NSAID screening for MRP4 inhibition: drug repositioning for PDAC treatment

RAMIRO HÉCTOR CERVIÑO; NATALIA GÓMEZ; ANA SAHORES; CARINA SHAYO; CARLOS DAVIO; AGUSTÍN YANEFF

Mar del Plata

Congreso; SAIC; 2022

SAIC

In a previous work, we validated the inhibition of the MRP4-dependant cAMP extrusion process as a promising therapeutic strategy for pancreatic ductal adenocarcinoma (PDAC). In view of the therapeutic challenge associated with this malignancy, we have identified non-steroidal anti-inflammatory drugs (NSAIDs) as an attractive pharmacological family for drug repositioning based on their ability to block MRP4 and on the fact that inflammation is critical for PDAC initiation and progression. In this work, we first selected several NSAIDs considering two aspects: the capacity to inhibit MRP4-cAMP transport and the potency to reduce cell proliferation in experimental in vitro PDAC models. The initial screening was performed using HEK-T cells expressing the EPAC-SH187 sensor, which allows rapid and efficient monitoring of the rise in intracellular cAMP levels that occurs upon treatment with the inhibitors. We tested 18 NSAIDs and only 11 compounds successfully increased intracellular cAMP concentrations (p