Ceefourin-1, a MRP4/ABCC4 inhibitor, induces apoptosis in AML cells enhanced by histamine

• Published in: Biochimica et biophysica acta. General subjects Vol. 1867; no. 4; p. 130322
• Main Authors: Sahores, Ana, González, Angela Rodríguez, Yaneff, Agustín, May, María, Gómez, Natalia, Monczor, Federico, Fernández, Natalia, Davio, Carlos, Shayo, Carina
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2023
• Subjects: Acute myeloid leukemia; Animals; Apoptosis; ATP-Binding Cassette Transporters; blood; cAMP; caspase-3; Ceefourin-1; cell differentiation; cell structures; cyclic AMP; histamine; Histamine - pharmacology; histology; Humans; intraperitoneal injection; Leukemia, Myeloid, Acute - metabolism; Mice; MRP4; Multidrug Resistance-Associated Proteins; myeloid leukemia; subacute toxicity; Western blotting; AML; CD; RBP; db-cAMP; DMSO; ip; e-cAMP; H2R; Ceefourin-1; cAMP; MRP4; PDE; BSA; i-cAMP; RPMI 1640; FBS; PI; MK-571; Acute myeloid leukemia; Apoptosis
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2023.130322

Ceefourin-1 is a specific MRP4/ABCC4 inhibitor with potential antileukemic activity. In this study, we evaluate the ability of ceefourin-1 alone or in combination with histamine, an approved antileukemic agent, to induce cell differentiation or apoptosis in human acute myeloid leukemic cells. We also examine ceefourin-1 toxicity in mice. U937, HL-60, and KG1a cells were used as models for human acute myeloid leukemia. Cyclic AMP efflux was estimated by measuring intracellular and extracellular cAMP levels. Cell differentiation was assessed by levels of CD14 and CD11b by FACS, and CD88 by western blot, and by cell morphology. Apoptosis was evaluated by cleavage of caspase-3 and PARP by western blot, and by annexin V binding assay. Subacute toxicity study of ceefourin-1 was carried out in BALB/c mice. Ceefourin-1 inhibits cAMP exclusion in AML cells and promotes intracellular signaling via CREB. Ceefourin-1 leads AML cells to apoptosis and histamine potentiates this effect, without evidence of cell differentiation. Intraperitoneal administration of ceefourin-1 shows no important alterations in mice blood parameters, hepatic, and renal functions, nor signs of histologic damage. These results show that ceefourin-1 promotes apoptosis in AML cells that is enhanced by histamine. General significance: This work indicates that ceefourin-1 represents a promising molecule that could be used alone or in combination with histamine for in vivo evaluation in acute myeloid leukemia malignancies. •Ceefourin-1, a specific MRP4 inhibitor, blocks cAMP extrusion in AML cells.•Ceefourin-1 induces apoptosis in AML cells, and not differentiation.•Histamine enhances ceefourin-1 proapoptotic capacity.•Ceefourin-1 can be administered intraperitoneally to mice without apparent toxicity.