ININFA   02677
INSTITUTO DE INVESTIGACIONES FARMACOLOGICAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Ceefourin-1: Therapeutic Potential of Multidrug Resistance Protein 4 (MRP4) Pharmacological Inhibition in Acute Myeloid Leukemia and Pancreatic Ductal Adenocarcinoma
Autor/es:
YANEFF, A; DIAZ NEBREDA, A; SAHORES, A; DI SIERVI, N; DAVIO, C; RODRIGUEZ-GONZALEZ, A; GOMEZ, N; SHAYO, C
Reunión:
Congreso; LXIII REUNION ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACION CLINICA (SAIC); 2018
Resumen:
Multidrug resistance-associatedprotein 4 (MRP4) transports anionic compounds and the dysregulationof its expression has been historically associated with drug resistance in severalpathological conditions, including cancer. Thus, this protein is a potentialtherapeutic target in some types of neoplasias. Ceefourin-1, a specific inhibitor of MRP4, hasrecently been developed. Taking in consideration that MRP4 is theprincipal transporter of cAMP and that the balance between intra- andextracellular levels of this cyclic nucleotide is crucial in acute myeloidleukemia (AML) and in pancreatic ductal adenocarcinoma (PDAC), ceefourin-1 seemsto be a promising compound for cancer therapy. The aim of this study was toassess the efficacy and mechanism of action of ceefourin-1 as an anticancerdrug in AML and PDAC models. We evaluated the effect of ceefourin-1 on cAMPextrusion in AML (U937; HL-60) and PDAC (Panc1; BxPC3) cell lines throughconcentration response curves in a radio-binding assay. Both systems revealed asignificant decrease in cAMP efflux in basal and stimulated (25µM forskolin) conditions.Ceefourin-1 inhibition of MRP4 activity was confirmed by measuringintracellular cAMP levels by FRET using Epac-SH187 as a cAMP molecular sensor inHEK293T cells. Treatment of leukemic and pancreaticcancer cells with different concentrations of ceefourin-1 showed that viabilityis affected only at the highest concentration (100µM; 200µM). MRP4 inhibition withceefourin-1 and a non-specific MRP4 inhibitor (MK-571)has a concentration-dependent anti-proliferative effect (p<0.01) inthese cell lines. Finally, acute toxicity was evaluated in Balb/c mice treatedwith ceefourin-1 for two weeks (sc; 2 and 10 mg/kg /3 times a week). Nosignificant toxic effects were observed, except for mild leukocytosis only withthe highest dose. These results show that ceefourin-1 represents a promisingselective MRP4 inhibitor for AML and PDAC and leads us to propose future experimentsto test its efficacy in vivo.