reperfusion (I/R) injury, are characterized bysustained elevation of plasma and interstitial catecholamine levels, as well as by the generation of reactive oxygen species (ROS) andreactive nitrogen species (RNS). Despite the continuous and extensive research on catecholamines since the early years of the XXthcentury, the mechanisms underlying catecholamine-induced cardiotoxicity are still not fully elucidated. The role of catecholamines inHF, stress cardiomyopathy, I/R injury, ageing, stress, and pheochromocytoma will be thoroughly discussed. Furthermore and althoughthe noxious effects resulting from catecholamine excess have traditionally been linked to adrenoceptors, in fact, several evidencesindicate that oxidative stress and the oxidation of catecholamines can have important roles in catecholamine-induced cardiotoxicity.Accordingly, the reactive intermediates formed during catecholamine oxidation have been associated with cardiac toxicity, both in invitro and in vivo studies. An insight into the influence of ROS, RNS, and catecholamine oxidation products on several heart diseases andtheir clinical course will be provided. In addition, the source and type of oxidant species formed in some heart pathologies will bereferred. In this review a special focus will be given to the research of cardiac pathologies where catecholamines and oxidative stress areinvolved. An integrated vision of these matters is required and will be provided along this review, namely how the concomitant surge ofcatecholamines and ROS occurs and how they can be interconnected. The concomitant presence of these factors can elicit peculiar andnot fully characterized responses on the heart. We will approach the existing data with new perspectives as they can help explainingseveral controversial results regarding cardiovascular diseases and the redox ability of catecholamines.
Anticancer Antioxidant Regulatory Functions of Phytochemicals by J.M. Mates, J.A. Segura, F.J. Alonso, J. Marquez (2315-2338).
Plant foods are not only a main source of nutrients, but they are also rich in physiologically bioactive bionutrients orphytochemicals. Consumption of fruit and vegetables is associated with a decreased risk of pathological status, including cancer.Reactive oxygen species play a key role in the genesis and development of cancer. Therefore, antioxidant functions of phytonutrientshave been thoroughly investigated in the last years in relation to their crucial effect in the pathophysiology associated with neoplasia.This review discusses current knowledge on phytochemicals in relation to their potential as chemopreventive and/or chemotherapeuticmolecule against human cancers. Finally, we will outline the use of bioactive phytochemicals on synergistic actions involved in theprevention and treatment of cancer as well as its future prospects.
Recent Insights on the Medicinal Chemistry of Sickle Cell Disease by J.L. dos Santos, C.M. Chin (2339-2358).
Sickle Cell Disease (SCD) is one of the most prevalent hematological diseases in the world. SCD is a genetic diseasecharacterized by punctual mutation that basis on the exchange of glutamic acid to valine in a beta chain of hemoglobin. In deoxygenatedstate, the interaction among the beta chains leads to hemoglobin polymerization carrying out to deformation of cytoskeleton structure ofred blood cells to a sickle shape. Currently, the treatment is performed with the antineoplasic drug hydroxyurea. This review summarizescurrent knowledge about possible targets and the approaches to discover new compounds to treat the SCD symptoms. Drug design basedon therapeutical application and molecular modifications strategies will be discussed.