Asunto(s)
Deferasirox/uso terapéutico , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/tratamiento farmacológico , Mielofibrosis Primaria/tratamiento farmacológico , Anciano , Deferasirox/farmacología , Femenino , Humanos , Quelantes del Hierro/farmacología , Masculino , Mielofibrosis Primaria/complicaciones , Estudios RetrospectivosAsunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/epidemiología , Factor 3 de Crecimiento de Fibroblastos/genética , Factor 4 de Crecimiento de Fibroblastos/genética , Amplificación de Genes/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pulmonares/epidemiología , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Animales , Femenino , Humanos , Masculino , Niacinamida/uso terapéutico , SorafenibRESUMEN
Inhibition of multiple myeloma (MM) plasma cells in their permissive bone marrow microenvironment represents an attractive strategy for blocking the tumor/vessel growth associated with the disease progression. However, target specificity is an essential aim of this approach. Here, we identified platelet-derived growth factor (PDGF)-receptor beta (PDGFRbeta) and pp60c-Src as shared constitutively activated tyrosine-kinases (TKs) in plasma cells and endothelial cells (ECs) isolated from MM patients (MMECs). Our cellular and molecular dissection showed that the PDGF-BB/PDGFRbeta kinase axis promoted MM tumor growth and vessel sprouting by activating ERK1/2, AKT, and the transcription of MMEC-released proangiogenic factors, such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). Interestingly, pp60c-Src TK-activity was selectively induced by VEGF in MM tumor and ECs, and the use of small-interfering (si)RNAs validated pp60c-Src as a key signaling effector of VEGF loop required for MMEC survival, migration, and angiogenesis. We also assessed the antitumor/vessel activity of dasatinib, a novel orally bioactive PDGFRbeta/Src TK-inhibitor that significantly delayed MM tumor growth and angiogenesis in vivo, showing a synergistic cytotoxicity with conventional and novel antimyeloma drugs (ie, melphalan, prednisone, bor-tezomib, and thalidomide). Overall data highlight the biologic and therapeutic relevance of the combined targeting of PDGFRbeta/c-Src TKs in MM, providing a framework for future clinical trials.