Cardiovascular & Haematological Disorders - Drug Targets - Volume 13, Issue 1, 2013

Multiple myeloma is a B-cell neoplasm that is characterized by clonal proliferation of terminally differentiated plasma cells. Approximately 20,000 new cases are diagnosed each year with a prevalence of about 60,000. Characteristic clinical features include bone disease, hypercalcemia, renal disease, anemia and infections. Advancements in our understanding of multiple myeloma have led to a significant impact in the natural history of the disease. Despite these advances the disease remains incurable and most patients invariably relapse and die. Our understanding of the transformation of normal plasma cells into myeloma cells and the interaction between myeloma cells and elements of the bone marrow microenvironment that sustain proliferation and survival has significantly improved. This knowledge has paved the way for the development of novel drugs that target the genetic and molecular changes that underlie myeloma pathophysiology. In this review we discuss several of these novel agents. We focus on the specific pathways targeted by these drugs and the role they may play in development or progression of multiple myeloma. We also discuss the proposed mechanism of action of these drugs and correlate these to clinical trials where they have been investigated.

Multiple myeloma (MM) remains an incurable disease, at least for the big majority of patients, in spite of the great progress with new drugs in the last years. New treatment strategies are needed to improve the outcome of patients. NF-κB activation in MM is caused by mutations in the factors involved in the NF-κB pathways contributing to their dysregulation and by signals from the bone marrow microenvironment. Agents with NF-κB inhibitory activity enhance the anti-MM effects of conventional chemotherapeutic agents. Bortezomib was the first approved member of a new class of anti-MM agents, the proteasome inhibitors. At least, five proteasome inhibitors of the next generation with greater efficacy (carfilzomib, marizomib (salinosporamide A, NPI-0052), threonine boronic acid-derived proteasome inhibitor CEP-18770, the peptide-semicarbazone S-2209, the tripeptide mimetic BSc2118, and MLN9708/2238) have been recently tested in preclinical models of MM. Carfilzomib has been recently approved for the treatment of patients with MM who have received at least two prior therapies, including bortezomib and immunomodulatory derivatives (IMiDs, thalidomide, lenalidomide or pomalidomide). More specific IκB kinase inhibitors were also used in preclinical studies. The analysis of MM genomes revealed also mutations in genes for histone methyltransferases (HMTases), histone demethylase (UTX) and serine/threonine protein kinase BRAF. Aberrant histone 3 lysine 27 trimethylation (H3K27me3) by mutant HMTases or UTX induces overexpression of the homeobox A9 (HOXA9) gene. HOXA9 is normally expressed in primitive bone marrow cells and is silenced when cells differentiate. HOXA9 is a MM oncogene and targeting of its expression by histone deacetylases inhibitors or by a phosphoinositide 3-kinase (PI3K) inhibitors through an epigenetic mechanism involving H3K27me3. Mutant BRAF kinase small-molecule, ATP-competitive, a highly selective, potent and orally bioavailable inhibitors (GDC-0879, PLX 4032 and PLX 4720) are already under investigation and PLX 4032 is in phase II and phase III clinical trials. Two key signaling pathways involved in the regulation of MM cell growth are the Ras/Raf/MEK/ERK and PI3K/Akt/mTOR pathways and their inhibition are anti-proliferative and pro-apoptotic and can overcome the development of resistance to common drugs.

Background: Trials studying iron repletion in patients with chronic heart failure (CHF) and iron deficiency are underpowered to find consistent hard endpoint (mortality and hospitalization) reductions. We conducted a meta-analysis of controlled trials to examine the effects of iron repletion on these parameters. Methods and Results: Pubmed, CENTRAL, EMBASE and NIH Clinical Trials databases were searched for controlled trials utilizing intravenous iron, with or without erythropoietin, in patients with CHF with NYHA class ≥ II, iron deficiency, and left ventricular dysfunction. Data regarding hospitalizations, mortality, adverse events, NYHA class, and ejection fraction were extracted, analyzed for heterogeneity, and pooled using the DerSimonian and Laird random effects model. We identified 5 controlled trials (n = 631 patients). Patients treated with intravenous iron had significant reductions in hospitalizations (OR 0.26, 95% CI 0.08-0.80), adverse events (OR 0.35, 95% CI 0.21-0.60), NYHA class (mean improvement 1.2 classes, 95% CI 0.69-1.78, and LVEF (mean improvement 5.0%, 95% CI 0.13-9.80) but no relationship was found on mortality (OR 0.66, 95% CI 0.30-1.44). Conclusion: Treatment of iron deficiency in patients with CHF reduces the risk of hospitalizations without increased adverse events, suggesting its role as a potential therapeutic target in this group of patients.

This study was aimed to examine the effect of lead acetate on inflammatory biomarkers in blood of guinea pigs in comparison with sensitized animals. Thirty guinea pigs were randomly allocated into control (group C), sensitized (group S), and three Pb-exposed (groups 0.1M Pb, 0.2M Pb and 0.4M Pb). Animal sensitized after aerosolized-ovalbumin (OA) challenge. Pb-exposed groups inhaled 0.1M, 0.2M and 0.4M lead acetate for 1 h, three times a week for two weeks. Total and differential WBC counts, PLA2 activity and total protein levels were evaluated in blood of all animal groups. Serum PLA2 activity, total protein and total WBC number in sensitized and animal exposed to lead were significantly higher as compared to control group (p<0.05). When compared to control group, the percentages of eosinophil, nuetrophil and basophiles were also increased in sensitized guinea pigs (p<0.01). The percentage of eosinophil and basophile in animals exposed to high level of lead and that of basophile in animals exposed to middle lead concentration versus to control group significantly increased (p<0.05). In addition, the significant difference between the lymphocyte percentages of Pb-exposed groups and control group were decreased in concentration dependent manner. The findings of the present study indicated that exposure to inhaled lead acetate may lead to asthma-like disease.

Phagocytes were first described by Dr. Metchnikoff in 1873. The roles of phagocytes in innate and adaptive immunity have been well established to date, although the molecular mechanisms involved in initiating phagocytosis (through Fc or other receptors) remain to be further explored. Phagocytes in the reticuloendothelial system, particularly macrophages, have been implicated in the clearance of senescent blood cells. The destruction of these cells may be primarily mediated via an Fc-independent pathway. Fc-independent phagocytosis may also play an important role in platelet clearance, including in autoimmune thrombocytopenia (ITP), and in clearance of platelet-rich emboli detached from sites of vascular injury. In ITP, the two major platelet auto-antigens have been located on glycoprotein (GP)IIbIIIa and the GPIb complex. It has been demonstrated that anti-GPIb antibodies, in contrast to anti-GPIIbIIIa, can induce thrombocytopenia in an Fc-independent manner. We further demonstrated in an animal model that intravenous IgG (IVIG) is unable to ameliorate thrombocytopenia caused by most anti-GPIb antibodies, despite its efficacy in anti- GPIIbIIIa-mediated thrombocytopenia. Our data was supported by subsequent retrospective studies with ITP patients by several independent groups. Most recently, we found that anti-GPIb-mediated ITP was also resistant to steroid therapy and that platelet activation and apoptosis induced by anti-GPIb antibodies may be involved in the Fc-independent platelet clearance. Therefore, identification of antibody specificity in patients, e.g. anti-GPIIbIIIa (Fc-dependent) versus anti-GPIb (Fc-independent), may be important for therapies against ITP, as well as other immune-mediated thrombocytopenias.

Cardiovascular disease (CVD) and associated risk factors such as obesity remain at the forefront of health concerns. Adipose tissue has been well established as an endocrine organ that becomes dysfunctional with increased adipose tissue mass. The secretion of several adipokines is altered in subjects with abdominal adiposity and these changes to the endocrine balance may contribute to increased CVD risk. The identification and characterization of disease-specific proteins within the adipose tissue offers a novel therapeutic target for prevention or treatment of cardiovascular complications. This review will discuss the latest developments on therapeutic targets within the context of adipokines, such as adiponectin, C1q/ tumor necrosis factor (TNF) related proteins (CTRPs), visfatin, vaspin, chemerin and omentin, and their involvement in obesity-related cardiovascular complications.

We review here some recent data about Glucose-6-phosphate dehydrogenase (G6PD), the housekeeping X-linked gene encoding the first enzyme of the pentose phosphate pathway (PPP), a NADPH-producing dehydrogenase. This enzyme has been popular among clinicians, biochemists, geneticists and molecular biologists because it is the most common form of red blood cell enzymopathy. G6PD deficient erythrocytes do not generate NADPH in any other way than through the PPP and for this reason they are more susceptible than any other cells to oxidative damage. Moreover, this enzyme has also been of crucial importance in many significant discoveries; indeed, G6PD polymorphisms have been instrumental in studying X-inactivation in the human species, as well as in establishing the clonal nature of certain tumors. G6PD deficiency, generally considered as a mild and benign condition, is significantly disadvantageous in certain environmental conditions like in presence of certain drugs. Nevertheless, G6PD deficiency has been positively selected by malaria, and recent knowledge seems to show that it also confers an advantage against the development of cancer, reduces the risk of coronary diseases and has a beneficial effect in terms of longevity.

Nitric oxide is a potent vasodilator that plays a critical role in disorders of erythrocyte function. Sickle cell disease, paroxysmal nocturnal hemoglobinuria and banked blood preservation are three conditions where nitric oxide is intimately related to dysfunctional erythrocytes. These conditions are accompanied by hemolysis, thrombosis and vasoocclusion. Our understanding of the interaction between nitric oxide, hemoglobin, and the vasculature is constantly evolving, and by defining this role we can better direct trials aimed at improving the treatments of disorders of erythrocyte function. Here we briefly discuss nitric oxide’s interaction with hemoglobin through the hypothesis regarding Snitrosohemoglobin, deoxyhemoglobin, and myoglobin as nitrite reductases. We then review the current understanding of the role of nitric oxide in sickle cell disease, paroxysmal nocturnal hemoglobinuria, and banked blood, and discuss therapeutics in development to target nitric oxide in the treatment of some of these disorders.