RESUMO
An activating mutation (V617F) in the pseudokinase domain of the Janus kinase (JAK)-2 tyrosine kinase has been described in 90% of patients with polycythemia vera (PV) and 50% of patients with essential thrombocythemia (ET) and primary myelofibrosis (MF). The discovery of JAK2V617F stirred the development of JAK2 inhibitors for treatment of patients with MF, ET and PV. Similar to other tyrosine kinase (TK) inhibitors in current use, JAK2 inhibitors target the adenosine triphosphate (ATP) binding site at the TK domain and not the pseudokinase domain, thus affecting both mutated and wild-type kinases. In fact, clinical trials of these compounds have demonstrated improvements in constitutional symptoms and splenomegaly in patients with both mutated and wild-type JAK2 MF. It is believed that these drugs may act not only through inhibition of neoplastic cell proliferation, but also by downregulating signaling through proinflammatory cytokine receptors. In this article, we review the current state of JAK2 inhibitors and discuss why these drugs could be a valuable addition to the treatment armamentarium for patients with and without the JAK2V617F mutation.
Assuntos
Janus Quinase 2/antagonistas & inibidores , Mutação Puntual , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Benzamidas/uso terapêutico , Benzamidas/toxicidade , Citocinas/imunologia , Humanos , Imidazóis/uso terapêutico , Imidazóis/toxicidade , Janus Quinase 2/química , Janus Quinase 2/genética , Janus Quinase 2/imunologia , Nitrilas , Mielofibrose Primária/genética , Mielofibrose Primária/imunologia , Inibidores de Proteínas Quinases/toxicidade , Pirazóis/uso terapêutico , Pirazóis/toxicidade , Piridazinas/uso terapêutico , Piridazinas/toxicidade , Pirimidinas/uso terapêutico , Pirimidinas/toxicidade , Pirrolidinas/uso terapêutico , Pirrolidinas/toxicidade , Sulfonamidas/uso terapêutico , Sulfonamidas/toxicidadeRESUMO
Chloridazon is a widely used organochlorine herbicide. In order to evaluate its perturbing effect on cell membranes it was made to interact with human erythrocytes, frog adrenergic neuroepithelial synapse and molecular models. These consisted in multilayers of dimyristoylphosphatidylethanolamine (DMPE) and of dimyristoylphosphatidyltidylcholine (DMPC), representative of phospholipid classes located in the inner and outer monolayers of the erythrocyte membrane, respectively. X-ray diffraction showed that chloridazon interacted preferentially with DMPC multilayers. Scanning electron microscopy revealed that 0.1 mM chloridazon induced erythrocyte crenation. According to the bilayer couple hypothesis, this is due to the preferential insertion of chloridazon in the phosphatidylcholine-rich external moiety of the red cell membrane. Electrophysiological measurements showed that nerve stimulation was followed immediately by a transient increase in short-circuit current (SCC) and in the potential difference (PD) of the neuroepithelial synapse. Increasing concentrations of chloridazon caused a dose-dependent and reversible decrease of the responses of both parameters to 76% of their control values. The pesticide induced a similar (28%) significant time-dependent decrease in the basal values of the SCC and of PD. These results are in accordance with a perturbing effect of chloridazon on the phospholipid moiety of the nerve fibre membrane leading to interference with total ion transport across the nerve skin junction.