Rilmenidine modulates intracellular accumulation of ABC transporter substrates in pancreatic ductal adenocarcinoma cells

The antihypertensive drug rilmenidine has been investigated as a candidate for drug repurposing in oncology for its cytotoxic and antimetastatic properties through activation of the tumor suppressor nischarin. We recently observed that rilmenidine was associated with fluorescent dye accumulation in pancreatic ductal adenocarcinoma (PDAC) cell lines. This study examined whether rilmenidine could modulate the accumulation of dyes and chemotherapeutics known to be ABC transporter substrates. We screened a panel of PDAC cell lines for expression of MDR-related ABC transporters (ABCB1, ABCC1, ABCC2, and ABCG2) and selected PANC-1, MIA PaCa-2, and AsPC- 1 as model systems. We found that rilmenidine treatment attenuated the efflux of calcein, Hoechst 33342, and doxorubicin, suggesting comparable modulation of ABCB1, ABCC1, and ABCC2 pump activity, although the effects were weaker than those of the known inhibitors. In silico examination suggested that rilmenidine could bind to the ligand pockets of these pumps. Finally, rilmenidine potentiated the effects of 5-fluorouracil (5-FU) and paclitaxel in PDAC cells measured in vitro. These findings suggest that rilmenidine can modulate MDR-associated ABC transporter activity and should be considered when evaluating its potential for repurposing as an adjunct in cancer therapy.