RESUMEN
N6-isopentenyladenosine is an anti-proliferative and pro-apoptotic atypical nucleoside for normal and tumor cells. Considering the role of angiogenesis in various diseases, we investigated the cytotoxic effect of N6-isopentenyladenosine on human microvascular endothelial cells, protagonists in angiogenesis. Our results show that N6-isopentenyladenosine induced a significant reduction of cell viability, upregulated p21 and promoted caspase-3 cleavage in a dose dependent manner leading to apoptotic cell death as detected by FACS analysis. To understand structure-function relationship of N6-isopentenyladenosine, we investigated the effect of some N6-isopentenyladenosine analogs. Our results suggest that N6-isopentenyladenosine and some of its derivatives are potentially novel angiostatic agents and might be associated with other anti-angiogenic compounds for a better outcome.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Endotelio Vascular/citología , Isopenteniladenosina/farmacología , Inhibidores de la Angiogénesis/administración & dosificación , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Células Endoteliales/efectos de los fármacos , Humanos , Interferón gamma/farmacología , Isopenteniladenosina/administración & dosificaciónRESUMEN
Signals released by leukocytes contribute to tumor growth and influence the efficacy of antineoplastic treatments. The outcome of peritoneal carcinomatosis treatments is unsatisfactory, possibly because chemotherapy activates events that have in the long-term deleterious effects. In this study we offer evidence that 5-fluorouracile (5-FU), besides provoking apoptosis of MC38 colon carcinoma cells, induces a striking attraction of leukocytes both in an orthotopic model of colon carcinomatosis in vivo and in monocyte-migration assays in vitro. Leukocyte attraction depends on the presence of High Mobility Group Box 1 (HMGB1), an endogenous immune adjuvant and chemoattractant released by dying cells. Leukocyte recruitment is prevented in vivo and in vitro using blocking antibodies against HMGB1 and its competitive antagonist BoxA or by interfering with HMGB1 expression. Autophagy is required for leukocyte chemoattraction, since the latter abates upon pharmacological blockade of the autophagic flux while activation of autophagy per se, in the absence of death of colon carcinoma cells, is not sufficient to attract leukocytes. Our results identify autophagy induction and HMGB1 release in colon carcinoma cells as key events responsible for 5-FU elicited leukocyte attraction and define a novel rate-limiting target for combinatorial therapies.