Ceefourin-1: Therapeutic Potential of Multidrug Resistance Protein 4 (MRP4) Pharmacological Inhibition in Acute Myeloid Leukemia and Pancreatic Ductal Adenocarcinoma?.

AGUSTÍN YANEFF; ANTONELA DÍAZ NEBREDA; ANA SAHORES; ÁNGELA RODRÍGUEZ GONZÁLEZ; NATALIA GÓMEZ; CARINA SHAYO ; NICOLÁS DI SIERVI; CARLOS DAVIO

Mar del Plata

Congreso; LXIII Reunión Científica anual de la Sociedad Argentina de Investigación Clínica; 2018

SAIC

Multidrug resistance-associated protein 4 (MRP4) transports anionic compounds and the dysregulation of its expression has been historically associated with drug resistance in several pathological conditions, including cancer. Thus, this protein is a potential therapeutic target in some types of neoplasias. Ceefourin-1, a specific inhibitor of MRP4, has recently been developed. Taking in consideration that MRP4 is the principal transporter of cAMP and that the balance between intra- and extracellular levels of this cyclic nucleotide is crucial in acute myeloid leukemia (AML) and in pancreatic ductal adenocarcinoma (PDAC), ceefourin-1 seems to be a promising compound for cancer therapy. The aim of this study was to assess the efficacy and mechanism of action of ceefourin-1 as an anticancer drug in AML and PDAC models. We evaluated the effect of ceefourin-1 on cAMP extrusion in AML (U937; HL-60) and PDAC (Panc1; BxPC3) cell lines through concentration response curves in a radio-binding assay. Both systems revealed a significant decrease in cAMP efflux in basal and stimulated (25µM forskolin) conditions. Ceefourin-1 inhibition of MRP4 activity was confirmed by measuring intracellular cAMP levels by FRET using Epac-SH187 as a cAMP molecular sensor in HEK293T cells. Treatment of leukemic and pancreatic cancer cells with different concentrations of ceefourin-1 showed that viability is affected only at the highest concentration (100µM; 200µM). MRP4 inhibition with ceefourin-1 and a non-specific MRP4 inhibitor (MK-571) has a concentration-dependent anti-proliferative effect (p