Sensitizing cholangiocarcinoma to chemotherapy by inhibition of the drug-export pump MRP3

Abstract

Aims: Drug export through ABC proteins hinders cancer response to chemotherapy. Here, we have evaluated the relevance of MRP3 (ABCC3) in cholangiocarcinoma (CCA) as a potential target to overcome drug resistance. Methods: Gene expression was analyzed in silico using the TCGA-CHOL database and experimentally (mRNA and protein) in resected CCA tumors. The effect of manipulating MRP3 function/expression was evaluated in vitro and in vivo. Results: High MRP3 expression at the plasma membrane of human CCA cells was found. MRP3 overexpression in HEK293T cells selectively impaired the cytotoxic effect of etoposide, cisplatin, SN-38, and mitoxantrone. Reduced MRP3 activity with shRNAs or pan-MRP blockers enhanced the sensitivity to these drugs. MRP3 interaction with natural and semisynthetic compounds (≈40,000) was evaluated by virtual drug screening and molecular docking. Two identified potential MRP3 inhibitors (EM-114, EM-188), and sorafenib impaired MRP3 transport activity and enhanced sensitivity of CCA cells to etoposide and cisplatin. The antitumor effect of cisplatin in the mouse xenograft model was enhanced by co-treatment with sorafenib, which was accompanied by a higher intratumor accumulation of cisplatin. Conclusions: Genetic and pharmacological MRP3 inhibition enhances the anti-CCA effect of several drugs, which constitutes a promising strategy to improve the response to chemotherapy in CCA patients.

Keywords

• ABC transporters
• Biliary tract cancer
• Chemosensitization
• Tyrosine kinase inhibitors
• Natural products