RESUMO
Evidence from cell line-based studies indicates that rho-kinase may play a role in the leukaemic transformation of human cells mediated by the BCR/ABL tyrosine kinase, manifest clinically as chronic myeloid leukaemia (CML). We therefore employed two separate inhibitors, Y-27632 and fasudil, to inhibit the activity of rho-kinase against ex vivo CD34(+) cells collected from patients with CML. We compared the effects of rho-kinase inhibition in those cells with the effects of direct inhibition of BCR/ABL using the specific inhibitor imatinib. We found that inhibition of rho-kinase inhibited the effective proliferation, and reduced survival of CML progenitor cells. When combined with imatinib, rho-kinase inhibition added to the anti-proliferative and pro-apoptotic effects of the BCR/ABL inhibitor. Our studies may indicate therapeutic benefit in some cases for the combination of rho-kinase inhibitors with imatinib.
Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Amidas/uso terapêutico , Antígenos CD34/metabolismo , Inibidores Enzimáticos/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Benzamidas , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Proteínas de Fusão bcr-abl , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Células-Tronco , Células Tumorais Cultivadas/efeitos dos fármacos , Quinases Associadas a rhoRESUMO
Understanding haematological malignancies at the protein level is important as the development of targeted treatments must be based on knowledge regarding the molecular pathogenesis of the tumour, inherited genetic variation and the mode of action of drugs. 'Proteomics' describes the analysis of the entire proteome of a cell or tissue and incorporates multiple technologies including Western blotting, two-dimensional gel electrophoresis, mass spectrometry, and ProteinChip-based technology. Although there are a limited number of studies to date in haematology those performed highlight the potential future impact of these technologies in the discovery of novel markers, proteins associated with drug resistance and the identification of tumour biomarkers which may facilitate the development of a rapid diagnostic test easily applicable in the clinical setting. Rapid large-scale analysis of the proteome in normal pathways and disease offers the opportunity of identification of potential diagnostic/prognostic markers and proteins associated with the malignant phenotype. This review discusses the current situation regarding the use of these technologies and the potential opportunities their future use may offer in the field of haematology.