RESUMEN
In this work, effects of bortezomib on apoptosis, clonal progenitor growth, cytokine production, and NF-κB expression in patients with MDS with cytopenias requiring transfusion support are examined. Bortezomib increased apoptosis in marrow mononuclear cells but had no effects on CFU-GM, BFU-E, or CFU-L content. No consistent effects on NF-κB activation in vivo were noted. To further define the role of bortezomib in AML and MDS, we examined it in combination with several targeted agents and chemotherapeutic agents in vitro. Combinations with arsenic trioxide, sorafenib, and cytarabine demonstrated synergistic in vitro effects in AML cell lines.
Asunto(s)
Antineoplásicos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Inhibidores de Proteasas/uso terapéutico , Inhibidores de Proteasoma , Pirazinas/uso terapéutico , Apoptosis/efectos de los fármacos , Trióxido de Arsénico , Arsenicales/farmacología , Azacitidina/farmacología , Bencenosulfonatos/farmacología , Ácidos Borónicos/farmacología , Bortezomib , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citarabina/farmacología , Citocinas/sangre , Farnesiltransferasa/antagonistas & inhibidores , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Leucemia Mieloide Aguda/patología , Síndromes Mielodisplásicos/patología , Niacinamida/análogos & derivados , Óxidos/farmacología , Compuestos de Fenilurea , Pirazinas/farmacología , Piridinas/farmacología , SorafenibRESUMEN
How leukemia progenitors interact with marrow microenvironment components is poorly understood. In this work, the effects of endothelial coculture on acute myelogenous leukemia (AML) blast survival is examined as are the effects of endothelial coculture on the impact of a cytotoxic agent such as cytarabine. Similar to marrow stromal cells, endothelial cells are able to increase survival and proliferation of AML blasts and to partially protect against cytarabine effects. The proteasome inhibitor, bortezomib, has inhibitory effects in multiple myeloma in part through effects on marrow stromal cells. Bortezomib has been found to inhibit AML blast survival. Such inhibition is less, however, in the presence of endothelial monolayers. Furthermore, AML blast transmigration through human umbilical vein endothelial cells is inhibited by bortezomib. These studies demonstrate that AML is subject to influence of endothelial cells and of agents such as bortezomib which have potential impact on AML interaction with the microenvironmental niche.