Cardiovascular & Haematological Disorders - Drug Targets - Volume 9, Issue 1, 2009

Despite the fact that sickle cell anemia was one of the first diseases to have a demonstrated genetic etiology, to date there is still only one approved therapy for this disease. Recent increases in our understanding of the pathophysiology of the disease should translate into improved and more rapid development of newer therapies. This review will focus on the following current and potential therapeutic strategies to reduce the morbidity of sickle cell anemia. 1) Therapies such as decitabine, hydroxyurea, butyrate, lenalidomide and pomalidomide, which decrease the polymerization rate of HbS by increasing the concentration of Hb F; 2) Drugs that decrease relative intracellular HbS concentration by increasing total cell volume via inhibition of normal membrane ion exchange channels, such as KCL Cotransporter and Gardos Channels. These inhibitors include magnesium pidolate, imidazole antimycotics, arginine and Senicapoc; 3) Treatment of sickle cell vasoocclusion through inhibition of endothelial or cell surface adhesion molecules, such ICAM 4 and αvβ3 integrins, by drugs related to the GPIIbIIIa inhibitors or adhesion molecule modulators, and 4) Attempts to achieve vasodilation by nitric oxide and antioxidant therapy. This review will discuss the status of these emerging therapies in the treatment of sickle cell anemia.

One of the key players in many thrombotic complications is von Willebrand factor (VWF), a large, multimeric glycoprotein that is present in plasma where it fulfils a crucial role in haemostasis. First, VWF recruits platelets to vascular lesions by acting as a linker molecule between the exposed collagen and free-flowing platelets in the circulation. Second, by serving as a carrier protein for the coagulation factor VIII, VWF protects this anti-haemophilic factor from rapid degradation. Quantitative or qualitative defects in VWF result in the most common bleeding disorder in man, known as von Willebrand disease, illustrating the central role of VWF in haemostasis. On the other hand, a thrombotic risk emerges when over-reactive VWF molecules can bind spontaneously to platelets. It is clear that because of its pivotal role in maintaining the fine balance between bleeding and thrombosis, VWF is an attractive but delicate drug target. This review focuses on the role of VWF in both haemostasis and thrombosis with special attention to the molecule as drug and drug target respectively.

The majority of patients with chronic phase chronic myeloid leukaemia (CP-CML) treated with imatinib achieves cytogenetic disease remission. Molecular monitoring for residual disease has prognostic significance: rising BCR-ABL levels may provide earliest indication that a patient has become resistant to treatment. The emergence of resistance to imatinib has dampened the enthusiasm for this drug. The most common cause of resistance is the selection of leukemic clones mutated in ABL kinase domain due to amino acid substitutions with prevention of appropriate binding of the drug. Amplification and over-expression of BCR-ABL, acquired cytogenetic aberrations and modulation of drug efflux or influx transporters have been reported. These observations have established the rationale for the creation of new compounds that have been explored in clinical trials. This review will discuss the underlying mechanisms of imatinib-resistance and new strategies to avoid and overcome this phenomenon.

Data concerning electrocardiographic (ECG) abnormalities in thalassemic cardiomyopathy are scanty. Current techniques to detect early findings of myocardial involvement in thalassemia (Magnetic Resonance, Stress Echo, Tissue Doppler Imaging) are not widely available. We sought to determine whether new ECG abnormalities emerge in thalassemia patients when heart failure due to cardiomyopathy occurs. ECG and Echo Doppler examinations of 28 consecutive adult thalassemia patients with heart failure observed at our hospital were compared with ECG and Echo Doppler examinations performed before the onset of heart dysfunction and with those of 60 age and sex-matched patients with thalassemia without evidence of cardiac involvement. All the patients with heart failure had new ECG abnormalities. New onset supraventricular arrhythmias, T wave inversion, low voltages, right QRS axis deviation and S1Q3 pattern developed respectively in 46%, 79%, 43%, 18% and 15% of thalassemic patients with heart failure. None of the patients without heart failure showed any ECG abnormality (P<0.001). In conclusion this study suggests that new onset ECG abnormalities are always evident in patients with and always absent in patients without heart failure due to thalassemic cardiomyopathy.

Thrombotic microangiopathies (TMA) encompass various diseases characterized by a microangiopathic hemolytic anemia, platelet clumping, and organ failure of variable severity. Thrombotic thrombocytopenic purpura (TTP) is a particularly severe form of TMA characterized by systemic organ failure which results from a severe defect in ADAMTS13, a plasma enzyme specifically involved in the cleavage of highly hemostatic unusually large (UL) von Willebrand factor (VWF) multimers into smaller and less adhesive VWF forms. Failure to degrade these UL-VWF multimers leads to excessive platelet aggregates and capillary occlusion. ADAMTS13 deficiency results from bi-allelic mutations in hereditary TTP, whereas in acquired forms it results from autoantibodies that alter the protein function. Patients with acquired idiopathic TTP have a trend to develop autoimmunity, since a clinical context of autoimmunity may be found in 30 p. cent of cases. Moreover, the remarkable efficiency of monoclonal antibodies directed against CD20 antigen of B lymphocytes in refractory or chronic relapsing forms provides an additional indirect argument to consider acquired TTP as an autoimmune disease. Hemolytic uremic syndrome (HUS) is characterized prominently by a renal failure. In most cases, HUS is caused by entero- hemorrhagic Escherichia coli (diarrhea-positive HUS). Diarrhea-negative HUS, termed atypical HUS, was associated with a dysfunction in complement pathway involving mutations in factor H, factor I, CD46/MCP, factor B and C3 components. The major improvement in our understanding of TMA pathophysiology allows now a more accurate molecular classification of TMA syndromes, which opens fascinating perspectives of targeted therapies in the forthcoming years.

Tumour cells are characterized by karyotype instability, which is accompanied by specific events in the chromatin structure and epigenetic patterns. Epigenetics involves heritable changes in the physical and biochemical state of chromatin, which have no effect on DNA sequences; therefore, changes in the nuclear radial arrangement of chromosomes can also be considered epigenetic events. Nuclear radial distributions of select genomic regions have been studied in many tumour cells and are not influenced by aberrations in chromosome number. On the other hand, genes involved in translocations take up new positions midway between the original coding sequences. The differentiation of leukaemia cells with clinically used agents is often accompanied by nuclear repositioning of tumour-related genes. However, the nuclear rearrangement is cell-type specific and not always associated with changes in the transcriptional activity. Similarly, cell typespecific chromatin structure is observed in tumour cells treated with select cytostatics and inhibitors of epigenetic processes, which have significant influences on the histone code. Chromatin structure and histone modifications were also affected by gamma radiation in leukaemia, multiple myeloma, and solid tumour cells. Interestingly, gamma radiation induced loci proximity, which has been suggested to increase the probability of exchange aberrations typically associated with tumour progression.

New chemotherapeutic agents are still required to further optimise treatment of leukemia patients. Proteasome inhibition by bortezomib, PR-171 (carfilzomib) and NPI-0052 (salinosporamide A) has been successfully used for the treatment of multiple myeloma and mantle cell lymphoma and is considered also as novel treatment strategy in leukemia. Combination of proteasome inhibitors bortezomib and NPI-0052 induces synergistic anti-multiple myeloma activity both in vitro using multiple myeloma cells and in vivo in a human plasmacytoma xenograft mouse model. Cell death resulting from proteasome inhibition requires caspase activation and increased levels of reactive oxygen species. While bortezomib induces several caspases, NPI-0052 activates predominantly caspase-8-dependent pathway. We studied the effect of bortezomib (10 nM) on DNA synthesis and apoptosis in human acute myeloid cell lines KASUMI-1, ML-1, ML-2 and CTV-1 cells. Bortezomib was potent inhibitor of DNA synthesis in all four types of leukemia cells and induced apoptosis in KASUMI-1, ML-2 and CTV-1 cells but not in ML-1 cells. Other research groups showed that histone deacetylase inhibitors (valproic acid or benzamide derivative MS-275) in combination with NPI-0052 or PR-171 induced greater levels of acute leukemia cell death than in combination with bortezomib. Proteasome inhibition as monotherapy and its combination with many conventional therapies as novel treatment strategies in leukemia are promising. Malignant cells are more sensitive to this treatment than normal hematopoietic cells.