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

Biomed Pharmacother. 2024 Nov:180:117533. doi: 10.1016/j.biopha.2024.117533. Epub 2024 Oct 13.

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; Natural products; Tyrosine kinase inhibitors.

MeSH terms

  • Animals
  • Antineoplastic Agents* / pharmacology
  • Bile Duct Neoplasms* / drug therapy
  • Bile Duct Neoplasms* / genetics
  • Bile Duct Neoplasms* / metabolism
  • Bile Duct Neoplasms* / pathology
  • Cell Line, Tumor
  • Cholangiocarcinoma* / drug therapy
  • Cholangiocarcinoma* / genetics
  • Cholangiocarcinoma* / metabolism
  • Cholangiocarcinoma* / pathology
  • Cisplatin* / pharmacology
  • Drug Resistance, Neoplasm* / drug effects
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Nude
  • Molecular Docking Simulation
  • Multidrug Resistance-Associated Proteins* / antagonists & inhibitors
  • Multidrug Resistance-Associated Proteins* / genetics
  • Multidrug Resistance-Associated Proteins* / metabolism
  • Xenograft Model Antitumor Assays*

Substances

  • multidrug resistance-associated protein 3
  • Multidrug Resistance-Associated Proteins
  • Antineoplastic Agents
  • Cisplatin